WO2026072983A1 - Methods for treatment of atopic dermatitis with an anti-tl1a antibody - Google Patents

Methods for treatment of atopic dermatitis with an anti-tl1a antibody

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Publication number
WO2026072983A1
WO2026072983A1 PCT/US2025/048218 US2025048218W WO2026072983A1 WO 2026072983 A1 WO2026072983 A1 WO 2026072983A1 US 2025048218 W US2025048218 W US 2025048218W WO 2026072983 A1 WO2026072983 A1 WO 2026072983A1
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antibody
dose
amino acid
acid sequence
seq
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PCT/US2025/048218
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French (fr)
Inventor
Jorge ALFONSO ROSS TERRES
Neil COLLINSON
Pascal Espie
Pierre-Eric JUIF
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F Hoffmann La Roche AG
Genentech Inc
Hoffmann La Roche Inc
Pfizer Inc
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F Hoffmann La Roche AG
Genentech Inc
Hoffmann La Roche Inc
Pfizer Inc
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Publication of WO2026072983A1 publication Critical patent/WO2026072983A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The present disclosure provides methods and compositions for treating a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, with a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody (Afimkibart).

Description

PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
METHODS FOR TREATMENT OF ATOPIC DERMATITIS WITH AN ANTI-TL1A ANTIBODY
SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 25, 2025, is named 50474-365WO3_Sequence_Listing_9_25_25 and is 75,534 bytes in size.
TECHNICAL FIELD
The present invention relates to the treatment of signs and symptoms of diseases and conditions involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis) dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, with an anti-tumor necrosis factor-like ligand 1 A (TL1 A) antibody.
BACKGROUND OF THE INVENTION
Atopic dermatitis (AD) is a common, pruritic, chronic, relapsing, inflammatory, immune-mediated skin disease that affects approximately 2% of adults and 4% of children worldwide. While 85% of AD occurs before the age of five, one in four adults having AD have adult-onset AD.
The diagnosis of AD is made clinically based on morphologic features and distribution of skin lesions. Clinical characteristics of AD include excoriations, erythema, edema/papulation, oozing/crusting, and lichenification that vary by disease severity and chronicity of lesions.
Intense pruritus is a hallmark of AD and is associated with sleep disturbances and impaired quality of life. Itch, depression, sleep disturbance, and anxiety are the most common symptoms among patients with atopic dermatitis; the highest rates of anxiety and depression have been noted among patients with AD. Further, patients with AD are more susceptible to Staphylococcus aureus colonization, and susceptibility to bacterial and viral infections may lead to impetigo, impetiginized AD, and eczema herpeticum. The quality of life of patients is significantly affected by the disease.
Though recent advancements in therapies in AD have improved outcomes, gaps remain, particularly for the significant number of patients who do not achieve adequate disease control with existing therapies and/or experience significant side effects leading to poor compliance and discontinuation of treatment.
Therefore, there is a significant unmet medical need for treatments with better benefit-risk profiles, greater rates of complete skin clearance, and sustained control of disease signs and symptoms in patients with AD. Further, there is a significant unmet medical need for treatments for other diseases and conditions involving inflammation in the skin, e.g., eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, and bullous pemphigoid. The present disclosure addresses these needs. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
SUMMARY OF THE INVENTION
In one aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0 of the dosing regimen; and (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 of the dosing regimen.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg. PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3
In some aspects, at least five doses of the anti-TL1 A antibody are subcutaneously administered to the patient.
In some aspects, following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks.
In some aspects, the dosing regimen comprises five subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen consists of five subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen has a duration of about 16 weeks.
In some aspects, (a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the dosing regimen; and (e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen.
In some aspects, the dosing regimen comprises nine subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen consists of nine subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen has a duration of about 32 weeks.
In some aspects, (a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the dosing regimen.
In some aspects, the method further comprises (i) determining that the patient has responded to treatment with the anti-TL1 A antibody following the dosing regimen; and (ii) administering to the patient an effective amount of the anti-TL1 A antibody in a second dosing regimen.
In some aspects, the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last previous dose of the anti- TL1 A antibody.
In some aspects, the second dosing regimen comprises subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose. In some aspects, (a) the first dose of the anti- TL1 A antibody is administered on about Day 1 of Week 0 of the second dosing regimen; and (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 of the second dosing regimen. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In some aspects, each dose of the anti-TL1 A antibody in the second dosing regimen is administered at a dose of between about 150 mg and about 450 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg. In some aspects, each dose of the anti- TL1 A antibody is administered at a dose of about 450 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg or about 450 mg, and the first and second doses of the second dosing regimen are each about 150 mg.
In some aspects, at least four doses of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen. In some aspects, following the administration of the first and second doses in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks. In some aspects, the second dosing regimen has a duration of at least one year. In some aspects, the second dosing regimen has a duration of about six years.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti- TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved a response as compared to a reference population.
In some aspects, the dosing regimen has a duration of about 16 weeks, and the treating results in an increase in the proportion of patients who have achieved a response at Week 16.
In some aspects, the dosing regimen has a duration of about 32 weeks, and the treating results in an increase in the proportion of patients who have achieved a response at Week 32.
In some aspects, the reference population is a population of patients who have not been treated with an anti-TL1 A antibody.
In some aspects, the reference population is a population of patients who have been treated with a placebo. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.
In some aspects, the anti-TL1 A antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.
In some aspects, the anti-TL1 A antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 11 ; and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody is afimkibart.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg. In some aspects, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the first dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti- TL1 A antibody is administered to the patient subcutaneously every four weeks in the first dosing regimen; and (iii) the first dosing regimen has a duration of about 32 weeks; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the second dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient was identified as having achieved a response to the treatment; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 method comprising administering to the patient an effective amount of an anti-TL1 A antibody in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein (a) the first dose is administered on about Day 1 of Week 0 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the first dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the first dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the first dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the first dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the first dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the first dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the first dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (a) the first dose is administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the second dosing regimen; and (c) following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks; the patient was identified as having achieved a response to the treatment at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the patient is a human.
In another aspect, the disclosure features a kit comprising an anti-TNF-like ligand 1 A (TL1 A) antibody and a package insert comprising instructions for using the antibody for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient in need thereof according to the method of any one of the aforementioned aspects.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3
CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 450 mg.
In another aspect, the disclosure features anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the first dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the first dosing regimen; and (iii) the first dosing regimen has a duration of about 32 weeks; and (II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the second dosing regimen is to PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 be administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is to be administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient was identified as having achieved a response to the treatment; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein (a) the first dose is to be administered on about Day 1 of Week 0 of the first dosing regimen; (b) the second dose is to be administered on about Day 1 of Week 2 of the first dosing regimen; (c) the third dose is to be administered on about Day 1 of Week 6 of the first dosing regimen; (d) the fourth dose is to be administered on about Day 1 of Week 10 of the first dosing regimen; (e) the fifth dose is to be administered on about Day 1 of Week 14 of the first dosing regimen; (f) the sixth dose is to be administered on about Day 1 of Week 18 of the first dosing regimen; (g) the seventh dose is to be administered on about Day 1 of Week 22 of the first dosing regimen; (h) the eighth dose is to be administered on about Day 1 of Week 26 of the first dosing regimen; and (i) the ninth dose is to be administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (a) the first dose is to be administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; (b) the second dose is to be administered on about Day 1 of Week 2 of the second dosing regimen; and (c) following the administration of the first and second doses, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks; the patient was identified as having achieved a response to the treatment at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti- TL1 A antibody is to be administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 450 mg.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0 of the dosing regimen; and (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 of the dosing regimen.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg.
In some aspects, at least five doses of the anti-TL1 A antibody are subcutaneously administered to the patient.
In some aspects, following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks.
In some aspects, the dosing regimen comprises five subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen consists of five subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen has a duration of about 16 weeks.
In some aspects, (a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen; (d) the fourth dose is PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 administered on about Day 1 of Week 10 of the dosing regimen; and (e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen.
In some aspects, the dosing regimen comprises nine subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen consists of nine subcutaneous doses of the anti-TL1 A antibody.
In some aspects, the dosing regimen has a duration of about 32 weeks.
In some aspects, (a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the dosing regimen.
In some aspects, the method further comprises (i) determining that the patient has responded to treatment with the anti-TL1 A antibody following the dosing regimen; and (ii) administering to the patient an effective amount of the anti-TL1 A antibody in a second dosing regimen.
In some aspects, response to treatment with the anti-TL1 A antibody is a reduction of a posttreatment Eczema Area and Severity Index (EASI) by at least 50% relative to a pre-treatment EASI. In some aspects, the dosing regimen has a duration of about 32 weeks, and the post-treatment EASI is determined about 36 weeks after administration of the first dose of the anti-TL1 A antibody in the dosing regimen.
In some aspects, the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last previous dose of the anti- TL1 A antibody.
In some aspects, the second dosing regimen comprises subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose. In some aspects, (a) the first dose of the anti- TL1 A antibody is administered on about Day 1 of Week 0 of the second dosing regimen; and (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 of the second dosing regimen.
In some aspects, each dose of the anti-TL1 A antibody in the second dosing regimen is administered at a dose of between about 150 mg and about 450 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg. In some aspects, each dose of the anti- TL1 A antibody is administered at a dose of about 450 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg or about 450 mg, and the first and second doses of the second dosing regimen are each about 150 mg. PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3
In some aspects, at least four doses of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen. In some aspects, following the administration of the first and second doses in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks. In some aspects, the second dosing regimen has a duration of at least one year. In some aspects, the second dosing regimen has a duration of about six years.
In some aspects, the atopic dermatitis is moderate to severe atopic dermatitis.
In some aspects, the patient has an Eczema Area and Severity Index (EASI) score of at least 16.
In some aspects, the patient has an Investigator Global Assessment (IGA) scale score for atopic dermatitis of at least 3.
In some aspects, the patient has atopic dermatitis involvement of at least 10% of their body surface area.
In some aspects, (i) the patient has previously been treated with a therapy selected from a topical corticosteroid (TCS) and a topical calcineurin inhibitor (TCI) and has experienced inadequate response to the therapy; or (ii) the patient is one for whom a topical treatment is medically inadvisable.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti- TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved at least a 75% improvement in EASI score as compared to a reference population.
In some aspects, the dosing regimen has a duration of about 16 weeks, and the treating results in an increase in the proportion of patients who have achieved at least a 75% improvement in EASI score at Week 16.
In some aspects, the dosing regimen has a duration of about 32 weeks, and the treating results in an increase in the proportion of patients who have achieved at least a 75% improvement in EASI score at Week 32.
In some aspects, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved a response as compared to a reference population.
In some aspects, the dosing regimen has a duration of about 16 weeks, and the treating results in an increase in the proportion of patients who have achieved a response at Week 16.
In some aspects, the dosing regimen has a duration of about 32 weeks, and the treating results in an increase in the proportion of patients who have achieved a response at Week 32.
In some aspects, the response is: (i) an IGA scale score of 0 or 1 with an improvement of at least two grades relative to a baseline IGA score; (ii) at least a 75% improvement in EASI score; or (Hi) at least a 90% improvement in EASI score.
In some aspects, the reference population is a population of patients who have not been treated with an anti-TL1 A antibody. PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3
In some aspects, the reference population is a population of patients who have been treated with a placebo.
In some aspects, the anti-TL1 A antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.
In some aspects, the anti-TL1 A antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.
In some aspects, the anti-TL1 A antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 11 ; and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody is afimkibart.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg. In some aspects, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the first dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the first dosing regimen; and (iii) the first dosing regimen has a duration of about 32 weeks; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the second dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein (a) the first dose is administered on about Day 1 of Week 0 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the first dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the first dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the first dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the first dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the first dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the first dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the first dosing regimen; and (i) the ninth dose is PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (a) the first dose is administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the second dosing regimen; and (c) following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks; the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the patient is a human.
In another aspect, the disclosure features a kit comprising an anti-TNF-like ligand 1 A (TL1 A) antibody and a package insert comprising instructions for using the antibody for treating atopic dermatitis in a patient in need thereof according to the method of any one of the aforementioned aspects.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In another aspect, the disclosure features an anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 450 mg.
In another aspect, the disclosure features anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the first dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the first dosing regimen; and (iii) the first dosing regimen has a duration of about 32 weeks; and PATENT
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(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the second dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is to be administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein (a) the first dose is to be administered on about Day 1 of Week 0 of the first dosing regimen; (b) the second dose is to be administered on about Day 1 of Week 2 of the first dosing regimen; (c) the third dose is to be administered on about Day 1 of Week 6 of the first dosing regimen; (d) the fourth dose is to be administered on about Day 1 of Week 10 of the first dosing regimen; (e) the fifth dose is to be administered on about Day 1 of Week 14 of the first dosing regimen; (f) the sixth dose is to be administered on about Day 1 of Week 18 of the first dosing regimen; (g) the seventh dose is to be administered on about Day 1 of Week 22 of the first dosing regimen; (h) the eighth dose is to be administered on about Day 1 of Week 26 of the first dosing regimen; and (i) the ninth dose is to be administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (a) the first dose is to be administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; (b) the second dose is to be administered on about Day 1 of Week 2 of the second dosing regimen; and (c) following the administration of the first and second doses, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks; the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 acid sequence of SEQ ID NO: 8. In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti- TL1 A antibody is to be administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- PATENT
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H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In another aspect, the disclosure features use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises: PATENT
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(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of between about 150 mg and about 450 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 50 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 150 mg.
In some aspects, each dose of the anti-TL1 A antibody is to be administered at a dose of about 450 mg.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram showing the design of the CS45570 study. SC = subcutaneous.
FIG. 2A is a set of graphs showing predicted pharmacokinetics (PK) profiles (afimkibart concentration in serum in pg/mL) for a set of dosing regimens in which afimkibart is administered subcutaneously (SC) at Weeks 0, 1 , 2, 6, 10, and 14. Left: 50 mg dose; center: 150 mg dose; right: 450 mg dose. The solid line shows the median value; dotted lines show the 95% confidence interval (Cl).
FIG. 2B is a set of graphs showing predicted pharmacodynamics (PD) profiles (percent engagement of the TL1 A target in serum) for a set of dosing regimens in which afimkibart is administered SC at Weeks 0, 1 , 2, 6, 10, and 14. Left: 50 mg dose; center: 150 mg dose; right: 450 mg dose. The solid line shows the median value; dotted lines show the 95% confidence interval (Cl).
FIG. 3A is a set of graphs showing predicted PK profiles (afimkibart concentration in serum in pg/mL) for a set of dosing regimens in which afimkibart is administered SC at Weeks 0, 2, 6, 10, and 14. Left: 50 mg dose; center: 150 mg dose; right: 450 mg dose. The solid line shows the median value; dotted lines show the 95% confidence interval (Cl).
FIG. 3B is a set of graphs showing predicted PD profiles (percent engagement of the TL1 A target in serum) for a set of dosing regimens in which afimkibart is administered SC at Weeks 0, 2, 6, 10, and 14. Left: 50 mg dose; center: 150 mg dose; right: 450 mg dose. The solid line shows the median value; dotted lines show the 95% confidence interval (Cl).
FIG. 4A is a set of graphs showing predicted PK profiles (afimkibart concentration in serum in pg/mL) for a set of dosing regimens in which afimkibart is administered SC at Weeks 0, 4, 8, 12, and 16. Left: 50 mg dose; center: 150 mg dose; right: 450 mg dose. The solid line shows the median value; dotted lines show the 95% confidence interval (Cl).
FIG. 4B is a set of graphs showing predicted PD profiles (percent engagement of the TL1 A target in serum) for a set of dosing regimens in which afimkibart is administered SC at Weeks 0, 4, 8, 12, and PATENT
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16. Left: 50 mg dose; center: 150 mg dose; right: 450 mg dose. The solid line shows the median value; dotted lines show the 95% confidence interval (Cl).
FIG. 5 is a schematic diagram showing the design of the CS45943 study. LTE = long-term extension. SC = subcutaneous. Q4W = every four weeks. DBL = database lock. Responders are patients having an Eczema Area and Severity Index (EASI) > 50 at Week 36 of the parent study CS45570.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides therapeutic methods and compositions for treatment of diseases and conditions involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, and bullous pemphigoid. The invention is based, at least in part, on the discovery that immunotherapies including an anti-TL1 A antibody can be useful in the treatment of such diseases and conditions. Compositions, uses, and kits involving such antibodies are also provided herein.
I. Definitions
It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.
The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”
As used herein, “afimkibart” (also known as RO7790121 , RVT-3101 , or PF-06480605) is an antibody that binds tumor necrosis factor (TNF) superfamily protein TNF-like 1 A (TL1 A) and comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.
The terms “antibody that binds to TL1 A” and “anti-TL1 A antibody” refer to an antibody that is capable of binding TL1 A with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting TL1 A. In one aspect, the extent of binding of an anti-TL1 A antibody to an unrelated, non-TL1 A protein is less than about 10% of the binding of the antibody to TL1 A as measured, e.g., by surface plasmon resonance (SPR). In one aspect, an antibody that binds to TL1 A has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8 M or less, e.g., from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M).The term “antibody” encompasses various antibody structures exhibiting the desired antigen-binding activity, including but not limited to: monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments.
The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the antibodies forming this population are essentially identical, except for possible post-translational modifications arising e.g. during manufacturing and/or storage. These antibodies are directed against the same epitope (or the same group of epitopes in the PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 case of multispecific monoclonal antibodies, e.g. the same pair of epitopes in the case of bispecific monoclonal antibodies). This definition expressly excludes polyclonal antibody preparations which are mixtures of antibodies directed against different epitopes. Monoclonal antibodies in accordance with the present invention may be made by a variety of techniques, including but not limited to hybridoma methodology, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
The term “full-length antibody” refers to an antibody having the structure of an immunoglobulin comprising two light chains and two heavy chains, and comprising an Fc region as defined herein. In one aspect, the antibody is a full-length IgG 1 antibody.
A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
A “humanized” antibody refers to an antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In one aspect, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non- human antibody, refers to an antibody that has undergone humanization.
“Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains (LC) and two identical heavy chains (HC) that are disulfide- bonded. From N- to C-terminus, each heavy chain has a heavy chain variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three heavy chain constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a light chain variable domain (VL), also called a variable light domain or a light chain variable region, followed by a light chain constant domain (CL).
An “antibody fragment” refers to a molecule other than a full-length antibody that comprises a portion of a full-length antibody that binds the antigen to which the full-length antibody binds. Examples of antibody fragments include but are not limited to Fv molecules, Fab molecules, Fab’ molecules, Fab’- SH molecules, F(ab’)2 molecules, diabodies, linear antibody molecules, single-chain antibody molecules (e.g., scFv and scFab molecules), and multispecific (e.g. bispecific) antibodies formed from antibody fragments.
The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three complementary determining regions (CDRs). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 PATENT
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(2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991 ).
Glutamine or glutamate residues at the N-terminus of antibody heavy or light chains may be converted to pyro-glutamate spontaneously (see e.g. Liu et al., Journal of Pharmaceutical Sciences 97, 2426-2447 (2008), Rehder et al., Journal of Chromatography A 1 102, 164-175 (2006), Chelius et al., Anal Chem 78, 2370-2376 (2006)). Hence, variable domains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus of the antibody heavy or light chain, may comprise an N-terminal pyro-glutamate (pyroE) residue instead of the N-terminal Q or E residue. Likewise, antibody heavy chains or light chains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus, may comprise an N-terminal pyroglutamate (pyroE) residue instead of the N-terminal Q or E residue. Accordingly, for each antibody heavy chain, light chain, or variable domain sequence disclosed herein that contains an N-terminal Q or E residue, the corresponding sequence with an N-terminal pyroE residue is also encompassed.
A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991 ) NIH Publication 91 -3242 (hereinafter “Kabat 1991 ”). In one aspect, for the VL, the subgroup is subgroup kappa I as in Kabat 1991 . In one aspect, for the VH, the subgroup is subgroup III as in Kabat 1991 .
The term “complementarity determining region” or “CDR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity. Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR- H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). CDRs are defined by a variety of methods/systems by those skilled in the art. These systems and/or definitions have been developed and refined over a number of years and include Kabat, Chothia, IMGT, AbM, and Contact. The Kabat definition is based on sequence variability and generally is the most commonly used. The Chothia definition is based on the location of the structural loop regions. The IMGT system is based on sequence variability and location within the structure of the variable domain. The AbM definition is a compromise between Kabat and Chothia. The Contact definition is based on analyses of the available antibody crystal structures. Software programs (e.g., abYsis: http://www.abysis.org/abysis/sequence_input/key_annotation/key_annotation.cgi) are available and known to those of skill in the art for analysis of antibody sequences and determination of CDRs.
Exemplary CDRs herein include (numbering of amino acid residues according to the reference cited, i.e ., Chothia numbering for the Chothia and Contact definition, Kabat numbering for the Kabat definition and IMGT numbering for the IMGT definition): PATENT
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(a) hypervariable loops occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26- 32 (H1 ), 53-55 (H2), and 96-101 (H3), according to Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987) (“Chothia definition”);
(b) CDRs occurring at amino acid residues 24-34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35B (H1 ), SO- 65 (H2), and 95-102 (H3), according to Kabat 1991 (“Kabat definition”);
(c) antigen contacts occurring at amino acid residues 30-36 (L1 ), 46-55 (L2), 89-96 (L3), 30-35 (H1 ), 47-58 (H2), and 93-101 (H3), according to MacCallum et al. J. Mol. Biol. 262: 732-745 (1996) (“Contact definition”); and
(d) CDRs occurring at amino acid residues residues 27-38 (L1 ), 56-65 (L2), 105-117 (L3), 27-38 (H1 ), 56-65 (H2), and 105-117 (H3), according to Lefranc et al. Dev. Comp. Immunol. 27: 55-77 (2003) (“IMGT definition”).
“Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -CDR-H1 (CDR-L1 )-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.
The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, Ig A1 , and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, s, y, and p, respectively. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.
The terms “constant region derived from human origin” or “human constant region” as used herein denotes a constant region of a human antibody, in particular a heavy chain constant region of a human antibody of the subclass IgG 1 , lgG2, lgG3, or lgG4 and/or a light chain kappa or lambda constant region. Such constant regions are well known in the state of the art and e.g. described by Kabat 1991 . Unless otherwise specified herein, numbering of amino acid residues in the constant region is according to the numbering system as described in Kabat 1991 . Specifically, the Kabat numbering system (referred to as “numbering according to Kabat” or “Kabat numbering” herein; see pages 647-660 of Kabat 1991 ) is used for the light chain constant domain of kappa and lambda isotype, and the Kabat EU index numbering system (referred to as “numbering according to Kabat EU index” or “Kabat EU index numbering” herein, see pages 661 -723 of Kabat 1991 ) is used for the heavy chain constant domains.
The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C- terminus of the heavy chain. Therefore an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case in particular where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, Kabat EU PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 numbering). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region are denoted herein without C-terminal lysine if not indicated otherwise. The corresponding sequence including a C-terminal lysine residue is also encompassed, however. Accordingly, in one aspect, a heavy chain including an Fc region as specified herein comprises an additional C-terminal lysine residue (K447, Kabat EU numbering). Also encompassed is the corresponding sequence without the C-terminal glycine residue. Accordingly, in one aspect, a heavy chain including an Fc region as specified herein lacks the C-terminal glycine residue (G446, Kabat EU numbering). In such a heavy chain, the C-terminal amino acid residue may be proline (P445, Kabat EU numbering) or proline amide (P445-NH2, Kabat EU numbering). Unless otherwise specified herein, numbering of amino acid residues in the Fc region or heavy chain constant region is according to the EU numbering system, also called the EU index, as described in Kabat 1991 .
“Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.
“Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. A preferred method for measuring affinity is Surface Plasmon Resonance (SPR).
An “isolated” antibody is one which has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC, affinity chromatography, size exclusion chromatography) methods. For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. 8848:79-87 (2007).
An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.
“Isolated nucleic acid encoding an antibody” refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell. PATENT
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The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors”.
The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein. Suitable host cells may include, for example, CHO cells, HEK-293 cells, Expi293F cells, PER.C6 cells, NSO cells, lymphocytic cells, prokaryotic cells such as E. coli, and other eukaryotic hosts such as plant cells and fungi. Human host cells are included with the proviso that they are not used within the human body.
A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.
“Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity for the purposes of the alignment. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, Clustal W, MegAlign (DNASTAR) software or the FASTA program package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Alternatively, the percent identity values can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087 and is described in WO 2001/007611.
Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values are generated using the ggsearch program of the FASTA package version 36.3.8c or later with a BLOSUM50 comparison matrix. The FASTA program package was authored by W. R. Pearson and D. J. Lipman (1988), “Improved Tools for Biological Sequence Analysis” Proc. Nat. Acad. Sci. 85:2444-2448; W. R. Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258; and Pearson et. al. (1997) Genomics 46:24-36 and is publicly available from www.fasta.bioch.virginia.edu/fasta_www2/fasta_down.shtml or www. ebi.ac.uk/Tools/sss/fasta. Alternatively, a public server accessible at fasta.bioch.virginia.edu/fasta_www2/index.cgi can be used to PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 compare the sequences, using the ggsearch (global protei protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure a global, rather than local, alignment is performed. Percent amino acid identity is given in the output alignment header.
As used herein, the term “treatment” refers to clinical intervention in an attempt to alter the natural course of a disease or condition (e.g., a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression of the disease or condition, ameliorating or palliating the disease state or the condition, and remission or improved prognosis. For purposes of this disclosure, beneficial or desired clinical results include reduction or improvement in signs and symptoms of the disease or condition, for example as compared to before administration of the anti-TL1 A antibody.
An “effective amount” of an agent, e.g., a pharmaceutical composition, refers to an amount of the antibody or medicament effective, at dosages and for periods of time necessary, to achieve the desired treatment as defined above. In more specific aspects, an effective amount prevents, alleviates or ameliorates signs or symptoms of a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease or condition, including biochemical, histological and/or behavioral symptoms of the disease or condition, its complications and intermediate pathological phenotypes presenting during development of the disease or condition. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more signs or symptoms of the disease or condition, decreasing the dose of other medications required to treat the disease or condition, enhancing the effect of another medication, and/or delaying the progression of the disease or condition in patients. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
Herein, an “effective amount” may refer to the amount of a therapeutic agent (e.g., an anti-TL1 A antibody (e.g., afimkibart)) or a combination of therapeutic agents (e.g., an anti-TL1 A antibody (e.g., afimkibart) and one or more additional therapeutic agents) that achieves a therapeutic result. In some examples the disease or condition is atopic dermatitis, and the effective amount of a therapeutic agent or a combination of therapeutic agents is the amount of the agent or of the combination of agents that achieves a clinical endpoint of clinical remission or clinical response (e.g., improved Eczema Area and PATENT
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Severity Index (EASI) (e.g., EASI-75 or EASI-90), improved Investigator Global Assessment (IGA) scale score for atopic dermatitis (e.g., an IGA scale score of 0 or 1 with an improvement of at least two grades relative to a baseline IGA score), improved peak pruritus numerical rating scale (PP-NRS), and/or improved Dermatology Life Quality Index (DLQI)). Improvement (e.g., in terms of clinical remission) may be relative to a suitable reference treatment, for example, treatment that does not include the anti-TL1 A antibody (e.g., afimkibart).
“Ameliorating” means a lessening or improvement of one or more signs or symptoms of a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, for example, as compared to not administering an anti-TL1 A antibody as described herein. “Ameliorating” also includes shortening or reduction in duration of a symptom.
The term “preventing” or “prevent” refers to (a) keeping a disorder, disease, or condition from occurring or (b) delaying the onset of a disorder, disease, or condition or onset of symptoms thereof.
Treatment “effectively improves” or “effectively reduces” when assessment of the sign or symptom of the disease or condition (e.g., disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) is quantified via a clinical measure relative to baseline and during and/or after the treatment period. The difference between the clinical measure at baseline and during/after treatment is compared and used to determine whether the sign or symptom has improved and the treatment is effective. This comparison can include comparison to placebo or to one or more of the prior therapies.
A “patient,” an “individual,” or a "subject," used interchangeably herein, is a mammal. In one aspect, the individual or subject is a human. In one aspect, the individual is in need of treatment with the medicament or antibody disclosed herein.
The term “pharmaceutical composition” or “pharmaceutical formulation” refers to a preparation of the antibody and one or more pharmaceutically acceptable carriers or excipients.
A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, which is nontoxic to a subject and includes, but is not limited to, a buffer, excipient, stabilizer, surfactant, and/or preservative.
The term “subcutaneous administration” refers to the administration of a substance into the subcutaneous layer.
II. Methods of Treating a Disease Associated with Inflammation in the Skin with Anti-TL1A Antibodies
The present disclosure provides a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient (e.g., a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 human patient), the method comprising administering to the patient an effective amount of an anti-TNF- like ligand 1 A (TL1 A) antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration (e.g., subcutaneous administration) of at least two doses of the anti- TL1 A antibody (e.g., comprising administration of at least a first and a second dose of the anti-TL1 A antibody), wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose (i.e., the doses are administered (e.g., subcutaneously administered) about two weeks apart). For example, the second dose may be administered two weeks after the first dose, administered about 14 days (e.g., 11 -17 days, 12-16 days, or 13-15 days) after the first dose, or administered 14 days after the first dose. The method may further comprise administration (e.g., subcutaneous administration) of one or more subsequent doses of the anti-TL1 A antibody, e.g., may comprise administration of at least a third dose of the anti-TL1 A antibody. In some aspects, following administration of the first and second doses, the method comprises administration (e.g., subcutaneous administration) of the anti-TL1 A antibody every four weeks (Q4W), e.g., comprises subcutaneous administration of a third dose of the anti-TL1 A antibody about four weeks after the second dose and administration of one or more Q4W doses (e.g., subcutaneous doses) thereafter.
The disclosure also provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient according to the methods provided herein and use of an anti-TL1 A antibody in the manufacture of a medicament for treating such a disease or condition according to the methods provided herein.
A. Methods of treating a disease or condition involving inflammation in the skin
In some aspects, the present disclosure provides a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient (e.g., a human patient), the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration (e.g., subcutaneous administration) of at least two doses of the anti-TL1 A antibody (e.g., comprising administration of at least a first and a second dose of the anti- TL1 A antibody), wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose (i.e., the doses are administered (e.g., subcutaneously administered) about two weeks apart). For example, the second dose may be administered two weeks after the first dose, administered about 14 days (e.g., 11 -17 days, 12-16 days, or 13-15 days) after the first dose, or administered 14 days after the first dose. The method may further comprise administration (e.g., subcutaneous administration) of one or more subsequent doses of the anti-TL1 A antibody, e.g., may comprise administration of at least a third dose of the anti-TL1 A antibody. In some aspects, following administration of the first and second doses, the method comprises administration (e.g., subcutaneous administration) of the anti-TL1 A antibody every four weeks (Q4W), e.g., comprises subcutaneous administration of a third dose of the PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 anti-TL1 A antibody about four weeks after the second dose and administration of one or more Q4W doses (e.g., subcutaneous doses) thereafter.
In some aspects, the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.
The disclosure also provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient according to the methods provided herein and use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) according to the methods provided herein.
In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino PATENT
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Attorney Docket No: 50474-365WO3 acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1 1 ; and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
Thus, in some aspects, the disclosure provides a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody is afimkibart. PATENT
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In some aspects of any of the methods of treatment provided herein, the first dose of the anti- TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 0 of the dosing regimen; and the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of the dosing regimen, e.g., the first dose and second dose of the anti-TL1 A antibody are administered about two weeks apart.
In some aspects of the method comprising administration of a third dose of the anti-TL1 A antibody, the third dose of the anti-TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 6 of the dosing regimen, e.g., the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose.
In some aspects, following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks. For example, in some aspects, at least 4, 5, 6, 7, 8, 9, or 10 doses (e.g., 4-6, 6-8, or 8-10 doses) or more than 10 doses (e.g., 10-12, 12- 14, 14-16, 16-18, or 18-20 doses) of the anti-TL1 A antibody are administered to the patient. Alternatively, following the administration of the first and second doses, the anti-TL1 A antibody may be administered at least daily, at least one day apart, at least 1 week apart, at least 2 weeks apart, at least 3 weeks apart, at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, or at least 6 months apart. In some aspects, the time interval between individual subsequent doses of the anti-TL1 A antibody is the same. In other aspects, the time interval between individual subsequent doses of the anti-TL1 A antibody is not the same.
For example, in some aspects, the dosing regimen comprises five subcutaneous doses of the anti-TL1 A antibody (e.g., wherein the third, fourth, and fifth doses are administered Q4W). In some aspects, the dosing regimen consists of five subcutaneous doses of the anti-TL1 A antibody. A dosing regimen consisting of five subcutaneous doses of the anti-TL1 A antibody may have a duration of about 16 weeks.
In dosing regimens comprising or consisting of five doses of the anti-TL1 A antibody, in some aspects, (a) the first dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1) of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 10 of the dosing regimen; and (e) the fifth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 14 of the dosing regimen.
In some aspects, the dosing regimen comprises nine subcutaneous doses of the anti-TL1 A antibody (e.g., wherein the third through ninth doses are administered Q4W). In some aspects, the dosing regimen consists of nine subcutaneous doses of the anti-TL1 A antibody. The dosing regimen consisting of nine subcutaneous doses of the anti-TL1 A antibody may have a duration of about 32 weeks.
In dosing regimens comprising or consisting of nine doses of the anti-TL1 A antibody, in some aspects, (a) the first dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1) of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 2 of the dosing regimen; (c) the third dose is administered on about Day PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 10 of the dosing regimen; (e) the fifth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1) of Week 14 of the dosing regimen; (f) the sixth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 18 of the dosing regimen; (g) the seventh dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 22 of the dosing regimen; (h) the eighth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 26 of the dosing regimen; and (i) the ninth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 30 of the dosing regimen.
In another example, the dosing regimen comprises more than nine doses of the of the anti-TL1 A antibody, e.g., comprises administration of at least 10, 12, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 doses (e.g., 10-20, 20-40, 40-60, 60-80, 80-100, 100-120, 120- 140, 140-160, 160-180, 180-200, 200-220, 220-240, 240-260, 260-280, 280-300, 300-320, 320-340, 340- 360, 360-380, or 380-400 doses) of the of the anti-TL1 A antibody. For example, the anti-TL1 A antibody may be administered (e.g., administered subcutaneously every four weeks) for a duration of at least 6 months, one year, two years, three years, four years, five years, or six years. In some aspects, the anti- TL1 A antibody is administered for a duration of about six years. In some aspects, the dosing regimen comprises a period in which the anti-TL1 A antibody is not administered for at least about six weeks (e.g., is not administered for six weeks), and, following the period without administration, comprises two reloading doses administered about two weeks apart. In some examples, following the re-loading doses, doses are administered Q4W.
The anti-TL1 A antibody may be administered at a dose of, e.g., 1 , 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg (e.g., may be administered at a dose of 1 -50 mg, 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300- 350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 800-850 mg, 850-900 mg, 900-950 mg, or 950-1000 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg (e.g., at a dose of 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350- 400 mg, or 400-450 mg, e.g., at a dose of about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg (e.g., a dose of 50 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg (e.g., a dose of 150 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg (e.g., a dose of 450 mg).
Accordingly, in one aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In another aspect, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
Administration of the anti-TL1A antibody in a further dosing regimen
In some aspects, following a dosing regimen (e.g., first dosing regimen) of the anti-TL1 A antibody, the method further comprises (i) determining that the patient has responded to treatment with the anti-TL1 A antibody following the dosing regimen (or identifying a patient who has been determined to have responded to treatment with the anti-TL1A antibody following the dosing regimen); and (ii) administering to the patient an effective amount of the anti-TL1 A antibody in a further (e.g., second) dosing regimen. Determining that the patient has responded to treatment in a dosing regimen (e.g., a first dosing regimen) may comprise assessment of any appropriate measure or assessment of responsiveness to treatment, e.g., assessment of a measure of the severity of the disease or condition. In some aspects, response to treatment with the anti-TL1 A antibody is a reduction of a post-treatment measure of the severity of the disease or condition by at least 10%, 25%, or 50% relative to a pretreatment measurement, e.g., a measure of severity assessed after the dosing regimen (e.g., one week, two weeks, three weeks, four weeks, five weeks, or six weeks after the administration of the last dose of the dosing regimen) that is reduced by at least 10%, 25%, or 50% relative to a measure of severity assessed before the administration of the first dose of the dosing regimen.
In some aspects, the dosing regimen (e.g., first dosing regimen) has a duration of about 32 weeks, and the post-treatment measure of severity is determined about 36 weeks after administration of the first dose of the anti-TL1 A antibody in the dosing regimen. For example, in some aspects, the dosing regimen (e.g., first dosing regimen) consists of nine subcutaneous doses of the anti-TL1 A antibody, wherein (a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the dosing regimen; (h) the eighth dose PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 is administered on about Day 1 of Week 26 of the dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the dosing regimen, and the post-treatment measure of severity is determined about 36 weeks after administration of the first dose of the anti-TL1 A antibody in the dosing regimen.
In some aspects, the first dose of the of the anti-TL1 A antibody in the further (e.g., second) dosing regimen is administered to the patient about six weeks after the administration of the last previous dose of the anti-TL1 A antibody (e.g., the last dose in the first dosing regimen). For example, following a dosing regimen consisting of nine subcutaneous doses of the anti-TL1 A antibody administered on Weeks 0, 2, 6, 10, 14, 18, 22, 26, and 30 as described above, the first dose of the of the anti-TL1 A antibody in the further (e.g., second) dosing regimen may be administered to the patient at Week 36 (Week 0 of the further (e.g., second) dosing regimen).
In some aspects, the second dosing regimen comprises subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose. For example, in some aspects, (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 0 of the second dosing regimen; and (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 2 of the second dosing regimen.
The anti-TL1 A antibody may be administered in the further (e.g., second) dosing regimen at any of the doses provided herein. In some aspects, each dose of the anti-TL1 A antibody in the further (e.g., second) dosing regimen is administered at a dose of between about 150 mg and about 450 mg (e.g., at a dose of 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, or 400-450 mg, e.g., at a dose of about 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg (e.g., a dose of 150 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg (e.g., a dose of 450 mg).
In some aspects, the dose of the anti-TL1 A antibody may be increased (escalated) during the second dosing regimen, e.g., in response to worsening of the disease or condition. For example, the dose may be increased from 150 mg to 450 mg in response to worsening of the disease or condition. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg or about 450 mg, and the first and second doses of the second dosing regimen are each about 150 mg.
In some aspects, the anti-TL1 A antibody was administered to the patient at a dose of about 50 mg (e.g., at a dose of 50 mg) in the first dosing regimen, and is administered to the patient at a dose of about 150 mg (e.g., a dose of 150 mg) in the second dosing regimen. In some aspects, the dose is escalated to about 450 mg (e.g., 450 mg) in the second dosing regimen, e.g., in response to worsening of the disease or condition.
In some aspects, the anti-TL1 A antibody was administered to the patient at a dose of about 150 mg (e.g., at a dose of 150 mg) in the first dosing regimen, and is administered to the patient at a dose of about 150 mg (e.g., a dose of 150 mg) in the second dosing regimen. In some aspects, the dose is PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 escalated to about 450 mg (e.g., 450 mg) in the second dosing regimen, e.g., in response to worsening of the disease or condition.
In some aspects, the anti-TL1 A antibody was administered to the patient at a dose of about 450 mg (e.g., at a dose of 450 mg) in the first dosing regimen, and is administered to the patient at a dose of about 450 mg (e.g., a dose of 450 mg) in the second dosing regimen.
In some aspects, at least four doses of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen.
In some aspects, following the administration of the first and second doses in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks.
In some aspects, at least 5, 10, 12, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 doses (e.g., 10-20, 20-40, 40-60, 60-80, 80-100, 100-120, 120-140, 140-160, 160-180, 180-200, 200-220, 220-240, 240-260, 260-280, 280-300, 300-320, 320-340, 340-360, 360-380, or 380-400 doses) of the of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen. For example, the anti-TL1 A antibody may be administered (e.g., administered subcutaneously every four weeks) for a duration of at least 6 months, one year, two years, three years, four years, five years, or six years. In some aspects, the anti-TL1 A antibody is administered for a duration of at least one year. In some aspects, the anti-TL1 A antibody is administered for a duration of about six years.
In some aspects, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the first dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the first dosing regimen; and (iii) the first dosing regimen has a duration of about 32 weeks; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the second dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had a measure of severity for the disease or condition that was reduced by at least 10%, 25%, or 50% relative to a pre-treatment measure of severity; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the disclosure features a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein (a) the first dose is administered on about Day 1 of Week 0 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the first dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the first dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the first dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the first dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the first dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the first dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the first dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (a) the first dose is administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the second dosing regimen; and (c) following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks; the patient had a measure of severity for the disease or condition that was reduced by at least 50% relative to a pre-treatment measure of severity at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the anti-TL1 A antibody comprises (a) VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 11 ; and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
/. Diseases and conditions
In some aspects, the disease or condition is atopic dermatitis (a form of eczema). In some aspects, the disease or condition is a form of eczema other than atopic dermatitis. In some aspects, the disease or condition is hidradenitis suppurativa. In some aspects, the disease or condition is vitiligo. In some aspects, the disease or condition is alopecia areata. In some aspects, the disease or condition is scleroderma (including systemic sclerosis). In some aspects, the disease or condition is dermatomyositis. In some aspects, the disease or condition is epidermolysis bullosa. In some aspects, the disease or condition is mastocytosis. In some aspects, the disease or condition is keloids (keloid scarring). In some aspects, the disease or condition is acne (e.g., acne vulgaris). In some aspects, the disease or condition is rosacea. In some aspects, the disease or condition is bullous pemphigoid.
In some aspects, the patient has fibrosis in the skin, e.g., skin fibrosis that is associated with the disease or condition.
//. Response to treatment
During and/or following the dosing regimen, the patient may experience a response characterized by an improvement in signs and symptoms of the disease or condition, e.g., as characterized by an appropriate clinical measure of the severity of the disease or condition. In some aspects, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved a response (e.g., as characterized by an appropriate clinical measure) as compared to a reference population. For example, in some aspects, the dosing regimen has a duration of about 16 weeks (e.g., has a duration of about 16 weeks and comprises administration of five subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved a response at Week 16. In some aspects, the dosing regimen has a duration of about 32 weeks (e.g., has a duration of about 32 weeks and comprises administration of nine subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved a response at Week 32.
Hi. Combination therapies
Anti-TL1 A antibodies of the disclosure can be administered alone or used in a combination therapy (e.g., for the treatment of a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid)). For instance, the combination therapy may include administering an anti-TL1 A antibody according to any of the methods provided herein and administering at least one additional therapeutic agent (e.g. one, two, three, four, five, or six additional therapeutic agents). In one aspect, the combination therapy comprises administering an antibody of the disclosure and administering at least one additional therapeutic agent.
Such combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate pharmaceutical composition(s)), and separate administration, in which case administration of the anti-TL1 A antibody can occur prior to, simultaneously with, and/or following, administration of the additional therapeutic agent or agents. In one aspect, administration of the anti-TL1 A antibody and administration of an additional therapeutic agent occur within about one, two, three, four, five, or six days, within about one, two or three weeks, or within about one month, of each other. In one aspect, the antibody and additional therapeutic agent are both administered to the patient on Day 1 of the treatment.
In some aspects, the disclosure provides a pharmaceutical composition that comprises any of the anti-TL1 A antibodies provided herein and at least one additional therapeutic agent.
B. Methods of treating atopic dermatitis
In some aspects, the present disclosure provides a method of treating atopic dermatitis (e.g., moderate to severe atopic dermatitis) in a patient (e.g., a human patient), the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration (e.g., subcutaneous administration) of at least two doses of the anti-TL1 A antibody (e.g., comprising administration of at least a first and a second dose of the anti-TL1 A antibody), wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose (i.e., the doses are administered (e.g., subcutaneously administered) about two weeks apart.) For example, the second dose may be administered two weeks after the first dose, administered about 14 days (e.g., 1 1 -17 days, 12-16 days, or 13-15 days) after the first dose, or administered 14 days after the first dose. The method may further comprise administration (e.g., subcutaneous administration) of one or more subsequent doses of the anti-TL1 A antibody, e.g., may comprise administration of at least a third dose of the anti-TL1 A antibody. In some aspects, following administration of the first and second doses, the method comprises administration (e.g., subcutaneous administration) of the anti-TL1 A antibody every four weeks (Q4W), e.g., comprises subcutaneous administration of a third dose of the anti-TL1 A antibody about four weeks after the second dose and administration of one or more Q4W doses (e.g., subcutaneous doses) thereafter.
In some aspects, the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.
The disclosure also provides an anti-TL1 A antibody for use in treating atopic dermatitis in a patient according to the methods provided herein and use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis according to the methods provided herein.
In some aspects, the disclosure provides a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the disclosure provides a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1 1 ; and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
Thus, in some aspects, the disclosure provides a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. In some aspects, the disclosure provides a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti- TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
In some aspects, the anti-TL1 A antibody is afimkibart.
In some aspects of any of the methods of treatment provided herein, the first dose of the anti- TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 0 of the dosing regimen; and the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of the dosing regimen, e.g., the first dose and second dose of the anti-TL1 A antibody are administered about two weeks apart.
In some aspects of the method comprising administration of a third dose of the anti-TL1 A antibody, the third dose of the anti-TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 6 of the dosing regimen, e.g., the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose.
In some aspects, following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks. For example, in some aspects, at least 4, 5, 6, 7, 8, 9, or 10 doses (e.g., 4-6, 6-8, or 8-10 doses) or more than 10 doses (e.g., 10-12, 12- 14, 14-16, 16-18, or 18-20 doses) of the anti-TL1 A antibody are administered to the patient. Alternatively, following the administration of the first and second doses, the anti-TL1 A antibody may be administered at least daily, at least one day apart, at least 1 week apart, at least 2 weeks apart, at least 3 weeks apart, at least 1 month apart, at least 2 months apart, at least 3 months apart, at least 4 months apart, at least 5 months apart, or at least 6 months apart. In some aspects, the time interval between individual subsequent doses of the anti-TL1 A antibody is the same. In other aspects, the time interval between individual subsequent doses of the anti-TL1 A antibody is not the same.
For example, in some aspects, the dosing regimen comprises five subcutaneous doses of the anti-TL1 A antibody (e.g., wherein the third, fourth, and fifth doses are administered Q4W). In some aspects, the dosing regimen consists of five subcutaneous doses of the anti-TL1 A antibody. A dosing regimen consisting of five subcutaneous doses of the anti-TL1 A antibody may have a duration of about 16 weeks. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
In dosing regimens comprising or consisting of five doses of the anti-TL1 A antibody, in some aspects, (a) the first dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 10 of the dosing regimen; and (e) the fifth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 14 of the dosing regimen.
In some aspects, the dosing regimen comprises nine subcutaneous doses of the anti-TL1 A antibody (e.g., wherein the third through ninth doses are administered Q4W). In some aspects, the dosing regimen consists of nine subcutaneous doses of the anti-TL1 A antibody. The dosing regimen consisting of nine subcutaneous doses of the anti-TL1 A antibody may have a duration of about 32 weeks.
In dosing regimens comprising or consisting of nine doses of the anti-TL1 A antibody, in some aspects, (a) the first dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 10 of the dosing regimen; (e) the fifth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 14 of the dosing regimen; (f) the sixth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 18 of the dosing regimen; (g) the seventh dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 22 of the dosing regimen; (h) the eighth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 26 of the dosing regimen; and (i) the ninth dose is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 30 of the dosing regimen.
In another example, the dosing regimen comprises more than nine doses of the of the anti-TL1 A antibody, e.g., comprises administration of at least 10, 12, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 doses (e.g., 10-20, 20-40, 40-60, 60-80, 80-100, 100-120, 120- 140, 140-160, 160-180, 180-200, 200-220, 220-240, 240-260, 260-280, 280-300, 300-320, 320-340, 340- 360, 360-380, or 380-400 doses) of the of the anti-TL1 A antibody. For example, the anti-TL1 A antibody may be administered (e.g., administered subcutaneously every four weeks) for a duration of at least 6 months, one year, two years, three years, four years, five years, or six years. In some aspects, the anti- TL1 A antibody is administered for a duration of about six years. In some aspects, the dosing regimen comprises a period in which the anti-TL1 A antibody is not administered for at least about six weeks (e.g., is not administered for six weeks), and, following the period without administration, comprises two reloading doses administered about two weeks apart. In some examples, following the re-loading doses, doses are administered Q4W.
The anti-TL1 A antibody may be administered at a dose of, e.g., 1 , 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg (e.g., may be PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 administered at a dose of 1 -50 mg, 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300- 350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-550 mg, 550-600 mg, 600-650 mg, 650-700 mg, 700-750 mg, 750-800 mg, 800-850 mg, 850-900 mg, 900-950 mg, or 950-1000 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg (e.g., at a dose of 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350- 400 mg, or 400-450 mg, e.g., at a dose of about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg (e.g., a dose of 50 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg (e.g., a dose of 150 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg (e.g., a dose of 450 mg).
Accordingly, in one aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In another aspect, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
Administration of the anti-TL1A antibody in a further dosing regimen
In some aspects, following a dosing regimen (e.g., first dosing regimen) of the anti-TL1 A antibody, the method further comprises (i) determining that the patient has responded to treatment with the anti-TL1 A antibody following the dosing regimen (or identifying a patient who has been determined to have responded to treatment with the anti-TL1A antibody following the dosing regimen); and (ii) administering to the patient an effective amount of the anti-TL1 A antibody in a further (e.g., second) dosing regimen. Determining that the patient has responded to treatment in a dosing regimen (e.g., a first dosing regimen) may comprise assessment of any appropriate measure or assessment of responsiveness to treatment, e.g., assessment of a measure of the severity of atopic dermatitis. Measures of responsiveness to treatment are described, e.g., in Section I l(C) , below. In some aspects, response to treatment with the anti-TL1 A antibody is a reduction of a post-treatment Eczema Area and Severity Index (EASI) by at least 50% relative to a pre-treatment EASI, e.g., an EASI measured after the dosing regimen (e.g., one week, two weeks, three weeks, four weeks, five weeks, or six weeks after the administration of the last dose of the dosing regimen) that is reduced by at least 50% relative to an EASI measured before the administration of the first dose of the dosing regimen.
In some aspects, the dosing regimen (e.g., first dosing regimen) has a duration of about 32 weeks, and the post-treatment EASI is determined about 36 weeks after administration of the first dose of the anti-TL1 A antibody in the dosing regimen. For example, in some aspects, the dosing regimen (e.g., first dosing regimen) consists of nine subcutaneous doses of the anti-TL1 A antibody, wherein (a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 the dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the dosing regimen, and the post-treatment EASI is determined about 36 weeks after administration of the first dose of the anti-TL1 A antibody in the dosing regimen.
In some aspects, the first dose of the of the anti-TL1 A antibody in the further (e.g., second) dosing regimen is administered to the patient about six weeks after the administration of the last previous dose of the anti-TL1 A antibody (e.g., the last dose in the first dosing regimen). For example, following a dosing regimen consisting of nine subcutaneous doses of the anti-TL1 A antibody administered on Weeks 0, 2, 6, 10, 14, 18, 22, 26, and 30 as described above, the first dose of the of the anti-TL1 A antibody in the further (e.g., second) dosing regimen may be administered to the patient at Week 36 (Week 0 of the further (e.g., second) dosing regimen).
In some aspects, the second dosing regimen comprises subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose. For example, in some aspects, (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 0 of the second dosing regimen; and (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 (e.g., Day 1 ±3 days, Day 1 ±1 day, or Day 1 ) of Week 2 of the second dosing regimen.
The anti-TL1 A antibody may be administered in the further (e.g., second) dosing regimen at any of the doses provided herein. In some aspects, each dose of the anti-TL1 A antibody in the further (e.g., second) dosing regimen is administered at a dose of between about 150 mg and about 450 mg (e.g., at a dose of 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, or 400-450 mg, e.g., at a dose of about 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg (e.g., a dose of 150 mg). In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg (e.g., a dose of 450 mg).
In some aspects, the dose of the anti-TL1 A antibody may be increased (escalated) during the second dosing regimen, e.g., in response to disease worsening. For example, the dose may be increased from 150 mg to 450 mg in response to disease worsening. In some aspects, each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg or about 450 mg, and the first and second doses of the second dosing regimen are each about 150 mg.
In some aspects, the anti-TL1 A antibody was administered to the patient at a dose of about 50 mg (e.g., at a dose of 50 mg) in the first dosing regimen, and is administered to the patient at a dose of about 150 mg (e.g., a dose of 150 mg) in the second dosing regimen. In some aspects, the dose is escalated to about 450 mg (e.g., 450 mg) in the second dosing regimen, e.g., in response to disease worsening.
In some aspects, the anti-TL1 A antibody was administered to the patient at a dose of about 150 mg (e.g., at a dose of 150 mg) in the first dosing regimen, and is administered to the patient at a dose of PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 about 150 mg (e.g., a dose of 150 mg) in the second dosing regimen. In some aspects, the dose is escalated to about 450 mg (e.g., 450 mg) in the second dosing regimen, e.g., in response to disease worsening.
In some aspects, the anti-TL1 A antibody was administered to the patient at a dose of about 450 mg (e.g., at a dose of 450 mg) in the first dosing regimen, and is administered to the patient at a dose of about 450 mg (e.g., a dose of 450 mg) in the second dosing regimen.
In some aspects, at least four doses of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen.
In some aspects, following the administration of the first and second doses in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks.
In some aspects, at least 5, 10, 12, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 doses (e.g., 10-20, 20-40, 40-60, 60-80, 80-100, 100-120, 120-140, 140-160, 160-180, 180-200, 200-220, 220-240, 240-260, 260-280, 280-300, 300-320, 320-340, 340-360, 360-380, or 380-400 doses) of the of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen. For example, the anti-TL1 A antibody may be administered (e.g., administered subcutaneously every four weeks) for a duration of at least 6 months, one year, two years, three years, four years, five years, or six years. In some aspects, the anti-TL1 A antibody is administered for a duration of at least one year. In some aspects, the anti-TL1 A antibody is administered for a duration of about six years.
In some aspects, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the first dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the first dosing regimen; and (iii) the first dosing regimen has a duration of about 32 weeks; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody in the second dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and (ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CORFU comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the disclosure features a method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein (a) the first dose is administered on about Day 1 of Week 0 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the first dosing regimen; (c) the third dose is administered on about Day 1 of Week 6 of the first dosing regimen; (d) the fourth dose is administered on about Day 1 of Week 10 of the first dosing regimen; (e) the fifth dose is administered on about Day 1 of Week 14 of the first dosing regimen; (f) the sixth dose is administered on about Day 1 of Week 18 of the first dosing regimen; (g) the seventh dose is administered on about Day 1 of Week 22 of the first dosing regimen; (h) the eighth dose is administered on about Day 1 of Week 26 of the first dosing regimen; and (i) the ninth dose is administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein (a) the first dose is administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; (b) the second dose is administered on about Day 1 of Week 2 of the second dosing regimen; and (c) following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks; the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
In some aspects, the anti-TL1 A antibody comprises (a) VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2, e.g., comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 11 ; and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10, e.g., comprises (a) a heavy chain PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3 comprising the amino acid sequence of SEQ ID NO: 9 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
/. Atopic dermatitis
In some aspects, the atopic dermatitis is moderate to severe atopic dermatitis (e.g., is moderate atopic dermatitis or is severe atopic dermatitis). In some aspects, a patient to be treated according to the methods provided herein has an Eczema Area and Severity Index (EASI) score of at least 16, has an Investigator Global Assessment (IGA) scale score for atopic dermatitis of at least 3, and/or has atopic dermatitis involvement of at least 10% of their body surface area (e.g., is identified as having moderate to severe atopic dermatitis on the basis of such an EASI score, IGA scale score, or body surface area involvement). In some aspects, a patient to be treated according to the methods provided herein has all three of an Eczema Area and Severity Index (EASI) score of at least 16, an Investigator Global Assessment (IGA) scale score for atopic dermatitis of at least 3, and atopic dermatitis involvement of at least 10% of their body surface area.
In some aspects, the patient has been treated with a topical therapy (e.g., a topical prescription therapy) (e.g., has previously been treated with a therapy selected from a topical corticosteroid (TCS) and a topical calcineurin inhibitor (TCI)) and has experienced inadequate response to the therapy (e.g., disease has not been adequately controlled by the therapy). In some aspects, the patient is one for whom a topical treatment (e.g., a TCS or TCI) is medically inadvisable, e.g., because of predicted or observed side effects or safety risks.
As discussed in further detail below, during and/or following the dosing regimen, the patient may experience a response characterized by an improvement in signs and symptoms of atopic dermatitis, e.g., characterized by an improved Eczema Area and Severity Index (EASI) score, Investigator Global Assessment Scale for Atopic Dermatitis (IGA) score, body surface area assessment (BSA), Dermatology Life Quality Index (DLQI), and/or Peak Pruritus Numerical Rating Scale (PP-NRS). In some aspects, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved a response as compared to a reference population. For example, in some aspects, the dosing regimen has a duration of about 16 weeks (e.g., has a duration of about 16 weeks and comprises administration of five subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved a response at Week 16. In some aspects, the dosing regimen has a duration of about 32 weeks (e.g., has a duration of about 32 weeks and comprises administration of nine subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved a response at Week 32. Exemplary responses to treatment are described in further detail below.
EASI score
Following the dosing regimen, the patient may experience an improvement in signs and symptoms of atopic dermatitis characterized by an improved (decreased) Eczema Area and Severity PATENT
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Index (EASI) score. The EASI is a validated, standardized tool (Hanifin et al., Dermatitis, 33: 187-192, 2022) that grades the area and severity of AD signs across 4 body regions, with scores ranging from 0 to 72 and higher values indicating more severe disease.
In some aspects, the patient achieves at least a 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% improvement (e.g., a 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% improvement) relative to a baseline (e.g., pre-treatment) EASI score. In some aspects, the patient achieves a 100% improvement relative to a baseline (e.g., pre-treatment) EASI score.
In some aspects, the patient achieves at least a 75% improvement in EASI score relative to a baseline (e.g., pre-treatment) EASI score, e.g., achieves an EASI-75 response.
In some aspects, in a population of patients treated according to any one of the methods provided herein, the treating results in an increase in the proportion of patients who have achieved an EASI-75 response as compared to a reference population. For example, in some aspects, the dosing regimen has a duration of about 16 weeks (e.g., has a duration of about 16 weeks and comprises administration of five subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved an EASI-75 at Week 16. For example, in some aspects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90- 100% of patients) in the population of patients have achieved an EASI-75 at Week 16. In some aspects, the proportion of patients in the population of patients who have achieved an EASI-75 at Week 16 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have achieved an EASI-75 at Week 16 in the reference population. In other aspects, the dosing regimen has a duration of about 32 weeks (e.g., has a duration of about 32 weeks and comprises administration of nine subcutaneous doses of the anti- TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved an EASI-75 at Week 32. For example, in some aspects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10- 20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have achieved an EASI-75 at Week 32. In some aspects, the proportion of patients in the population of patients who have achieved an EASI-75 at Week 32 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have achieved an EASI-75 at Week 32 in the reference population.
In some aspects, the patient achieves at least a 90% improvement in EASI score relative to a baseline (e.g., pre-treatment) EASI score, e.g., achieves an EASI-90 response.
In some aspects, in a population of patients treated according to any one of the methods provided herein, the treating results in an increase in the proportion of patients who have achieved an EASI-90 response as compared to a reference population. For example, in some aspects, the dosing regimen has a duration of about 16 weeks (e.g., has a duration of about 16 weeks and comprises administration of five subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved an EASI-90 at Week 16. For example, in some aspects, at least 5%, 10%, PATENT
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15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90- 100% of patients) in the population of patients have achieved an EASI-90 at Week 16. In some aspects, the proportion of patients in the population of patients who have achieved an EASI-90 at Week 16 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have achieved an EASI-90 at Week 16 in the reference population. In other aspects, the dosing regimen has a duration of about 32 weeks (e.g., has a duration of about 32 weeks and comprises administration of nine subcutaneous doses of the anti- TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved an EASI-90 at Week 32. For example, in some aspects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10- 20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have achieved an EASI-90 at Week 32. In some aspects, the proportion of patients in the population of patients who have achieved an EASI-90 at Week 32 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have achieved an EASI-90 at Week 32 in the reference population.
In any of the methods provided herein, the reference population may be any population that serves as an appropriate control. For example, in some aspects, the reference population is a population of subjects having atopic dermatitis (e.g., moderate to severe atopic dermatitis)) who have not been treated with an anti-TL1 A antibody (e.g., have been treated with a placebo). In some aspects, the reference population is a population of subjects having atopic dermatitis (e.g., moderate to severe atopic dermatitis)) who have been treated with fewer doses of anti-TL1 A antibody. For example, in aspects in which the dosing regimen consists of administration of nine subcutaneous doses of the anti-TL1 A antibody (e.g., has a duration of about 32 weeks and consists of administration of nine subcutaneous doses of the anti-TL1 A antibody), the reference population may be a population of subjects that received five doses of a placebo followed by five doses of the anti-TL1 A antibody.
IGA scale score
Following the dosing regimen, the patient may experience an improvement in signs and symptoms of atopic dermatitis characterized by an improved (decreased) Investigator Global Assessment scale for Atopic Dermatitis (IGA) score. IGA (also called validated IGA (vIG A)) is a standardized static assessment of the overall severity of the participant’s atopic dermatitis that uses a 5-point scale ranging from 0 (clear) to 4 (severe); see Table 11 , below. A score is selected from morphological descriptors that best describe the overall appearance of atopic dermatitis lesions at a given timepoint.
In some aspects, the patient achieves an IGA scale score of 0 (clear) or 1 (almost clear). In some aspects, the patient achieves an IGA scale score of 0 (clear) or 1 (almost clear), with an improvement of at least two grades relative to a baseline (e.g., pre-treatment) IGA scale score.
In some aspects, in a population of patients treated according to any one of the methods provided herein, the treating results in an increase in the proportion of patients who have achieved an IGA scale score of 0 or 1 as compared to a reference population. For example, in some aspects, the dosing PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 regimen has a duration of about 16 weeks (e.g., has a duration of about 16 weeks and comprises administration of five subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved an IGA scale score of 0 or 1 at Week 16. For example, in some aspects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40- 50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have achieved an IGA scale score of 0 or 1 at Week 16. In some aspects, the proportion of patients in the population of patients who have achieved an IGA scale score of 0 or 1 at Week 16 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have achieved an IGA scale score of 0 or 1 at Week 16 in the reference population. In other aspects, the dosing regimen has a duration of about 32 weeks (e.g., has a duration of about 32 weeks and comprises administration of nine subcutaneous doses of the anti-TL1 A antibody), and the treating results in an increase in the proportion of patients who have achieved an IGA scale score of 0 or 1 at Week 32. For example, in some aspects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have achieved an IGA scale score of 0 or 1 at Week 32. In some aspects, the proportion of patients in the population of patients who have achieved an IGA scale score of 0 or 1 at Week 32 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have achieved an IGA scale score of 0 or 1 at Week 32 in the reference population.
In any of the methods provided herein, the reference population may be any population that serves as an appropriate control. For example, in some aspects, the reference population is a population of subjects having atopic dermatitis (e.g., moderate to severe atopic dermatitis)) who have not been treated with an anti-TL1 A antibody (e.g., have been treated with a placebo). In some aspects, the reference population is a population of subjects having atopic dermatitis (e.g., moderate to severe atopic dermatitis)) who have been treated with fewer doses of anti-TL1 A antibody. For example, in aspects in which the dosing regimen consists of administration of nine subcutaneous doses of the anti-TL1 A antibody (e.g., has a duration of about 32 weeks and consists of administration of nine subcutaneous doses of the anti-TL1 A antibody), the reference population may be a population of subjects that received five doses of a placebo followed by five doses of the anti-TL1 A antibody.
PP-NRS
Following the dosing regimen, the patient may experience an improvement in signs and symptoms of atopic dermatitis characterized by an improved (decreased) Peak Pruritus Numerical Rating Scale (PP-NRS). PP-NRS is a single-item, validated, participant-reported assessment to evaluate the worst itch intensity in adults with moderate-to-severe AD during the previous 24 hours. The item response is reported on an 11 -point scale ranging from “no itch” to “worst itch imaginable.”
In some aspects, the patient achieves at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, improvement (e.g., a 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90- PATENT
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100% improvement) relative to a baseline (e.g., pre-treatment) PP-NRS. In some aspects, the patient achieves a 100% improvement relative to a baseline (e.g., pre-treatment) PP-NRS.
DLQI
Following the dosing regimen, the patient may experience an improvement in signs and symptoms of atopic dermatitis characterized by an improved (decreased) Dermatology Life Quality Index (DLQI). The Dermatology Life Quality Index (DLQI) is a ten-item, validated, participant-reported questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on health-related quality of life (Badia et al., Br J Dermatol., 141 : 698-702, 1999); a low score equals better health-related quality of life.
In some aspects, the patient achieves at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% improvement (e.g., a 10-20%, 20-30%, 30- 40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% improvement) relative to a baseline (e.g., pre-treatment) DLQI. In some aspects, the patient achieves a 100% improvement relative to a baseline (e.g., pre-treatment) DLQI.
Hi. Combination therapies
Anti-TL1 A antibodies of the disclosure can be administered alone or used in a combination therapy for the treatment of atopic dermatitis. For instance, the combination therapy may include administering an anti-TL1 A antibody according to any of the methods provided herein and administering at least one additional therapeutic agent (e.g. one, two, three, four, five, or six additional therapeutic agents). In one aspect, the combination therapy comprises administering an antibody of the disclosure and administering at least one additional therapeutic agent. Exemplary therapeutic agents that may be administered in combination with an anti-TL1 A antibody are provided below.
Such combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate pharmaceutical composition(s)), and separate administration, in which case administration of the anti-TL1 A antibody can occur prior to, simultaneously with, and/or following, administration of the additional therapeutic agent or agents. In one aspect, administration of the anti-TL1 A antibody and administration of an additional therapeutic agent occur within about one, two, three, four, five, or six days, within about one, two or three weeks, or within about one month, of each other. In one aspect, the antibody and additional therapeutic agent are both administered to the patient on Day 1 of the treatment.
In some aspects, the disclosure provides a pharmaceutical composition (e.g., a composition for treatment of atopic dermatitis) that comprises any of the anti-TL1 A antibodies provided herein and at least one additional therapeutic agent, e.g., as described below.
In some aspects, the anti-TL1 A antibody is administered in combination with a topical corticosteroid (TCS).
In some aspects, the anti-TL1 A antibody is administered in combination with a topical calcineurin inhibitor (TCI), e.g., pimecrolimus or tacrolimus.
In some aspects, the anti-TL1 A antibody is administered in combination with a topical PATENT
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Attorney Docket No: 50474-365WO3 phosphodiesterase-4 (PDE4) inhibitor, e.g., crisaborole or roflumilast (ARQ-151 ),
In some aspects, the anti-TL1 A antibody is administered in combination with a topical Janus kinase (JAK) inhibitors, e.g., ruxolitinib or delgocitinib.
In some aspects, the anti-TL1 A antibody is administered in combination with a topical aryl hydrocarbon receptor (AhR) agonist, e.g., tapinarof.
In some aspects, the anti-TL1 A antibody is administered in combination with a phototherapy, e.g., narrow-band ultraviolet B (NB-UVB).
In some aspects, the anti-TL1 A antibody is administered in combination with a conventional systemic immunosuppressant, e.g., cyclosporine, methotrexate, or azathioprine and mycophenolate mofetil.
In some aspects, the anti-TL1 A antibody is administered in combination with an IL4 or/and IL13 inhibitor, e.g., dupilumab, tralokinumab, or lebrikizumab.
In some aspects, the anti-TL1 A antibody is administered in combination with an IL-31 inhibitor, e.g., nemolizumab.
In some aspects, the anti-TL1 A antibody is administered in combination with an 0X40 inhibitor, e.g., rocatinlimab (KHK4083/AMG 451 ) or amlitelimab (SAR445229, KY1005).
In some aspects, the anti-TL1 A antibody is administered in combination with a thymic stromal lymphopoietin (TSLP) inhibitor, e.g., tezepelumab.
In some aspects, the anti-TL1 A antibody is administered in combination with an IL-33 inhibitor, e.g., itepekimab.
In some aspects, the anti-TL1 A antibody is administered in combination with an oral Janus kinase (JAK) Inhibitor, e.g., abrocitinib, upadacitinib, or baricitinib.
In some aspects, the anti-TL1 A antibody is administered in combination with a sphingosine-1 - phosphate (S1 P) receptor modulator, e.g., etrasimod.
III. Anti-TL1 A Antibodies
The methods of the present disclosure include the administration of an anti-TL1 A antibody. Exemplary anti-TL1 A antibodies of the disclosure are set forth in Table 1 .
Table 1. Sequences of Exemplary Antibodies of the Disclosure PATENT
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In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody comprises one, two, three, four, five, six, seven, or all eight of the framework region sequences shown in SEQ ID NOs: 13-20.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody comprises one, two, three, four, five, six, seven, or all eight of the framework region sequences shown in SEQ ID NOs: 14-21 .
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain variable domain (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1 ) and/or comprises a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2).
In some aspects of the disclosure, the anti-TL1 A antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and/or comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 2.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a VH having the sequence shown in SEQ ID NO: 1 and a VL having the sequence shown in SEQ ID NO: 2.
In some aspects of the disclosure, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1 1 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9 or SEQ ID NO: 1 1 ); and/or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10).
In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and/or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 1 1 . In some embodiments, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 1 1 and a light chain having the sequence shown in PATENT
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SEQ ID NO: 10, wherein the C-terminal lysine (K) of the heavy chain amino acid sequence of SEQ ID NO: 1 1 is optional. In some embodiments, the heavy chain does not have the C-terminal lysine (K). In some embodiments, the heavy chain has the sequence shown in SEQ ID NO: 9. In some embodiments, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 9 and a light chain having the sequence shown in SEQ ID NO: 10.
In some aspects of the disclosure, the anti-TL1 A antibody is afimkibart (also known as
RO7790121 , RVT-3101 , or PF-06480605).
Further exemplary anti-TL1 A antibodies are set forth in Table 2 and below. Table 2. Sequences of Exemplary Antibodies of the Disclosure PATENT
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In some aspects of the disclosure, the anti-TL1 A antibody comprises a VH encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VH having ATCC accession number PTA-120639 and a VL encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VL having ATCC accession number PTA-120640.
In some aspects of the disclosure, the anti-TL1 A antibody competes for binding with an anti-TL1 A antibody comprising a variable heavy chain region having the sequence shown in SEQ ID NO: 1 and a variable light chain region having the sequence shown in SEQ ID NO: 2.
In some aspects of the disclosure, the anti-TL1 A antibody competes for binding with an antibody comprising a VH encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VH having ATCC accession number PTA-120639 and a VL encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VL having ATCC accession number PTA-120640. PATENT
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In some aspects of the disclosure, the anti-TL1 A antibody comprises sequence pairs selected from the group consisting of SEQ ID NOs: 2 and 22; SEQ ID NOs: 2 and 23; SEQ ID NOs: 2 and 24; SEQ ID NOs: 2 and 25; SEQ ID NOs: 2 and 26; SEQ ID NOs: 2 and 27; SEQ ID NOs: 2 and 28; SEQ ID NOs: 2 and 29; SEQ ID NOs: 2 and 30; SEQ ID NOs: 31 and 35; SEQ ID NOs: 32 and 36; SEQ ID NOs: 33 and 37; SEQ ID NOs: 34 and 38; SEQ ID NOs: 39 and 40; SEQ ID NOs: 41 and 42; SEQ ID NOs: 43 and 44; SEQ ID NOs: 45 and 54; SEQ ID NOs: 63 and 64; SEQ ID NOs: 71 and 72; SEQ ID NOs: 73 and 74; SEQ ID NOs: 75 and 74; SEQ ID NOs: 76 and 74; and SEQ ID NOs: 77 and 74.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 having the sequence shown in SEQ ID NO: 47, a CDR-H2 having the sequence shown in SEQ ID NO: 49, a CDR- H3 having the sequence shown in SEQ ID NO: 51 , a CDR-L1 having the sequence shown in SEQ ID NO: 56, a CDR-L2 having the sequence shown in SEQ ID NO: 58, and a CDR-L3 having the sequence shown in SEQ ID NO: 60.
In some aspects of the disclosure, the anti-TL1 A antibody comprises heavy chain framework regions as shown in SEQ ID NOs: 46, 48, 50, and 52 and/or comprises light chain framework regions as shown in SEQ ID NOs: 55, 57, 59, and 61 .
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain variable region having the sequence shown in SEQ ID NO: 63 and a light chain variable region having the sequence shown in SEQ ID NO: 64.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain tail sequence as provided in SEQ ID NO: 53. In some aspects of the disclosure, the anti-TL1 A antibody comprises a light chain tail sequence as provided in SEQ ID NO: 62.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 45 and/or a light chain having the sequence shown in SEQ ID NO: 54. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 45 and a light chain having the sequence shown in SEQ ID NO: 54.
In some aspects of the disclosure, the anti-TL1 A antibody is tulisokibart.
In some aspects, the antibody used in any of the methods, compositions, uses, and compositions for use provided herein is an anti-TL1 A antibody provided in Table 2A of U.S. Patent No. 11 ,136,386, which is incorporated herein by reference in its entirety.
In some aspects of any of the methods, compositions, uses, and compositions for use provided herein, the anti-TL1 A antibody is an anti-TL1 A antibody provided in U.S. Patent No. 10,322,174, U.S. Patent No. 10,689,439, U.S. Patent No. 11 ,292,848, U.S. Patent No. 10,138,296, U.S. Patent No. 10,822,422, and U.S. Patent No. 11 ,220,549, which are incorporated herein by reference in their entirety. In some embodiments, the anti-TL1 A antibody comprises the CDR sequences of the 320-179 clone provided in U.S. Patent No. 10,689,439. In some embodiments, the anti-TL1 A antibody is the 320-179 clone provided in U.S. Patent No. 10,689,439.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 having the sequence shown in SEQ ID NO: 65, a CDR-H2 having the sequence shown in SEQ ID NO: 66, a CDR- H3 having the sequence shown in SEQ ID NO:67, a CDR-L1 having the sequence shown in SEQ ID NO: PATENT
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68, a CDR-L2 having the sequence shown in SEQ ID NO: 69, and a CDR-L3 having the sequence shown in SEQ ID NO: 70.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain variable region having the sequence shown in SEQ ID NO: 71 and a light chain variable region having the sequence shown in SEQ ID NO: 72.
In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 73, 75, 76, or 77 and/or a light chain having the sequence shown in SEQ ID NO:74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 73, 75, 76, or 77 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 73 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 75 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 76 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 77 and a light chain having the sequence shown in SEQ ID NO: 74.
In some aspects of the disclosure, the anti-TL1 A antibody is TEV-48574.
In some aspects of the disclosure, the anti-TL1 A antibody is C03V. C03V has been described, for example, in Clarke AW, Poulton L, Shim D, Mabon D, Butt D, Pollard M, Pande V, Hasten J, Lyons J, Tian C, Doyle AG. An anti-TL1 A antibody for the treatment of asthma and inflammatory bowel disease. MAbs. 2018 May/Jun;10(4):664-677. doi: 10.1080/19420862.2018.1440164. Epub 2018 Mar 5. PMID: 29436901 : PMCID: PMC5973687.
In some aspects of the disclosure, the anti-TL1 A antibody is SPY002. SPY002 has been described, for example, in Zhu, E., et al. "P91 1 Development and Characterization of SPY002, a Novel Extended Half-life Monoclonal Antibody Drug Candidate Targeting TL1 A for the Treatment of IBD." Journal of Crohn's and Colitis 18. Supplement 1 (2024): II 666-11666.
In some aspects of the disclosure, the anti-TL1 A antibody is FG-M701 .
IV. Articles of Manufacture and Kits
In another aspect of the invention, an article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders, diseases, and conditions described above (e.g., a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) is provided. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition (e.g., a composition comprising an anti-TL1 A antibody) which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an antibody of the disclosure (e.g., an anti-TL1 A antibody, e.g., afimkibart). The label or package insert indicates that the composition is used for treating the disease or condition of choice (e.g., a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid). Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody of the disclosure; and (b) a second container with a composition contained therein, wherein the composition comprises a further therapeutic agent. The article of manufacture in this aspect of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition (e.g., a disease or condition involving inflammation in the skin, e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid). Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
The disclosure also provides kits comprising any or all of the anti-TL1 A antibodies described herein. Kits of the disclosure include one or more containers comprising an anti-TL1 A antibody described herein and instructions for use in accordance with any of the methods of the disclosure described herein. Generally, these instructions comprise a description of administration of the anti-TL1 A antibody for the above-described therapeutic treatments. In some aspects, kits are provided for producing a single-dose administration unit. In certain aspects, the kit can contain both a first container having a dried protein and a second container having an aqueous formulation. In certain aspects, kits containing single and multichambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.
The instructions relating to the use of an anti-TL1 A antibody generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi dose packages) or sub-unit doses. Instructions supplied in the kits of the disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
The kits of this disclosure are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump. A kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 hypodermic injection needle). At least one active agent in the composition is an anti-TL1 A antibody. The container may further comprise a second pharmaceutically active agent.
Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.
V. Compositions and Formulations
A. Compositions
In a further aspect, provided are pharmaceutical compositions comprising an effective amount of an anti-TL1 A antibody as described herein, and such pharmaceutical compositions for use in any of the methods of treatment provided herein. In one aspect, a pharmaceutical composition comprises any of the antibodies provided herein and a pharmaceutically acceptable carrier. In another aspect, a pharmaceutical composition comprises any of the antibodies provided herein and at least one additional therapeutic agent, e.g., as described below.
Pharmaceutical compositions (formulations) of an anti-TL1 A antibody as described herein can be prepared by combining the antibody with pharmaceutically acceptable carriers or excipients known to the skilled person. See, for example Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) and Falconer R.J., Biotechnology Advances 37: 107412 (2019). Exemplary pharmaceutical compositions of an anti-TL1 A antibody as described herein may be lyophilized, aqueous, frozen, etc.
Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as histidine, phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG).
The pharmaceutical composition herein may also contain more than one active ingredient as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
The pharmaceutical compositions to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.
The anti-TL1 A antibody, and compositions thereof, can also be used in conjunction with, or administered separately, simultaneously, or sequentially with other agents that serve to enhance and/or complement the effectiveness of the agents. PATENT
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B. Formulations
Therapeutic formulations of the anti-TL1 A antibody used in accordance with the present disclosure are prepared for storage by mixing the protein having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).
Liposomes that may contain the anti-TL1 A antibody are prepared by methods known in the art, such as described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatinmicrocapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000).
Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained- release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid. PATENT
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The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Therapeutic anti-TL1 A antibody compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
The compositions according to the present disclosure may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 to about 500 mg of the active ingredient of the present disclosure. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as INTRALIPID™, LIPOSYN™, INFONUTROL™, LIPOFUNDIN™ and LIPIPHYSAN™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion.
Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1 .0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0. PATENT
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The emulsion compositions can be those prepared by mixing an anti-TL1A antibody with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some aspects, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
In aspects that refer to a method of treating a disease or condition involving inflammation in the skin (e.g., atopic dermatitis, eczema other than atopic dermatitis, hidradenitis suppurativa, vitiligo, alopecia areata, scleroderma (including systemic sclerosis), dermatomyositis, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid) as described herein, such aspects are also further aspects of an anti-TL1 A antibody for use in that treatment, or alternatively of the use of an anti- TL1 A antibody in the manufacture of a medicament for use in that treatment.
VII. Examples
Example 1. A Phase II, Multicenter, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Afimkibart in Patients with Moderate to Severe Atopic Dermatitis
The CS45570 study provided in Examples 1 -6 is a Phase II dose-ranging study designed to assess the efficacy and safety of afimkibart (formerly PF 06480605, RVT-3101 , or RO7790121 ) in patients with moderate to severe atopic dermatitis (AD).
Afimkibart is a fully human neutralizing monoclonal antibody (lgG1 mAb) against TL1 A (TNF-like ligand 1 , TNFSF15). TL1 A, a member of the tumor necrosis factor (TNF) superfamily of proteins (TNFSF) that is encoded by the TNFSF15 gene, plays a key role in regulating the inflammatory pathways and cell types governing skin inflammation in AD by binding to its functional receptor, Death Receptor 3 (DR3) (Richard et al., J. Immunol., 195: 3567-3582, 2015; Meylan et al., Mucosal Immunol., 7: 958-968, 2014). The mechanism of action of afimkibart is to neutralize the binding and subsequent signaling of TL1 A to its functional receptor (DR3) on immune cells of the innate and adaptive immune system.
TL1 A, a member of the TNFSF family that is encoded by the TNFSF15 gene, plays a key role in regulating the inflammatory pathways and cell types governing skin inflammation in atopic dermatitis by binding its receptor, DR3 (Richard et al., J. Immunol., 195: 3567-3582, 2015; Meylan et al., Mucosal Immunol., 7: 958-968, 2014). Based on its role as a modulator of key cell types underlying AD, antagonism of TL1 A by afimkibart is expected to confer benefit to patients with moderate or severe AD.
The immunopathobiology underlying the development and progression of AD is driven by an innate response to external pathogens or the environment leading to skin inflammation mediated by specific T-cell (Th2, Th9, Th17, Th22) and Innate Lymphoid cell (ILC2) populations (Brandt et al., J Clin Cell Immunol., 2: 110, 2011 ; Gittler et al., J Allergy Clin Immunol., 130: 1344-1354, 2012; Mashiko et al., PATENT
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J Dermatol Sci., 88: 167-174, 2017). TL1 A and its receptor DR3 are an innate amplifier of the activity of ILC2, Th2, Th17 and Th22 cell populations and thus an upstream regulator of disease activity (Meylan et al., Mucosal Immunol., 7: 958-968, 2014; Yu et al., Mucosal Immunol., 7: 730-740, 2014; Schmitt et al., J Exp Med., 221 : e20231236, 2024; Thomas et al., J Leukoc Biol., 101 : 727-737, 2017; Meylan et al., Immunity, 29: 79-89, 2008). Mediators such as IL-22, IL-4, and IL-13, generated by these cell populations, further drive the development of AD and pruritus (Wang et al., Immunity, 52: 753-766, 2020; Dalgard et al., J Invest Dermatol, 135: 984-991 , 2015).
In a mouse model of atopic dermatitis, Malhotra et al. {Sci Immunol., eaao6923, 2018) identified TL1 A as having a role in driving skin inflammation. Local TL1 A blockade by intradermal injection of neutralizing antibody to TL1 A significantly reduced skin inflammation in mice. In humans, TL1 A expression by immunohistochemistry was demonstrated in the epithelium of patients with AD and virtually absent in normal controls. Serum TL1 A levels were also elevated in patients with AD compared to healthy controls (Hisamoto et al., Int J Mol Sci, 24: 1813, 2023).
The study provided in Examples 1 -6 is designed to evaluate the efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of afimkibart administered subcutaneously (SC) compared with placebo in patients with moderate to severe atopic dermatitis.
A. Primary objective and corresponding estimands
The primary objective of the CS45570 study is to evaluate the efficacy of afimkibart at a dose of 450 mg administered subcutaneously (SC) in achieving an EASI-75 response at Week 16 compared with placebo (see Table 3). EASI-75 response is at least a 75% reduction of the Eczema Area and Severity Index score compared to baseline. Statistical inference supporting this evaluation targets estimands representing the effect of assignment to the treatment conditions (afimkibart vs. placebo) on a specified outcome (endpoint) in the population of participants with moderate to severe AD, as identified by key trial inclusion and exclusion criteria. Primary objectives for the study are expressed using the estimand framework in accordance with the International Council for Harmonisation (ICH) E9(R1 ) statistical principles for clinical trials (International Council for Harmonisation. E9 (R1 ) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials (ICH) 2020).
PATENT
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Table 3. Co-Primary Objectives and Endpoints
The availability or interpretation of endpoint measurements may be affected by the occurrence of intercurrent events (ICEs; ICH 2020) arising between randomization and endpoint assessment. Strategies to address anticipated ICEs are summarized in Table 4.
Table 4. Strategies for Anticipated Intercurrent Events
B. Secondary objectives and corresponding estimands The efficacy of the 450 mg dose of afimkibart compared to placebo and characterization of the dose response of 450 mg, 150 mg, and 50 mg afimkibart are further considered in secondary objectives, as described in Table 5. As with the primary objective, the secondary efficacy objectives have PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 corresponding estimands of interest representing an effect comparing the same treatment conditions (afimkibart vs. placebo) on a specified endpoint, within the same overall population of participants, and using the same strategies for anticipated ICEs (Table 4). These treatment effects are defined in the same manner as those for the primary endpoint, with effects on binary efficacy endpoints summarized by afimkibart versus placebo difference between proportions. For other efficacy endpoints, the effect is generally a difference in a summary outcome measure, such as a mean score or mean change from baseline score.
Table 5. Secondary Objectives and Endpoints PATENT
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C. Exploratory objectives and endpoints
Exploratory objectives and corresponding endpoints are described in Table 6, below. Estimands for exploratory efficacy objectives are defined in a similar manner to those supporting primary and secondary objectives.
Table 6. Exploratory Objectives and Endpoints PATENT
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Example 2. Study Design
A. Overall design
The CS45570 study is a multicenter, Phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of afimkibart (study drug) in participants with moderate to severe atopic dermatitis (AD). The study evaluates three doses of afimkibart (450 mg, 150 mg, or 50 mg administered subcutaneously (SC)) versus placebo during the double-blind placebo-controlled period to Week 16. The assigned study doses during the double-blind placebo-controlled period are continued at the same dose in the blinded extension period in participants randomized to the study drug arms, while the placebo arm receives afimkibart at a dose of 450 mg SC during the blinded extension period from Week 16 to Week 32. The duration of study drug dosing is 30 weeks, with follow-up to Week 44. A study schema is provided in Fig. 1 .
Participants who meet eligibility criteria at Week 36 may have the option to receive afimkibart in a long-term extension study to further characterize the long-term safety and efficacy of afimkibart (see Examples 8-12).
Approximately 70 sites globally will participate to enroll approximately 160 participants.
The trial consists of a screening period up to 28 days; a double-blind, placebo-controlled period; a blinded extension period; and a post-treatment follow up period.
Topical therapies are discontinued at least 7 days prior to the baseline visit, except for bland emollients, which are at least once daily for at least 7 days prior to baseline.
After the screening period, eligible participants who meet the inclusion and exclusion criteria are randomized using permuted block randomization into four treatment arms (1 :1 :1 :1 ) and stratified by disease severity (Eczema Area and Severity Index (EASI) score 16 to 21 (moderate) vs. >21 (severe)) and by geographical location (North America (US/Canada) vs. rest of world).
In the double-blind placebo-controlled period, two loading doses of the assigned dose of afimkibart (450 mg, 150 mg, or 50 mg) or placebo are administered subcutaneously (SC) two weeks apart (i.e., at Week 0 and Week 2), followed by dosing every 4 weeks (Q4W) through to Week 16 to evaluate the efficacy and safety of afimkibart.
In order to assess treatment response and safety beyond 16 weeks of treatment, the double-blind placebo-controlled period is followed by a blinded extension period from Week 16 through to Week 32. During this period, participants who initially received placebo receive afimkibart at a dose of 450 mg SC and participants assigned to receive afimkibart continue with their originally assigned doses. To maintain blinding, blinded loading doses are administered at Week 16 and Week 18 to all patients. The study treatment administration schedule is provided in Table 7. PATENT
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Table 7. Study Treatment Administration Schedule
The study includes a post-treatment follow up period after Week 32, with a visit at Week 32 and then monthly follow-up visits at Weeks 4, 8, and 12 after the Week 32 visit to evaluate safety and durability of response after treatment discontinuation.
Participants who have worsening of disease, defined as (i) an EASI score increase of 25% or more from their baseline EASI score at any two consecutive scheduled study visits from Weeks 4-32 or (ii) no change from Baseline EASI score at Week 6, discontinue study treatment and receive standard of care rescue treatment, with choice of treatment at the investigator's discretion.
Efficacy is assessed by the primary endpoint of proportion of participants who achieve EASI-75 response (>75% improvement from baseline) at Week 16.
The secondary, exploratory, safety, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and other objectives and corresponding endpoints of this study are presented in Example 1 . Optional skin biopsies are collected from participants at baseline, Week 4, Week 16, and Week 32 for exploratory PD and biomarker analyses. Optional photographs of AD are collected from participants participating in optional skin biopsies at baseline, Week 16, and Week 32.
The total duration of study participation for an individual is expected to be approximately 48 weeks, including a screening period of up to 28 days.
B. Selection of study population
The CS45570 study assesses the efficacy and safety of afimkibart in adult patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies, such as (but not limited) to topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI), or for whom topical treatments are medically inadvisable (e.g. because of important side effects or safety risks).
Topical treatments, such as corticosteroids, calcineurin inhibitors, PDE-4 inhibitors and JAK PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 inhibitors are used commonly for treatment of mild to moderate AD, and as an adjunct therapy for persistent or relapsing AD lesions in cases not controlled by systemic agents (Sideris et al., J Clin Med, 11 : 4974, 2022).
Participants who do not respond or respond partially to topical treatments or have moderate to severe disease may benefit from systemic treatments. Approved systemic therapies to date include monoclonal antibodies targeting IL-4 and IL-13 (such as dupilumab) or targeting IL13 (such as tralokinumab), oral JAK inhibitors (abrocitinib, baricitinib, and upadacitinib), and cyclosporine. Phototherapy may also be used to treat AD.
Despite recent advances in the treatments for moderate to severe AD, there is still an unmet need for safe, well-tolerated, and effective treatments that target multiple pathways that contribute to the acute and chronic skin lesions of AD. Inhibiting TL1 A, a regulator of immune pathways and cytokine expression relevant to AD, may confer benefit in patients who have moderate to severe disease without general immunosuppression.
C. Dose and schedule
The doses for afimkibart in the CS45570 study are 50 mg, 150 mg, and 450 mg and are scheduled to be administered subcutaneously (SC) at Weeks 0, 2, 6, 10, 14, 16, 18, 22, 26, and 30. Subjects randomized to one of the active treatment arms receive afimkibart on Weeks 0 and 2 (loading regimen), and then receive a Q4W dosing regimen. Placebo is administered at Week 16 only in order to maintain the blind when participants originally assigned to placebo receive their first active loading dose in the blinded extension period. Subjects randomized to the placebo group switch to active treatment (afimkibart) on Weeks 16 and 18 (loading regimen), followed by a Q4W dosing regimen of afimkibart. This allows all study participants to receive active drug with the same dosing regimen, i.e. two loading doses two weeks apart followed by dosing Q4W. The dosing schedule with an initial Q2W loading regimen is designed to establish early pharmacokinetic (PK) steady state conditions and maximize onset of efficacy. This is followed by a Q4W dosing regimen to maintain exposure throughout the study.
Example s. Study Population
Approximately 160 adult patients with moderate to severe AD who have an investigator-reported history of inadequate response to a topical corticosteroid (TCS) or a topical calcineurin inhibitor (TCI) or for whom topical treatments are medically inadvisable (e.g. because of important side effects or safety risks) and who have not previously received dupilumab or topical or systemic JAK inhibitors are enrolled in the CS45570 study.
A. Inclusion criteria
Potential participants are eligible to be included in the study only if all of the following criteria apply.
I. General inclusion criteria
• Age > 18 years.
• Body weight >40 kg. PATENT
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• AD diagnosis confirmed by a dermatologist according to the Hanifin/Rajka criteria at least 1 year prior to screening.
• Moderate to severe atopic dermatitis (AD) as defined by:
- Eczema Area and Severity Index (EASI) score > 16 at screening and baseline visits,
- Investigator Global Assessment scale for Atopic Dermatitis (IGA) score > 3 (5-point scale) at screening and baseline visits, and
- AD involvement of >10% body surface area (BSA) at screening and baseline visits.
• Participant has an investigator-reported history (within 12 months of the screening visit) of inadequate response to TCS or TCI, or is one for whom topical treatments are otherwise medically inadvisable (e.g. because of important side effects or safety risks).
• At least once daily use of an additive-free, bland emollient for at least 7 days prior to the baseline visit and during the study.
B. Exclusion criteria
Potential participants are excluded from the study if any of the following criteria apply.
/. General exclusion criteria
• Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 95 days after the last dose of afimkibart.
//. AD-specific exclusion criteria
• Evidence of other skin conditions that would interfere with the assessment of AD, including, but not limited to, cutaneous T-cell lymphoma or allergic contact dermatitis.
• Prior or current treatment with any approved or investigational biologies.
• Past or current use of dupilumab or any systemic or topical JAK inhibitors.
Hi. Medical history-related exclusion criteria
• Lack of peripheral venous access.
• Any major surgery within 6 weeks prior to screening or a major surgery planned during the study.
• Any serious, chronic and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with the potential participant's safety, provision of informed consent, or compliance with trial procedures.
• Previous severe allergic reaction or anaphylactic reaction to biologic agents, including humanized, murine, or fully human monoclonal antibodies, or known hypersensitivity to any excipients of the study drug.
• Evidence of any new or uncontrolled concomitant disease that, in the investigator’s judgment, would preclude patient participation, including, but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders. PATENT
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• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 95 days after the final dose of the study drug.
• History of malignancy, with the exception non-metastatic basal cell or cutaneous squamous cell cancer adequately treated with electrodesiccation and curettage or resection or in situ cervical cancer adequately treated and cured. iv. Infection or infection risk exclusion criteria
• Any active infection or other active skin diseases that required treatment with parenteral anti-infectives within 4 weeks or oral anti-infective treatment within 2 weeks prior to baseline.
• Any active infection that required treatment with topical anti-infectives for AD within 7 days prior to baseline.
• Active tuberculosis requiring treatment within the 12 months prior to baseline.
• Evidence of acute or chronic hepatitis or known liver cirrhosis.
• Known immunodeficiency, including HIV infection.
• Positive HIV test at screening.
• Positive test results for hepatitis B infection at screening, defined as meeting either of the following criteria: (i) Positive hepatitis B surface antigen (HbsAg) test at screening; or (ii) quantitative HBV DNA above the lower limit of quantification in patients with a negative hepatitis B surface antibody (HbsAb) test and positive total hepatitis B core antibody (HbcAb) test.
• Positive hepatitis C virus (HCV) antibody test at screening
• Positive for tuberculosis (TB) during screening or within 3 months prior to screening, defined as a positive QUANTIFERON® TB-Gold test (QFT) or, if QFT is not available, a positive purified protein derivative (PPD) skin test according to local guidelines or regulations or other locally approved TB enzyme-linked immunosorbent assay (ELISA) tests (e.g., T-SPOT®), with the following exceptions:
- Potential participants with a history of Bacillus Calmette-Guerin vaccination who have a positive PPD skin test will not be excluded if they have a negative QFT at screening.
- Potential participants who have a positive or indeterminate QFT and those with no history of BCG vaccination who have a positive PPD skin test will not be excluded if they meet all the following criteria: no symptoms that are consistent with TB, documented history of a completed course of adequate prophylaxis (completed treated for latent TB) per local standard of care prior to screening, no known exposure to a case of active TB after most recent prophylaxis, and no evidence of active TB on chest X- ray performed during screening or within 3 months prior to screening.
• History of organ transplant.
• Acquired or congenital immunodeficiency. v. Laboratory results-related exclusion criteria
• Clinically significant abnormality on laboratory tests during screening (hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk in administering study treatment to the potential participant. PATENT
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• ALT, AST, or ALP > 2.5 x upper limit of normal (ULN), total bilirubin > 2 x ULN, or presence of abnormalities in synthetic liver function tests judged to be clinically significant by the investigator. Patients with known Gilbert syndrome who have unconjugated hyperbilirubinemia will not be excluded.
• ANC < 1.5 x 109/L (1500/pL) with one exception: Participants with benign ethnic neutropenia (BEN): ANC <1 .3 x 109/pL (1300/pL).
• Platelet count < 100,000/pL
• Hemoglobin < 8 g/dL.
• Absolute lymphocyte count < 500/pL. vi. Prohibited medication-related exclusion criteria
• Topical anti-infective for AD within 7 days prior to baseline.
• Prior or current treatment with any approved or investigational biologies, including but not limited to dupilumab, tralokinumab, and lebrikizumab.
• Past or current use of any systemic JAK inhibitors.
• Use of an investigational agent within 4 weeks or within 5 half-lives of the investigational agent, whichever is longer, prior to baseline.
• Intravenous (IV), intramuscular (IM), intralesional (IL), or orally administered corticosteroids (inhaled, ophthalmic drops, and nasal corticosteroids are allowed) within 4 weeks of the baseline visit and during the study.
• Use of one or more systemic therapies that are also used in the treatment of AD, including, but not limited to methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil within 4 weeks of the baseline visit and during the study.
• Phototherapy (including UVB, UVA, PUVA, UV laser) and tanning bed use within 4 weeks of the baseline visit and during the study.
• Topical treatment for AD including, but not limited to topical corticosteroids; topical calcineurin Inhibitors; topical PDE-4 inhibitors; and prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea or filaggrin within 7 days prior to the baseline visit and during the study.
• Oral or parenteral traditional Chinese or herbal medicines within 4 weeks prior to baseline.
• Participants must not have received any live vaccine within 4 weeks (or longer if required locally) prior to the first dose of study drug or expected need of live vaccination during study participation including at least 4 weeks (or longer if required locally) after the last dose of study drug.
Example 4. Trial Intervention and Concomitant Therapy
In the CS45570 study, “study treatment” refers to the combination of treatments assigned to participants as part of the study (i.e. , afimkibart and placebo). Table 8 provides a description of assigned study treatments. PATENT
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Table 8. Description of Trial Intervention
A. Investigational trial intervention administration
Administration of afimkibart is performed subcutaneously in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions. The post-dose observation period for SC injection is 30 minutes.
B. Participant assignment to investigational trial intervention, randomization, and blinding
The CS45570 study is a randomized, double-blind study. Participants are randomly assigned to one of four treatment arms: afimkibart at a dose of 450 mg, afimkibart at a dose of 150 mg, afimkibart at a dose of 50 mg, or placebo. Randomization occurs in a 1 :1 :1 :1 ratio through use of a permuted-block randomization method to ensure a balanced assignment to each treatment arm. The stratification factors are disease severity (EASI score 16 to 21 (moderate) vs. >21 (severe)) and geographical location (North America (US/Canada) vs. rest of world. Study site personnel and participants are blinded to treatment assignment during the study.
C. Concomitant therapy
Permitted and prohibited concomitant therapies for AD are outlined in Table 9. Permitted and prohibited concomitant therapies not related to AD are outlined in Table 10. In general, investigators may manage a participant's care (including preexisting conditions) through use of supportive therapies, as clinically indicated and per local standard practice, with the exception of prohibited therapies defined in Tables 9 and 10.
Table 9. Permitted and Prohibited Concomitant Therapies Related to AD PATENT
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Table 10. Permitted and Prohibited Concomitant Therapies Not Related to AD
Example 5. Study Assessments and Procedures A. Clinical outcome assessments
Patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) instruments are completed to assess the treatment benefit of afimkibart.
ClinRO data are collected through use of the following instruments, which are performed in the following order: • Validated Investigator Global Assessment (vIGA).
• Eczema Area and Severity Index (EASI).
• body surface area assessment (BSA).
PRO data are collected through use of the following instruments: • Dermatology Life Quality Index (DLQI).
• Peak Pruritus Numerical Rating Scale (PP-NRS).
• Patient Oriented Eczema Measure (POEM). PATENT
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/. EASI
The Eczema Area and Severity Index (EASI) is a validated, standardized tool (Hanifin et al., Dermatitis, 33: 187-192, 2022) that grades the area and severity of AD signs across 4 body regions, with scores ranging from 0 to 72 and higher values indicating more severe disease. The EASI has demonstrated responsiveness and intra-observer and inter-observer reliability for use in clinical trials. The EASI takes approximately 6 minutes when performed by a trained investigator. The efficacy assessor should be a dermatologist or skilled physician AD assessor.
The validated Investigator Global Assessment (vIGA) is a standardized static assessment of the overall severity of the participant’s AD. The vIGA is a 5-point scale ranging from 0 (clear) to 4 (severe) (Table 1 1 ). A score is selected from morphological descriptors that best describe the overall appearance of AD lesions at a given timepoint. The vIGA has demonstrated reliability and responsiveness for use in clinical trials. The vIGA must be conducted prior to the EASI and BSA assessments. The efficacy assessor should be a dermatologist or skilled physician AD assessor.
Table 11. vIGA
Hi. BSA
The body surface area (BSA) assessment is a clinician estimation of the total percentage of BSA involved with AD. It does not incorporate lesion severity. BSA is determined by the dermatologist or skilled physician AD assessor using the anterior surface of the participant’s hand as a guide. iv. DLQI
The Dermatology Life Quality Index (DLQI) is a ten-item, validated, participant-reported questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on health-related quality of life (HRQoL) (Badia et al., Br J Dermatol., 141 : 698-702, 1999). The DLQI covers six domains: symptoms and feelings (two items), daily activities (two items), leisure (two items), work and school (one item), personal relationships (two items), and treatment (one item). Each item has a one-week recall period (i.e., last seven days). The response options are dichotomous: Yes/No and 3- and 4-point Likert/Likert-type scale (0 to 3 where 0 is “not at all” and 3 is “very much”) with a total PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 score of 0 to 30; a low score equals better HRQoL. The DLQI takes approximately two minutes to complete. v. PP-NRS
The Peak Pruritus Numerical Rating Scale (PP-NRS) is a single-item, validated, participant- reported assessment to evaluate the worst itch intensity in adults with moderate-to-severe AD during the previous 24 hours (Yosipovitch et al., Br J Dermatol, 181 : 761 -769, 2019). The item response is reported on an 1 1 -point scale ranging from “no itch” to “worst itch imaginable.” The PP-NRS takes approximately one minute to complete. The PP-NRS is collected daily during screening in the seven days immediately before randomization and throughout the study. vi. POEM
The Patient Oriented Eczema Measure (POEM) is a seven-item, validated, participant-reported questionnaire for monitoring AD severity. It focuses on signs and symptoms experienced by the participant and monitors disease activity. POEM has been recommended for use by clinical guidelines including those issued by the National Institute for Health and Care Excellence (NICE). It is also recommended by the Harmonizing Outcome Measures for Eczema (HOME) initiative as the core outcome instrument for measuring participant-reported symptoms in AD trials. The domain is unidimensional: AD disease activity. Each item has a one-week recall period (i.e. last seven days). Response options are on a 5-point Likert/Likert-type scale (0 to 4 where 0 is “no days” and 4 is “every day”) with a total score of 0 to 28; a low score equals better HRQoL. The POEM takes approximately one to two minutes to complete.
Example 6. Statistical Considerations
This Example provides a summary of the statistical aspects of the CS45570 study design and the general approach to analysis of endpoints supporting the study objectives.
A. Statistical hypotheses
Under the primary objective for the study, it is hypothesized that 450 mg afimkibart is superior to placebo in achieving a reduction in the EASI score. In statistical testing the relevant null and alternative hypotheses are formulated as follows:
HO: pAfimkibart - pPIacebo =0 versus HA: pAfimkibart - pPIacebo 0, where pAfimkibart - pPIacebo represents the treatment effect (estimand) of interest, the difference in the proportion of participants achieving EASI-75 at a particular timepoint (Week 16) after assignment to afimkibart 450 mg versus placebo.
The study is considered positive if the null hypotheses based on EASI-75 at Week 16 is rejected in favor of afimkibart 450 mg. The two-sided tests are carried out at the 10% significance level. Tests are not prioritized into a hierarchy and there is no Type 1 error control.
Tests on secondary endpoints consider null and alternative hypotheses like those defined for the primary endpoint above. For secondary efficacy endpoints that correspond to a continuous PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 measurement, the treatment effect is generally summarized by a difference in mean outcome. Where a continuous endpoint has a relevant baseline measurement, the treatment arm means for the change from baseline may be estimated for interpretability.
The change from baseline in EASI-75 response at Week 16 is included in the dose response assessment. The dose-response relationship is assessed using a MCP-mod approach (Bretz et al., Biometrics, 61 : 738-748, 2005). The candidate models are fitted to the EASI-75 response at Week 16 and multiple contrast tests (two-sided a=0.1 ) are produced along with the corresponding multiplicity adjusted p-values. From the statistically significant candidate models, the most appropriate (based on Akaike information criterion (AIC)) is selected.
B. Sample size determination
The primary analysis tests afimkibart 450 mg vs. placebo. A total of approximately 80 participants are randomized 1 :1 to either afimkibart 450 mg or placebo. The expected proportion of participants with an EASI-75 response at Week 16 on the placebo arm is 15%, and the expected proportion of participants with an EASI-75 response at Week 16 on the afimkibart 450 mg arm is 50%. Based on these assumptions and using Fisher’s exact test with a 0.1 two-sided significance level and a sample size of 40 per treatment group, and an overall discontinuation rate of about 20%, the study has approximately 90% power to detect a statistically significant difference between the two proportions.
The total sample size of 160 participants, with discontinuations around 20%, provides approximately 90% power of observing a positive dose response curve using a two-sided alpha level of 0.1 , and assuming a placebo EASI-75 response of 15% and active afimkibart response of 50%, i.e., a delta effect size of 35%.
C. Analysis sets
The participant analysis sets for the purposes of analyses are defined in Table 12.
Each planned analysis incorporates data from a particular set of participants. These participant analysis sets are broadly defined in Table 12. In general, the relevant data for a given participant in an analysis set may consider all measurements for parameters under analysis, from baseline up to the timing of the endpoint in question, such as Week 16 for the primary and secondary endpoints and Week 32 for certain secondary endpoints.
Table 12. Analysis data sets PATENT
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Example 7. Selection of the Dosing Regimen
As discussed in Examples 1 -6, above, the doses for afimkibart in the CS45570 study are 50 mg, 150 mg, and 450 mg, administered subcutaneously (SC). Subjects randomized to one of the active treatment arms receive afimkibart on Weeks 0 and 2 (“loading regimen”) and then monthly (every 4 weeks (Q4W)) from Week 6 to Week 30 (see Table 7). As is discussed in further detail below, this dosing regimen is optimized to rapidly achieve efficacious concentrations of afimkibart by Week 2, thereby increasing the likelihood of an early onset of action in inflamed tissues in atopic dermatitis.
A. Rationale and methodology
The dosing regimen selected for the CS45570 study incorporates prior knowledge (pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety data) from studies conducted with afimkibart in healthy participants ( NCT01989143 (B7541001 ), NCT04269538 (B7541006), and NCT05107492 (B7541013)) and participants with ulcerative colitis (UC) ( NCT02840721 (B7541002), NCT0409041 1 (B7541007)).
A population PK/PD model was developed to jointly characterize the pharmacokinetics (PK, measured from total soluble TL1 A level in serum) and pharmacodynamics (PD, measured from antibodybound TL1 A level in serum as an estimate for TL1 A target engagement) of afimkibart in Phase 1 and Phase 2 trials using a two-compartment model with first-order subcutaneous absorption, quasi steady state approximated target-mediated clearance, and an additional nonlinear, time-dependent clearance component to account for potential impact of ADAs (anti-drug antibodies) on PK and PD. This population PK/PD model was used to estimate individual participants’ PK parameters and individual PK and individual PD profiles in serum for participants with atopic dermatitis in the CS45570 study.
Factors known to affect monoclonal antibodies’ PK and drug exposure in immune diseases (including inflammatory bowel disease (IBD) and atopic dermatitis) include patient-related and disease- related covariates, as well as target distribution (soluble and membrane-associated antigens). Factors influencing PK in ulcerative colitis (UC) include body size, inflammatory burden, concomitant immunosuppression, and immunogenicity.
In the population PK/PD model for afimkibart, weight, baseline serum albumin, and positive ADA status were identified as covariates on afimkibart PK that can explain variability in PK.
Similar covariates are assumed to be relevant for patients with atopic dermatitis and with UC, including similar TL1 A expression for both indications.
The following dosing regimens of afimkibart were evaluated as appropriate for the CS45570 study:
1 . Option 1 : SC dosing on Weeks 0, 1 , 2, 6, 10 and 14 (PK/PD profiles shown in Figs. 2A and 2B), followed by monthly dosing. PATENT
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2. Option 2: SC dosing on Weeks 0, 2, 6, 10 and 14 (PK/PD profiles in Figs. 3A and 3B), followed by monthly dosing.
The reference PK/PD profiles for the 50 mg, 150 mg, and 450 mg SC regimens from the Phase 2b Study NCT04090411 (B7541007) in UC (dosing on Weeks 0, 4, 8, 12, 16, then monthly) are shown in Figs. 4A and 4B.
In Study NCT04090411 (B7541007) (UC), steady-state conditions for PK are achieved by Week 8 (Fig. 4A), with full target engagement observed at the 150 mg and 450 mg regimens (Fig. 4B).
For the selected dosing regimen in the CS45570 study (50 mg, 150 mg, or 450 mg SC on Weeks 0, 2, 6, 10, and 14; Option 2), steady-state conditions for PK are established by Week 2 (Fig. 3A), which is likely to enhance the likelihood of an early onset of action in atopic dermatitis.
An additional dose on Week 1 (Option 1 ; Figs. 2A and 2B) results in higher trough concentrations at Week 2 (Fig. 2A) compared to Option 2. However, this increase is not substantial enough to offer a significant benefit when weighed against the increased burden on the patient that would result from weekly dosing for the first three doses.
The extent and duration of target engagement (TL1 A suppression in serum) for Option 1 (Fig. 2B) and Option 2 (Fig. 3B) are similar, with full target engagement observed at the 150 mg and 450 mg regimens.
Example 8. An Extension Study to Evaluate the Long-Term Safety and Efficacy of Afimkibart in Patients with Atopic Dermatitis who Participated in Previous Afimkibart Clinical Trials
The CS45943 study provided in Examples 8-12 is a long-term extension study designed to assess the long-term safety and efficacy of continuous monthly subcutaneous (SC) dosing of afimkibart (formerly PF 06480605, RVT-3101 , or RO7790121 ) in patients with moderate to severe atopic dermatitis (AD) who completed the CS45570 study described in Examples 1 -6 (“the parent study”) and responded to afimkibart treatment in that study.
Though recent advancements in therapies in AD have improved outcomes, long-term disease control and efficacy off-treatment is not always achieved. In order to address this important medical need for a safe and efficacious long-term therapy, the purpose of this long-term extension study is to assess the long-term safety and efficacy of afimkibart in participants with moderate to severe AD who received afimkibart during the CS45570 study. The CS45943 study evaluates a longer treatment duration for safety and efficacy and dose escalation when necessary to achieve optimal treatment benefit.
A. Primary objective and corresponding estimand/endpoint
The primary objective of the CS45943 study is to evaluate the long-term safety and tolerability of afimkibart (see Table 13). PATENT
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Table 13. Primary Objective and Corresponding Estimand/Endpoint
Table 14. Strategies for Anticipated Intercurrent Events (ICE) B. Secondary objectives and corresponding estimands
The key secondary objective of the CS45943 study is provided in Table 15. PATENT
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Table 15. Key Secondary Objective and Corresponding Estimands/Endpoints
Other secondary objectives of the CS45943 study are provided in Table 16.
Table 16. Other Secondary Objectives and Corresponding Estimands/Endpoints
Example 9. Extension Study Design
The design of the CS45943 study is summarized below.
A. Study CS45570 (Phase lib) Participants
In order to maintain the blind in the ongoing parent study CS45570, there is a blinded period until the database lock of the parent study (approximately 14 months), followed by an open-label treatment period. PATENT
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To be eligible for the CS45943 long-term extension (LTE) study, participants from study CS45570 (the parent study) must have adequately completed the assessments and visits required in the parent study and achieved an EASI50 response relative to baseline at the Week 36 visit of the parent study.
Approximately 120 participants enrolled from approximately 70 sites globally from the parent study CS45570 are anticipated to enroll into the LTE study. The duration of the study drug dosing will be approximately 6 years. For participants who roll over from the parent study CS45570, the baseline visit for study CS45943 is to occur on the same day as the Week 36 follow-up visit in the parent study, at which the participant is screened for eligibility by the Investigator. Assessments that are common to both studies at the Week 36 follow up visit in study CS45570 and the baseline visit in Study CS45943 are performed only once. All required assessments in Study CS45570 should be completed before enrollment in the long-term extension study.
B. Study CS45943 (LTE)
The CS45943 study evaluates the long-term safety and tolerability of two different doses of afimkibart (450 mg or 150 mg administered SC) during a blinded period and an open-label period. The blinded period continues until the database lock of the parent study. After the database lock, participants receive open-label treatment.
Participants assigned to the 50 mg or 150 mg SC dose in the parent study CS45570 (see Examples 1 -6) receive afimkibart at a dose of 150 mg SC, and participants assigned to the 450 mg SC dose in the parent study continue on their assigned dose of 450 mg SC.
At treatment initiation in Study CS45493, two loading doses of the assigned dose of afimkibart (450 mg or 150 mg) are administered subcutaneously (SC) 2 weeks apart (i.e. , at Week 0 and Week 2) followed by dosing every 4 weeks (Q4W) to evaluate the safety, tolerability, and efficacy of afimkibart.
The use of rescue medications for AD is allowed at any time from Week 8 of the study at investigator discretion, if the participant’s EASI response is < EASI50, i.e. a less than 50% reduction in their EASI score from their baseline EASI in the parent study. Treatment with afimkibart may be continued if permitted rescue medication is administered. The study drug must be discontinued if a prohibited medication is administered as rescue therapy.
Participants who do not respond to permitted rescue medication in the investigator’s judgement during the blinded period are to discontinue the study. During the open-label period, participants on 150 mg SC are offered dose escalation to the highest dose of 450 mg SC. Participants already on the highest dose 450 mg who do not respond to permitted rescue medication are to discontinue the study. Dose escalation is available only in the open-label period, and not in the blinded period, in order to maintain the blind of the parent study.
Safety and tolerability are determined by assessment of the incidence and severity of adverse events, serious adverse events, adverse events leading to study treatment discontinuation, and adverse events of special interest.
The secondary efficacy, safety, PK, immunogenicity, and other objectives and corresponding endpoints of the study are found in Tables 13, 15, and 16, above.
A study schema is provided in Fig. 5. PATENT
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C. Duration of Participation
Treatment for a participant in the CS45943 study is expected to continue for up to approximately 6 years or when commercialization occurs in every participating country.
D. Rationale for Trial Design
AD is a chronic, pruritic inflammatory skin condition characterized by intermittent flares and requires long-term management. Therefore, the CS45943 study further assesses the benefit and risk of afimkibart by assessing the long-term safety, tolerability and efficacy of afimkibart in adult participants with moderate to severe AD who responded to treatment with afimkibart in the CS45570 parent study.
As patients start this long-term extension study 6 weeks after completion of the parent study treatment, the study will provide safety and efficacy information on re-loading and exposure to afimkibart, particularly regarding the evolution of immunogenicity and by further characterizing the relationships between ADAs, afimkibart PK, and clinical parameters.
Example 10. Extension Study Population
Approximately 120 participants from Study CS45570 are enrolled in the CS45943 study.
A. Inclusion Criteria
Potential participants are eligible to be included in the study only if all of the following criteria apply.
/. Parent Clinical Trial-Specific Inclusion Criteria
Participants must be study CS45570 participants who:
- Completed the treatment period of the parent study.
- Continued to be evaluated at the Week 36 follow up visit and achieved > EASI50 response from study baseline.
- Have a body weight > 40 kg.
B. Exclusion criteria
Potential participants are excluded from the study if any of the following criteria apply.
/. General exclusion criteria
• Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 95 days after the last dose of afimkibart.
//. Parent Clinical Trial-Specific Inclusion Criteria
• Withdrawal of consent and/or premature discontinuation from parent study.
• Any permanent discontinuation of study drug in parent study.
• Investigator determination that treatment discontinuation is in the best interest of the participant. PATENT
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• Use of a prohibited therapy during the parent study.
• History of severe allergic reaction or anaphylactic reaction to any biologic agent or known hypersensitivity to any component of afimkibart.
Hi. AD-specific exclusion criteria
• Evidence of other skin conditions that would interfere with the assessment of AD, including, but not limited to, cutaneous T-cell lymphoma or allergic contact dermatitis. iv. Medical history-related exclusion criteria
• Lack of peripheral venous access.
• Any major surgery within 6 weeks prior to screening or a major surgery planned during the study.
• Evidence of any new or uncontrolled concomitant disease that, in the investigator’s judgment, would preclude patient participation, including, but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders.
• History of malignancy, with the exception non-metastatic basal cell or cutaneous squamous cell cancer adequately treated with electrodesiccation and curettage or resection or in situ cervical cancer adequately treated and cured. v. Infection or infection risk exclusion criteria
• Active tuberculosis requiring treatment within the 12 months prior to baseline.
• Evidence of acute or chronic hepatitis or known liver cirrhosis.
• Known immunodeficiency, including HIV infection or HIV seropositivity.
• Known history of positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody.
• Positive for tuberculosis (TB) during screening or within 3 months prior to screening, defined as a positive QUANTIFERON® TB-Gold test (QFT) or, if QFT is not available, a positive purified protein derivative (PPD) skin test according to local guidelines or regulations or other locally approved TB enzyme-linked immunosorbent assay (ELISA) tests (e.g., T-SPOT®), with the following exceptions:
- Potential participants with a history of Bacillus Calmette-Guerin vaccination who have a positive PPD skin test will not be excluded if they have a negative QFT at screening.
- Potential participants who have a positive or indeterminate QFT and those with no history of BCG vaccination who have a positive PPD skin test will not be excluded if they meet all the following criteria: no symptoms that are consistent with TB, documented history of a completed course of adequate prophylaxis (completed treated for latent TB) per local standard of care prior to screening, no known exposure to a case of active TB after most recent prophylaxis, and no evidence of active TB on chest X- ray performed during screening or within 3 months prior to screening. vi. Laboratory results-related exclusion criteria
• Clinically significant abnormality on laboratory tests during screening (hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk in administering study treatment to the potential participant. PATENT
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• ALT, AST, or ALP > 2.5 x upper limit of normal (ULN), total bilirubin > 2 x ULN, or presence of abnormalities in synthetic liver function tests judged to be clinically significant by the investigator. Patients with known Gilbert syndrome who have unconjugated hyperbilirubinemia will not be excluded.
• ANC < 1 .5 x 109/L (1500/pL) with one exception: Participants with benign ethnic neutropenia (BEN): ANC <1 .3 x 109/pL (1300/pL).
• Platelet count < 100,000/pL
• Hemoglobin < 8 g/dL.
• Absolute lymphocyte count < 500/pL.
Example 11. Trial Intervention and Concomitant Therapy
In the CS45943 study, “study treatment” refers to treatments assigned to participants as part of the study (i.e., afimkibart). Table 17 provides a description of assigned study treatments.
Table 17. Description of Trial Intervention
A. Investigational trial intervention administration
Administration of afimkibart is performed subcutaneously in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions. The post-dose observation period for SC injection is 30 minutes.
B. Randomization
Participants are not randomized. Instead, participants assigned to a 50 mg dose in the parent study receive a 150 mg dose in the long-term extension study, while all other treatment arms continue receiving the treatment they were assigned in the parent study double-blind extension phase.
C. Blinding
In order to maintain the blinding of the parent study, until the date of the primary readout of the parent study (Week 16 data for all subjects), the treatment assignment in the long-term extension study remains blinded to site personnel (with the exception of the unblinded pharmacist), participants, and the Sponsor and its agents, with the exception of individuals who require access to participant treatment assignments to fulfill their job roles. After unblinding of the Sponsor, participants and site personnel remain blinded until the readout of the blinded extension of the parent study (Week 32 for all subjects). PATENT
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D. Concomitant Topical Therapy for Atopic Dermatitis
In addition to moisturizers (emollients) received in study CS45570, which are continued in the CS45943 study, the study site supplies the following concomitant medications for atopic dermatitis that may be used if the participant experiences loss of response, defined as <EASI50:
• Topical corticosteroids (TCS).
• Topical calcineurin inhibitors (TCI).
• Topical PDE4 inhibitors (PDE4i).
The choice of TCS, TCI, and/or PDE4i, as well as formulation (e.g. cream, ointment), potency, and duration, is at the investigator’s discretion and according to local practice.
The above topical medications may be administered at any time from Week 8 of the study if the participant has < EASI50, i.e. a less than 50% reduction in their EASI score from their baseline EASI in the parent study. Administration of the study drug may be continued while the above allowed topical medication(s) is administered.
During the open label period of the long-term extension, dose escalation to 450 mg Q4W for participants on 150 mg Q4W will be allowed if the participant develops < EASI50, i.e. less than 50% reduction in their EASI score from their baseline EASI in the parent study. If despite dose escalation, there has been no improvement or the disease is worsening at the next scheduled or unscheduled visit, any of the allowed topical therapies for atopic dermatitis may be added adjunctively, or the participant may be treated with another locally approved atopic dermatitis medication. Those participants who are already receiving 450 mg Q4W are not eligible for dose escalation. If, however, a participant requires therapy that is on the prohibited medications list (Table 18), they will need to discontinue study drug and be withdrawn from the study.
E. Concomitant Therapy
Permitted and prohibited concomitant therapies for atopic dermatitis are provided in Table 18.
Permitted and prohibited concomitant therapies not related to atopic dermatitis are provided in Table 19.
Table 18. Permitted and Prohibited Concomitant Therapies Related to Atopic Dermatitis PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
Table 19. Permitted and Prohibited Concomitant Therapies Not Related to Atopic Dermatitis
Example 12. Study Assessments and Procedures
A. Efficacy clinical outcome assessments
Participant-reported outcome (PRO) and clinician-reported outcome (ClinRO) instruments are completed to assess the treatment benefit of afimkibart. Assessments by the participant (PRO) are made before the clinician assessments (ClinRO). PRO data is collected through use of the following instruments: Dermatology Life Quality Index (DLQI) and Patient Oriented Eczema Measure (POEM).
ClinRO data is collected through use of the following instruments, and the clinician assessments are performed in the following order:
1 . Validated Investigator Global Assessment scale (vIGA) for Atopic Dermatitis.
2. Eczema Area and Severity Index (EASI).
The DLQI, POEM, EASI, and vIGA are each described in Example 5, above.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

PATENT Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 WHAT IS CLAIMED IS:
1 . A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti- TL1 A antibody is administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs):
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
2. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
3. The method of claim 1 or 2, wherein:
(a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0 of the dosing regimen; and
(b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 of the dosing regimen. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
4. The method of any one of claims 1 -3, wherein each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg.
5. The method of any one of claims 1 -4, wherein each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg.
6. The method of any one of claims 1 -4, wherein each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg.
7. The method of any one of claims 1 -5, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg.
8. The method of any one of claims 1 -6, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg.
9. The method of any one of claims 1 -4 and 6, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg.
10. The method of any one of claims 1 -9, wherein at least five doses of the anti-TL1 A antibody are subcutaneously administered to the patient.
1 1 . The method of claim 10, wherein, following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks.
12. The method of any one of claims 1 -1 1 , wherein the dosing regimen comprises five subcutaneous doses of the anti-TL1 A antibody.
13. The method of claim 12, wherein the dosing regimen consists of five subcutaneous doses of the anti-TL1 A antibody.
14. The method of any one of claims 1 -13, wherein the dosing regimen has a duration of about 16 weeks.
15. The method of claim 14, wherein:
(a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen;
(b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen;
(c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen;
(d) the fourth dose is administered on about Day 1 of Week 10 of the dosing regimen; and
(e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
16. The method of any one of claims 1 -12, wherein the dosing regimen comprises nine subcutaneous doses of the anti-TL1 A antibody.
17. The method of claim 16, wherein the dosing regimen consists of nine subcutaneous doses of the anti-TL1 A antibody.
18. The method of any one of claims 1 -12, 16, and 17, wherein the dosing regimen has a duration of about 32 weeks.
19. The method of claim 18, wherein:
(a) the first dose is administered on about Day 1 of Week 0 of the dosing regimen;
(b) the second dose is administered on about Day 1 of Week 2 of the dosing regimen;
(c) the third dose is administered on about Day 1 of Week 6 of the dosing regimen;
(d) the fourth dose is administered on about Day 1 of Week 10 of the dosing regimen;
(e) the fifth dose is administered on about Day 1 of Week 14 of the dosing regimen;
(f) the sixth dose is administered on about Day 1 of Week 18 of the dosing regimen;
(g) the seventh dose is administered on about Day 1 of Week 22 of the dosing regimen;
(h) the eighth dose is administered on about Day 1 of Week 26 of the dosing regimen; and
(i) the ninth dose is administered on about Day 1 of Week 30 of the dosing regimen.
20. The method of any one of claims 1 -12 and 16-19, wherein the method further comprises:
(i) determining that the patient has responded to treatment with the anti-TL1 A antibody following the dosing regimen; and
(ii) administering to the patient an effective amount of the anti-TL1 A antibody in a second dosing regimen.
21 . The method of claim 20, wherein response to treatment with the anti-TL1 A antibody is a reduction of a post-treatment Eczema Area and Severity Index (EASI) by at least 50% relative to a pre-treatment EASI.
22. The method of claim 21 , wherein the dosing regimen has a duration of about 32 weeks, and wherein the post-treatment EASI is determined about 36 weeks after administration of the first dose of the anti-TL1 A antibody in the dosing regimen.
23. The method of any one of claims 20-22, wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last previous dose of the anti-TL1 A antibody.
24. The method of any one of claims 20-23, wherein the second dosing regimen comprises subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein: PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose.
25. The method of claim 24, wherein:
(a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0 of the second dosing regimen; and
(b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 of the second dosing regimen.
26. The method of any one of claims 20-25, wherein each dose of the anti-TL1 A antibody in the second dosing regimen is administered at a dose of between about 150 mg and about 450 mg.
27. The method of any one of claims 20-26, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg.
28. The method of any one of claims 20-26, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg.
29. The method of any one of claims 24-26, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg or about 450 mg, and the first and second doses of the second dosing regimen are each about 150 mg.
30. The method of any one of claims 20-29, wherein at least four doses of the anti-TL1 A antibody are subcutaneously administered to the patient in the second dosing regimen.
31 . The method of claim 30, wherein, following the administration of the first and second doses in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks.
32. The method of any one of claims 20-31 , wherein the second dosing regimen has a duration of at least one year.
33. The method of claim 32, wherein the second dosing regimen has a duration of about six years.
34. The method of any one of claims 1 -33, wherein the atopic dermatitis is moderate to severe atopic dermatitis.
35. The method of claim 34, wherein the patient has an Eczema Area and Severity Index (EASI) score of at least 16. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
36. The method of claim 34 or 35, wherein the patient has an Investigator Global Assessment (IGA) scale score for atopic dermatitis of at least 3.
37. The method of any one of claims 34-36, wherein the patient has atopic dermatitis involvement of at least 10% of their body surface area.
38. The method of any one of claims 1 -37, wherein:
(i) the patient has previously been treated with a therapy selected from a topical corticosteroid (TCS) and a topical calcineurin inhibitor (TCI) and has experienced inadequate response to the therapy; or
(ii) the patient is one for whom a topical treatment is medically inadvisable.
39. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
40. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
41 . A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
42. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
43. The method of any one of claims 1 -11 , 20, 21 , and 23-42, wherein, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved at least a 75% improvement in EASI score as compared to a reference population. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
44. The method of claim 43, wherein the dosing regimen has a duration of about 16 weeks, and the treating results in an increase in the proportion of patients who have achieved at least a 75% improvement in EASI score at Week 16.
45. The method of claim 43, wherein the dosing regimen has a duration of about 32 weeks, and the treating results in an increase in the proportion of patients who have achieved at least a 75% improvement in EASI score at Week 32.
46. The method of any one of claims 1 -11 , 20, 21 , and 23-42, wherein, in a population of patients treated according to the method, the treating results in an increase in the proportion of patients who have achieved a response as compared to a reference population.
47. The method of claim 46, wherein the dosing regimen has a duration of about 16 weeks, and the treating results in an increase in the proportion of patients who have achieved a response at Week 16.
48. The method of claim 46, wherein the dosing regimen has a duration of about 32 weeks, and the treating results in an increase in the proportion of patients who have achieved a response at Week 32.
49. The method of any one of claims 46-48, wherein the response is:
(i) an IGA scale score of 0 or 1 with an improvement of at least two grades relative to a baseline IGA score;
(ii) at least a 75% improvement in EASI score; or
(Hi) at least a 90% improvement in EASI score.
50. The method of any one of claims 43-49, wherein the reference population is a population of patients who have not been treated with an anti-TL1 A antibody.
51 . The method of claim 50, wherein the reference population is a population of patients who have been treated with a placebo.
52. The method of any one of claims 1 -51 , wherein the anti-TL1 A antibody comprises:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and/or
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.
53. The method of claim 52, wherein the anti-TL1 A antibody comprises:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and/or
(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
54. The method of claim 53, wherein the anti-TL1 A antibody comprises:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and
(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.
55. The method of any one of claims 1 -54, wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1 1 ; and/or
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10.
56. The method of claim 55, wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and/or
(b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
57. The method of claim 56, wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and
(b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.
58. The method of any one of claims 1 -57, wherein the anti-TL1 A antibody is afimkibart.
59. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
60. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
61 . The method of claim 59 or 60, wherein each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 450 mg.
62. The method of any one of claims 59-61 , wherein each dose of the anti-TL1 A antibody is administered at a dose of between about 50 mg and about 150 mg.
63. The method of any one of claims 59-61 , wherein each dose of the anti-TL1 A antibody is administered at a dose of between about 150 mg and about 450 mg.
64. The method of any one of claims 59-62, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg.
65. The method of any one of claims 59-63, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 150 mg.
66. The method of any one of claims 59-61 and 63, wherein each dose of the anti-TL1 A antibody is administered at a dose of about 450 mg.
67. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody in the first dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and
(ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the first dosing regimen; and
(iii) the first dosing regimen has a duration of about 32 weeks; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody in the second dosing regimen is administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and
(ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks in the second dosing regimen; PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
68. A method of treating atopic dermatitis in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein:
(a) the first dose is administered on about Day 1 of Week 0 of the first dosing regimen;
(b) the second dose is administered on about Day 1 of Week 2 of the first dosing regimen;
(c) the third dose is administered on about Day 1 of Week 6 of the first dosing regimen;
(d) the fourth dose is administered on about Day 1 of Week 10 of the first dosing regimen;
(e) the fifth dose is administered on about Day 1 of Week 14 of the first dosing regimen;
(f) the sixth dose is administered on about Day 1 of Week 18 of the first dosing regimen;
(g) the seventh dose is administered on about Day 1 of Week 22 of the first dosing regimen;
(h) the eighth dose is administered on about Day 1 of Week 26 of the first dosing regimen; and
(i) the ninth dose is administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein:
(a) the first dose is administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen;
(b) the second dose is administered on about Day 1 of Week 2 of the second dosing regimen; and
(c) following the administration of the first and second doses, the anti-TL1 A antibody is administered to the patient subcutaneously every four weeks; the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
69. The method of any one of claims 1 -68, wherein the patient is a human.
70. A kit comprising an anti-TNF-like ligand 1 A (TL1 A) antibody and a package insert comprising instructions for using the antibody for treating atopic dermatitis in a patient in need thereof according to the method of any one of claims 1 -69.
71 . An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti- TL1 A antibody is to be administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
72. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
73. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
74. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
75. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
76. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
77. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti- TL1 A antibody is to be administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
78. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
79. The anti-TL1 A antibody for use of claim 77 or 78, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 450 mg.
80. The anti-TL1 A antibody for use of any one of claims 77-79, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 150 mg.
81 . The anti-TL1 A antibody for use of any one of claims 77-79, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of between about 150 mg and about 450 mg.
82. The anti-TL1 A antibody for use of any one of claims 77-81 , wherein each dose of the anti-TL1 A antibody is to be administered at a dose of about 50 mg.
83. The anti-TL1 A antibody for use of any one of claims 77-81 , wherein each dose of the anti-TL1 A antibody is to be administered at a dose of about 150 mg.
84. The anti-TL1 A antibody for use of any one of claims 77-79 and 81 , wherein each dose of the anti- TL1 A antibody is to be administered at a dose of about 450 mg.
85. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody in the first dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and
(ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the first dosing regimen; and
(iii) the first dosing regimen has a duration of about 32 weeks; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein: PATENT
Genentech Docket No: P39491 -WO-1
Attorney Docket No: 50474-365WO3
(i) the second dose of the anti-TL1 A antibody in the second dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and
(ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is to be administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
86. An anti-TL1 A antibody for use in treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein:
(a) the first dose is to be administered on about Day 1 of Week 0 of the first dosing regimen;
(b) the second dose is to be administered on about Day 1 of Week 2 of the first dosing regimen;
(c) the third dose is to be administered on about Day 1 of Week 6 of the first dosing regimen;
(d) the fourth dose is to be administered on about Day 1 of Week 10 of the first dosing regimen;
(e) the fifth dose is to be administered on about Day 1 of Week 14 of the first dosing regimen;
(f) the sixth dose is to be administered on about Day 1 of Week 18 of the first dosing regimen;
(g) the seventh dose is to be administered on about Day 1 of Week 22 of the first dosing regimen;
(h) the eighth dose is to be administered on about Day 1 of Week 26 of the first dosing regimen; and
(i) the ninth dose is to be administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein:
(a) the first dose is to be administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen;
(b) the second dose is to be administered on about Day 1 of Week 2 of the second dosing regimen; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(c) following the administration of the first and second doses, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks; the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
87. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
88. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
89. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is between 50 mg and 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
90. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 50 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
91 . Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 150 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
92. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein each dose of the anti-TL1 A antibody is about 450 mg; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
93. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising subcutaneous administration of two doses of the anti-TL1 A antibody, wherein the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose, and wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
94. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3 dosing regimen comprising subcutaneous administration of at least three doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; and
(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; wherein the anti-TL1 A antibody comprises:
(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and
(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.
95. The use of claim 93 or 94, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 450 mg.
96. The use of any one of claims 93-95, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of between about 50 mg and about 150 mg.
97. The use of any one of claims 93-95, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of between about 150 mg and about 450 mg.
98. The use of any one of claims 93-95, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of about 50 mg.
99. The use of any one of claims 93-97, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of about 150 mg.
100. The use of any one of claims 93-95 and 97, wherein each dose of the anti-TL1 A antibody is to be administered at a dose of about 450 mg.
101 . Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in: (I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody in the first dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the first dosing regimen; and
(ii) following the administration of the first and second doses of the anti-TL1 A antibody in the first dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the first dosing regimen; and
(iii) the first dosing regimen has a duration of about 32 weeks; and PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein:
(i) the second dose of the anti-TL1 A antibody in the second dosing regimen is to be administered about two weeks after the first dose of the anti-TL1 A antibody in the second dosing regimen; and
(ii) following the administration of the first and second doses of the anti-TL1 A antibody in the second dosing regimen, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks in the second dosing regimen; wherein the first dose of the of the anti-TL1 A antibody in the second dosing regimen is to be administered to the patient about six weeks after the administration of the last dose of the anti-TL1 A antibody in the first dosing regimen; wherein following the first dosing regimen, and preceding the second dosing regimen, the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
102. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating atopic dermatitis in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in:
(I) a first dosing regimen comprising subcutaneous administration of nine doses of the anti-TL1 A antibody, wherein the dosing regimen has a duration of about 32 weeks; and wherein:
(a) the first dose is to be administered on about Day 1 of Week 0 of the first dosing regimen;
(b) the second dose is to be administered on about Day 1 of Week 2 of the first dosing regimen;
(c) the third dose is to be administered on about Day 1 of Week 6 of the first dosing regimen;
(d) the fourth dose is to be administered on about Day 1 of Week 10 of the first dosing regimen;
(e) the fifth dose is to be administered on about Day 1 of Week 14 of the first dosing regimen;
(f) the sixth dose is to be administered on about Day 1 of Week 18 of the first dosing regimen;
(g) the seventh dose is to be administered on about Day 1 of Week 22 of the first dosing regimen;
(h) the eighth dose is to be administered on about Day 1 of Week 26 of the first dosing regimen; and
(i) the ninth dose is to be administered on about Day 1 of Week 30 of the first dosing regimen; wherein each dose of the anti-TL1 A antibody is administered at a dose of about 50 mg, about 150 mg, or about 450 mg; and
(II) a second dosing regimen comprising subcutaneous administration of at least three doses of the anti- TL1 A antibody, wherein:
(a) the first dose is to be administered on about Day 1 of Week 0 of the second dosing regimen, wherein Day 1 of Week 0 of the second dosing regimen is about six weeks after Day 1 of Week 30 of the first dosing regimen; PATENT
Genentech Docket No: P39491 -WO-1 Attorney Docket No: 50474-365WO3
(b) the second dose is to be administered on about Day 1 of Week 2 of the second dosing regimen; and
(c) following the administration of the first and second doses, the anti-TL1 A antibody is to be administered to the patient subcutaneously every four weeks; the patient had an EASI that was reduced by at least 50% relative to a pre-treatment EASI at a time point about six weeks after Day 1 of Week 30 of the first dosing regimen; and wherein the anti-TL1 A antibody comprises the following CDRs:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;
(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;
(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;
(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;
(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and
(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
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