CN111973739B - The use of anti-PD-L1 monoclonal antibodies in cancer treatment - Google Patents

Abstract

The present invention provides the use of an anti-PD-L1 monoclonal antibody for the treatment of cancer, in particular for the treatment of mediastinal large B-cell lymphoma, comprising administering to said subject a therapeutically effective amount of an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1, wherein the inhibitor is anti-PD-L1 monoclonal antibody, and clinical trial results show that disease progression is significantly controlled.

Description

Use of anti-PD-L1 monoclonal antibodies for the treatment of cancer

Technical Field

The present invention provides a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of an inhibitor of the interaction between a PD-1 receptor and its ligand PD-L1.

Background

The innate immune system comprising T lymphocytes has a powerful anticancer capacity, a broad capacity and a fine specificity, responding to various tumor antigens. Emerging cancer immunotherapy enhances anti-tumor immune responses by adoptive transfer of activated effector cells, immunization against related antigens, or provision of non-specific immunostimulants. Over the past decade, researchers have struggled to develop specific immune checkpoint inhibitors and expected to provide new immunotherapeutic regimens for the treatment of cancer, including the development of antibodies (anti-bodies) Ipilimumab (Ipilimumab) that bind to and inhibit CTLA-4 For the treatment of patients with advanced melanoma (Hodi et al (2010) N Engl J Med 363:711-23), and development of antibodies such as Na Wu Liyou mab (Nivolumab) in the form of a kit>And palbockizumab (Pembrolizumab)/(f)>They specifically bind to the programmed death receptor-1 (PD-1) and block the inhibitory PD-1/PD-1 ligand pathway (Topalian et al (2012 a) N Engl J Med 366:2443-54). Among them, PD-1 (programmed desath-1, PD-1) is a key immunocheckpoint receptor expressed by activated T lymphocytes and B lymphocytes and mediates immunosuppression, and its ligands include at least PD-L1 and PD-L2.

PD-L1 (Programmed desath-ligand 1), also known as CD274 and B7-H1, is a type 1 transmembrane protein of 40kDa encoded by the CD274 gene, a ligand for PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and consist of two extracellular Ig domains, an N-terminal V domain and a C-terminal constant domain. The binding interface of PD-L1 to programmed death receptor 1 (PD-1) and B7-1 (CD 80) is on the IgV-like domain (Lin et al (2008) PNAS 105:3011-3016). While PD-L1 contains a conserved short intracellular tail (about 30 amino acids), PD-1 contains two cytoplasmic tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switching motif (ITSM). Following T cell stimulation, PD-1 recruits tyrosine phosphatase SHP-2 to its ITSM motif within the cytoplasmic tail, resulting in dephosphorylation of effector molecules involved in the CD 3T cell signaling cascade (such as CD3 zeta, PKC theta and ZAP 70) (Freeman et al (2000) J Exp Med 192:1027-34; latchman et al (2001) Nat Immunol 2:261-8; carter et al (2002) Eur J Immunol32: 634-43). PD-L1 is widely distributed not only on white blood cells and non-hematopoietic cells in lymphoid and non-lymphoid tissues, but also on various cancer cells, is highly expressed on the surfaces of various tumor cells, and the malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. There are clinical data showing that high tumor expression of PD-L1 is associated with increased tumor invasiveness and poor prognosis. The formation of the PD-1/PD-L1 complex transmits an inhibitory signal and negatively modulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al (2011) Nature Immunology 10:1185-1193); inducing depletion or anergy among cognate antigen-specific T cells (Hofmeyer et al (2011) Journal of Biomedicine and Biotechnology 2011:1-9); promoting differentiation of Th1 cells into Foxp3+ regulatory T cells (armamath et al (2011) Science TransMed 3:1-13; francisco et al (2009) J.exp. Med. 206:3015-3029); and induces apoptosis of effector T cells. Disruption of the PD-L1 gene results in an upregulated T cell response and production of autoreactive T cells (Latchman et al (2004) PNAS 101:10691-10696). Antibody blockade of PD-1 or PD-L1 results in increased anti-tumor immunity (Iwai et al (2002) PNAS 99:12293-12297).

The anti-PD-L1 antibody can prevent the related negative regulation signals from being started and conducted by blocking the interaction of PD-L1, PD-1 and CD80, so that the activity of effector T cells in a tumor microenvironment is prevented from being inhibited, and the T cells can play a role in killing and inhibiting tumor cells. The anti-PD-L1 antibody can directly act on tumor tissues, so that the anti-PD-L1 antibody has higher specificity and safety. The currently major anti-PD-L1 mab drug products include Atezolizumab, durvalumab from Aspirin and Avelumbab from Merck & pyro, among others. Patent WO2016022630 also discloses anti-PD-L1 antibodies, which have a higher affinity for PD-L1, are capable of significantly inhibiting the interaction of PD-L1 and PD-1 on the cell surface, and significantly promoting the secretion of IL-2 and IFN- γ by T cells.

Malignant lymphoma is an immunocytotumor of lymph nodes and extranodal lymphoid tissue, derived from malignant lesions of lymphocytes or histiocytes. Malignant lymphomas are divided into two major categories, hodgkin's Disease (HD) and non-hodgkin's lymphomas (NHL). In China, the incidence of malignant lymphoma is 11-13 malignant tumors, and in recent years, the incidence of malignant lymphoma tends to increase, and at least more than 25000 cases are seen each year. The incidence rate in western countries such as Europe, america and Australia can be as high as 11/10 ten thousand-18/10 ten thousand, which is slightly higher than the sum of various leukemias. At least 3 thousands of new cases are found annually in the united states. At present, the treatment of malignant lymphoma is changed from the prior treatment mainly comprising nonspecific cytotoxic drug chemotherapy and radiotherapy to multidisciplinary comprehensive treatment comprising multiple modes such as biological targeting treatment. NHL is in turn classified into invasive and indolent lymphomas. Primary mediastinal large B-cell lymphomas (PMBCL) are an aggressive NHL histological subtype, accounting for about 5% of aggressive lymphomas, 2% of all lymphomas. PMBCL has unique molecular markers compared to diffuse large B-cell lymphoma (DLBCL), which is common to nodular sclerosis non-hodgkin's lymphoma. PMBCL is mainly found in women, and the tumor is frequently found in the anterior mediastinum, the growth rate is high, the tumor diameter is more than 10cm, and the symptoms of infiltration in the respiratory system and local chest (lung, chest wall, pleura and pericardium) are often accompanied. 50% of patients may have symptoms and signs of superior vena cava syndrome at the time of onset, such as facial edema, jugular vein anger, sometimes with upper limb edema and/or deep vein thrombosis. Approximately 20% of patients are associated with systemic symptoms, mainly fever and weight loss, and 70% of patients may develop elevated Lactate Dehydrogenase (LDH). Most patients are in stage I-II at the time of initial treatment, with only 20% of patients being stage III-IV. Distant metastasis outside the chest is not common in primary patients, but kidney, adrenal gland, liver, ovary and central nervous system are easily affected in recurrent patients, but bone marrow infiltration is rare. Recurrent/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) treatment is generally referred to as recurrent/refractory diffuse large B-cell lymphoma, and patients who relapse after autologous stem cell transplantation treatment or who are unsuitable for high dose treatment are recommended to participate in clinical trials or to receive a two-wire chemotherapy regimen, palliative radiation therapy, or supportive care. In a study of 106 PMBCL patients (Lazzarino M, orlandi E, pauli M, et al, treatment outcome and prognostic factors for primary mediastinal (thymoc) B-cell lymphoma: a multicenter study of 106patients.J Clin Oncol.1997;15 (4): 1646-1653.), doxorubicin-containing treatment was poor in rrPMBCL outcome, 0% for 35 refractory PMBCL and only 4 (22%) of 18 recurrent PMBCL patients; another study (Kuruvilla J, pintillie M, tsang R, nagy T, keting A, crump M.Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma.Leuk Lymphoma.) for treating rrPMBCL showed a total effective rate of 25% for rescue chemotherapy.

Disclosure of Invention

Summary of the invention

The invention provides a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of an inhibitor of the interaction between a PD-1 receptor and its ligand PD-L1, wherein the inhibitor is a PD-L1 antibody.

The invention also provides the use of an anti-PD-L1 antibody for the treatment of cancer comprising administering to the subject a therapeutically effective amount of an inhibitor of the interaction between a PD-1 receptor and its ligand PD-L1, wherein the inhibitor is an anti-PD-L1 antibody.

The invention also provides the use of an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of cancer.

In some embodiments, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.

In some embodiments, the anti-PD-L1 antibody is administered at a dose of 1mg/kg, 2mg/kg, 3mg/kg, 5mg/kg, 6mg/kg, 9mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 30mg/kg body weight for sustained administration.

In some embodiments, the anti-PD-L1 antibody is administered in one or more uniform doses that are effective to treat the cancer. In some embodiments, wherein the uniform dose is in the range of about 20mg to about 2000mg of the anti-PD-L1 antibody. In some embodiments, wherein the uniform dose is selected from about 300mg, about 600mg, about 900mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2100mg, or about 2400mg of the anti-PD-L1 antibody. In some embodiments, the uniform dose is selected from about 1200mg of anti-PD-L1 antibody.

In some embodiments, the anti-PD-L1 antibody is administered about weekly (q 1 w), about every 2 weeks (q 1 w), about every 3 weeks (q 1 w), or about every 4 weeks (q 1 w). In some embodiments, a uniform dose of anti-PD-L1 antibody is administered to the patient about every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 1200mg per patient, about once every 3 weeks, for continuous administration.

In some embodiments, the anti-PD-L1 antibody is administered as an intravenous infusion. In some embodiments, the anti-PD-L1 antibody is administered as an about 1-2 hour intravenous infusion, preferably about 1 hour intravenous infusion.

In some embodiments, the anti-PD-L1 antibody is a naked antibody, an intact antibody, or an antibody fragment comprising an antigen binding region.

In some embodiments, the method results in an objective response, preferably a complete response or a partial response.

In some embodiments, the subject has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject is post-operatively relieved to the extent that disease progression is again present. In some embodiments, the subject fails to completely or partially alleviate after surgery. In some embodiments, the subject is fully relieved after chemotherapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate following chemotherapy. In some embodiments, the subject is fully relieved after radiation therapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate after radiation treatment. In some embodiments, the subject has previously received surgery and chemotherapy. In some embodiments, the subject is fully relieved after surgery and chemotherapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate following surgery and chemotherapy. In some aspects, the subject has previously been subjected to surgery and radiation therapy. In some embodiments, the subject is fully relieved after surgery and radiation therapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate following surgery and radiation therapy. In some embodiments, the subject has previously received chemotherapy and radiation therapy. In some embodiments, the subject is fully relieved after chemotherapy and radiation therapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate following chemotherapy and radiation therapy. In some embodiments, the subject has previously received surgery, chemotherapy, and radiation therapy. In some embodiments, the subject is fully relieved after surgery, chemotherapy, and radiation therapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate following surgery, chemotherapy, and radiation therapy.

In some embodiments, the subject has received autologous stem cell transplantation after receiving surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject is again in disease progression after complete remission following surgery, chemotherapy, and/or autologous stem cell transplantation. In some embodiments, the subject fails to completely or partially alleviate following surgery, chemotherapy, and/or autologous stem cell transplantation. In some aspects, the subject has received autologous stem cell transplantation after receiving the surgery. In some embodiments, the subject is again in disease progression after complete remission following surgery and autologous stem cell transplantation. In some embodiments, the subject fails to completely or partially alleviate following surgery and autologous stem cell transplantation. In some embodiments, the subject has received autologous stem cell transplantation after receiving the chemotherapy. In some embodiments, the subject is again in disease progression after complete remission following chemotherapy and autologous stem cell transplantation. In some embodiments, the subject fails to completely or partially alleviate following chemotherapy and autologous stem cell transplantation. In some embodiments, the subject has received autologous stem cell transplantation after receiving radiation therapy. In some embodiments, the subject is fully relieved after radiation therapy and autologous stem cell transplantation and disease progression is again indicated. In some embodiments, the subject fails to completely or partially alleviate following radiation therapy and autologous stem cell transplantation. In some aspects, the subject has received autologous stem cell transplantation after having received surgery and chemotherapy. In some embodiments, the subject is again in disease progression after complete remission following surgery, chemotherapy, and autologous stem cell transplantation. In some embodiments, the subject fails to completely or partially alleviate following surgery, chemotherapy, and autologous stem cell transplantation. In some aspects, the subject has received autologous stem cell transplantation after having received surgery and radiation therapy. In some embodiments, the subject is treated with surgery, radiation therapy, and autologous stem cell transplantation to obtain complete remission before disease progression. In some embodiments, the subject fails to completely or partially alleviate following surgery, radiation therapy, and autologous stem cell transplantation. In some embodiments, the subject has received autologous stem cell transplantation after receiving chemotherapy and radiation therapy. In some embodiments, the subject is again in disease progression after complete remission following chemotherapy, radiation therapy, and autologous stem cell transplantation. In some embodiments, the subject fails to completely or partially alleviate following chemotherapy, radiation therapy, and autologous stem cell transplantation.

In some aspects, the subject has received autologous stem cell transplantation after receiving the surgery. In some embodiments, the subject is again in disease progression after complete remission following autologous stem cell transplantation. In some embodiments, the subject fails to completely or partially alleviate following autologous stem cell transplantation.

In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the cancer is mediastinal large B-cell lymphoma. In some embodiments, the mediastinal large B-cell lymphoma has progressed following chemotherapy and/or radiation therapy. In some embodiments, the cancer is recurrent or refractory mediastinal large B-cell lymphoma. In some embodiments, the mediastinal large B-cell lymphoma is recurrent. In some embodiments, the mediastinal large B-cell lymphoma is refractory. In some embodiments, the mediastinal large B-cell lymphoma is metastatic. In some embodiments, the cancer treatment is a two-line treatment of recurrent or refractory mediastinal large B-cell lymphoma. In some embodiments, the cancer treatment is a two-line treatment of metastatic mediastinal large B-cell lymphoma. In some embodiments, the recurrent or refractory mediastinal large B-cell lymphoma does not progress during completion of first-line therapy and/or after radiation therapy. In some embodiments, the metastatic large mediastinal B-cell lymphoma does not progress during completion of first-line therapy and/or after radiation therapy. In some embodiments, the recurrent or refractory mediastinal large B-cell lymphoma has progressed following chemotherapy and/or radiation therapy. In some embodiments, the metastatic large mediastinal B-cell lymphoma has progressed following chemotherapy and/or radiation therapy.

The present invention provides articles of manufacture comprising a container containing a fixed dose of an anti-PD-L1 antibody. The invention also provides the use of an anti-PD-L1 antibody in the manufacture of a preparation for use in the treatment of cancer comprising a fixed dose of a container of an anti-PD-L1 antibody. In some embodiments, the container is a vial. The fixed dose is selected from the group consisting of about 300mg, about 600mg, about 900mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2100mg, and about 2400mg of an anti-PD-L1 antibody. In some embodiments, the article of manufacture further comprises a package insert or pharmaceutical instructions instructing the user to administer the fixed dose to a cancer patient. In some embodiments, the article comprises 1 or more vials containing about 300mg or 600mg of the anti-PD-L1 antibody. In some embodiments, the article comprises 1 vial containing about 300mg of anti-PD-L1 antibody. In some embodiments, the article comprises 1 vial containing about 600mg of the anti-PD-L1 antibody.

Detailed description of the invention and preferred embodiments

The present invention provides a method for treating a subject having cancer or tumor comprising administering to the subject a therapeutically effective amount of an inhibitor of the interaction between a PD-1 receptor and its ligand PD-L1.

The invention also provides a method for treating a subject having cancer or tumor, the method comprising administering to the subject a therapeutically effective amount of: an antibody or antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and/or inhibits PD-L1 activity.

The invention also provides a monotherapy for treating a subject having cancer or a tumor, the method comprising separately administering to the subject a therapeutically effective amount of: an antibody or antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and/or inhibits PD-L1 activity.

The invention also provides a method of treating a subject having a cancer or tumor that is a mediastinal large B-cell lymphoma, comprising: (i) Measuring the level of PD-L1 in a sample of the subject, wherein the subject is PD-L1 positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof.

The present invention provides a method for treating a subject having cancer or a tumor. In other embodiments, the subject is a patient with a histopathologically confirmed mediastinally large B-cell lymphoma (MBCL). In other embodiments, the subject is a patient with recurrent or refractory primary mediastinal large B-cell lymphoma (PMBCL). In other embodiments, the subject is a patient with recurrent or refractory primary mediastinal large B-cell lymphoma. In other embodiments, the subject is a patient with recurrent primary mediastinal large B-cell lymphoma, where recurrent refers to the recurrence of disease progression after complete remission has been achieved by treatment. In other embodiments, the subject is a patient with refractory primary mediastinal large B-cell lymphoma, where refractory means that complete or partial relief is not obtained after treatment. In other embodiments, the subject is a patient with metastatic mediastinal large B-cell lymphoma. In some embodiments, the metastasis is lymph node metastasis. In other embodiments, the metastatic property is pleural and/or local chest wall metastasis.

In some embodiments, the subject is a patient with recurrent and refractory primary mediastinal large B-cell lymphoma (PMBCL). In some embodiments, the subject is a patient with metastatic recurrent and refractory mediastinal large B-cell lymphoma. In some embodiments, the subject is a patient with metastatic recurrent or refractory mediastinal large B-cell lymphoma.

The invention also provides a method for identifying a subject having a mediastinal large B-cell lymphoma, said subject being suitable for anti-PD-L1 antibody therapy, said method comprising measuring the level of PD-L1 in a sample of said subject, and wherein a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof is administered to said subject.

The invention also provides a kit for treating a subject suffering from a mediastinal large B-cell lymphoma, said kit comprising: (a) an anti-PD-L1 antibody or antigen-binding portion thereof; (b) instructions for treating the tumor.

The present invention provides methods of treating cancer using one or more immunocheckpoint inhibitors, e.g., an anti-PD-L1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof. In one embodiment, the cancer is a primary cancer. In one embodiment, the cancer is a metastatic or recurrent cancer. In one embodiment, the cancer is a recurrent or refractory cancer. In one embodiment, the cancer is primary mediastinal large B-cell lymphoma. In one embodiment, the cancer is recurrent or refractory primary mediastinal large B-cell lymphoma.

The invention also provides the use of an anti-PD-L1 antibody in the first line treatment of primary mediastinal large B-cell lymphomas. The invention also provides an application of the anti-PD-L1 antibody in secondary therapy of primary mediastinum large B cell lymphoma. The invention also provides an application of the anti-PD-L1 antibody in three-line treatment of primary mediastinum large B cell lymphoma. In some embodiments, the anti-PD-L1 antibody is used for the second line treatment of recurrent or refractory primary mediastinal large B-cell lymphoma. In some embodiments, the anti-PD-L1 antibody is used for trilinear treatment of recurrent or refractory primary mediastinal large B-cell lymphoma. In some embodiments, the anti-PD-L1 antibody is used alone for two-wire or three-wire treatment of recurrent or refractory primary mediastinal large B-cell lymphoma. In some embodiments, the anti-PD-L1 antibody is used for the subsequent treatment of recurrent or refractory primary mediastinal large B-cell lymphoma. In some embodiments, the anti-PD-L1 antibody is used alone for two-wire or three-wire therapy in patients with recurrent or refractory primary mediastinal large B-cell lymphomas.

Treatment of primary mediastinal large B-cell lymphomas can be found in NCCN guidelines version 2017, 5. Optimal first line treatment is more controversial than the other NHL subtypes, however, these treatment regimens include: dose-adjusted DA-EPOCH-R ([ etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin ] + rituximab) for 6 cycles; RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Times.6 cycles of radiation treatment; RCHOP 4X is followed by ICE (ifosfamide, carboplatin, etoposide) X3 cycle.+ -. Radiotherapy, etc.

In certain embodiments, the subject is a human patient. In certain embodiments, the subject has received another cancer treatment (e.g., chemotherapy), but is resistant or refractory to such another cancer treatment.

In some embodiments, the subject has previously been treated with an EPOH-R or RCHOP treatment. In some embodiments, the subject is treated with EPOCH-R or RCHOP to obtain complete remission before disease progression. In some embodiments, the subject fails to completely or partially alleviate following treatment with an EPOCH-R or RCHOP.

In certain embodiments, the invention provides a method for treating a subject having a tumor, the method comprising administering to the subject a therapeutically effective amount of an immunocheckpoint inhibitor, e.g., an anti-PD-L1 antibody. In certain embodiments, the invention relates to a method of treating a subject having a tumor that is a relapsed or refractory primary large mediastinal B-cell lymphoma, comprising: (i) Measuring the level of PD-L1 in a sample of the subject, wherein the subject expresses PD-L1, and (ii) administering to the subject a therapeutically effective amount of an immunocheckpoint inhibitor, e.g., an anti-PD-L1 antibody or antigen-binding portion thereof. In certain embodiments, the anti-PD-1 antibody is 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 mab. In other embodiments, the anti-PD-1 antibody competes for binding with 5G11 mab.

In some embodiments, the cancer or tumor expresses PD-L1. The PD-L1 status of a tumor in a subject can be measured prior to administration of any composition or using any method disclosed herein. In one embodiment, the PD-L1 expression level of the tumor is at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 20%, or greater than at least about 20%. In another embodiment, the PD-L1 status of the tumor is at least about 1%. In other embodiments, the PD-L1 status of the subject is at least about 5%. In a particular embodiment, the PD-L1 status of the tumor is at least about 10%. Measurement of PD-L1 status can be performed using antibody, in situ mRNA hybridization, automated IHC, and the like.

The invention provides methods of treating a subject having cancer or tumor, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof, wherein a tumor sample obtained from the patient has been determined to have detectable expression levels of PD-L1 in cells comprising about 1% or more (e.g., about 1%, about 2%, about 3%, or about 4% or more). In some embodiments, a tumor sample obtained from the patient has been determined to have a detectable level of expression of PD-L1 in about 1% to about 65% or more (e.g., about 1% to about 5%, about 5% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, or about 50% to about 65%) of the cells. The invention also provides a method of determining whether a patient suffering from primary mediastinal large B-cell lymphoma is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody, the method comprising determining the expression level of PD-L1 in tumor cells in a tumor sample obtained from the patient, wherein detectable expression levels of PD-L1 in cells comprising about 1% or more of the tumor sample are indicative that the patient is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody. The invention also provides a method for predicting responsiveness of a patient suffering from primary mediastinal large B-cell lymphoma to treatment with a therapeutic agent comprising an anti-PD-L1 antibody, the method comprising determining the expression level of PD-L1 in cells in a tumor sample obtained from the patient, wherein detectable expression levels of PD-L1 in tumor cells comprising about 1% or more of the tumor sample indicate that the patient is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody. The invention also provides a method for selecting a therapy for a patient suffering from primary mediastinal large B-cell lymphoma, the method comprising determining the expression level of PD-L1 in tumor cells in a tumor sample obtained from the patient, and selecting a therapy comprising a therapeutic agent that is anti-PD-L1 antibody for the patient based on the expression level of PD-L1 detectable in tumor cells comprising about 1% or more of the tumor sample. In some embodiments, a tumor sample obtained from the patient has been determined to have a detectable level of expression of PD-L1 in tumor cells that constitute about 5% or more of the tumor sample. In some embodiments, a tumor sample obtained from the patient has been determined to have a detectable level of expression of PD-L1 in tumor cells that constitute at least about 10% of the tumor sample. The invention also provides a method for determining whether a patient suffering from primary large mediastinum B-cell lymphoma is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody or antigen-binding portion thereof, the method comprising determining a subtype of a tumor from a tumor sample obtained from the patient, wherein recurrent and/or refractory large primary mediastinum B-cell lymphoma indicates that the patient is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody. The present invention provides a method for predicting responsiveness of a patient suffering from primary large mediastinal B-cell lymphoma to treatment with a therapeutic agent comprising an anti-PD-L1 antibody, the method comprising determining a subtype of a tumor from a tumor sample obtained from the patient, wherein recurrent and/or refractory primary large mediastinal B-cell lymphoma indicates that the patient is likely to respond to treatment with a therapeutic agent comprising an anti-PD-L1 antibody. The present invention provides a method for selecting a therapy for a patient suffering from primary large mediastinal B-cell lymphoma, the method comprising determining a subtype of a tumor from a tumor sample obtained from the patient, and selecting a therapy comprising a therapeutic agent against a PD-L1 antibody for the patient based on the primary large mediastinal B-cell lymphoma determined to be recurrent and/or refractory by the tumor. In some embodiments, the method further comprises administering to the patient a therapeutically effective amount of a therapeutic agent that is an anti-PD-L1 antibody based on the expression level of PD-L1 in tumor cells in the tumor sample.

In certain embodiments, the level of expression of at least one of CD15, CD30, PAX5, CD20, EBV-EBER, CCL17, and/or CCL22 in a tumor sample or blood tissue sample obtained from the patient has been determined to be altered, e.g., increased, relative to a reference level of the at least one gene; and/or the expression level of at least one of CD15, CD45, CD20, CD99 and/or CD3 in a tumor sample obtained from the patient has been determined to be altered, e.g. reduced, relative to a reference level of the at least one gene. In other embodiments, the expression level of miR135a in a tumor sample obtained from the patient has been determined to be altered relative to the reference level of the minute RNA (micro RNA), and in some specific examples, the alteration is a decrease in the expression level. In some embodiments, the reference level is a reference to a non-tumor sample or a blood tissue sample of a non-diseased subject. In some embodiments, the reference level is a reference to a non-tumor sample of the patient.

In certain embodiments, the level of gene mutation, the level of gene modification, the level of transcription and/or the level of expression of at least one of PD-L1, TMB, MSI, 9p24.1 in a tumor sample or blood tissue sample obtained from the patient has been determined to be altered relative to a reference level of the at least one gene. In some embodiments, the reference level is a reference to a non-tumor sample or a blood tissue sample of a non-diseased subject. In some embodiments, the reference level is a reference to a non-tumor sample of the patient.

In certain embodiments, the objective response rate of a subject administered a therapeutically effective amount of an anti-PD-L1 antibody is between about 10% to about 40% (e.g., about 10% to about 20%, about 20% to about 30%, about 30% to about 40%). In yet another embodiment, the objective response rate of a patient administered a therapeutically effective amount of an anti-PD-L1 antibody, or antigen-binding portion thereof, is between about 15% to about 25%. In other embodiments, the objective response rate of a patient administered a therapeutically effective amount of a therapeutic agent against a PD-L1 antibody is at least about 15%. In other embodiments, the objective response rate of a patient administered a therapeutically effective amount of a therapeutic agent against a PD-L1 antibody is at least about 20%.

In certain embodiments, the therapies of the invention (e.g., anti-PD-L1 antibodies) are effective to increase the duration of survival of a subject. In certain embodiments, the anti-PD-L1 antibody therapies of the invention increase the duration of survival of a subject compared to standard of care therapies. In certain embodiments, the therapies of the invention increase overall survival of the subject. In certain embodiments, the subject exhibits an overall survival of at least about 6 months, 7 months, 8 months, 9 months, 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration. In certain embodiments, the survival or total survival duration of the subject is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, or at least about 75% when compared to another subject treated with standard of care therapy alone. In other embodiments, the survival or total survival duration of the subject is increased by at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years when compared to another subject treated with standard of care only therapy.

In certain embodiments, the therapies of the invention are effective to increase the duration of progression free survival of a subject. For example, progression free survival of the subject is increased by at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 1 year when compared to another subject treated with standard of care alone. In certain embodiments, the subject exhibits a total response rate of at least about 30%, 35%, 36%, 37%, 39%, 40%, 45%, or 50% after administration of the anti-PD-L1 antibody therapy compared to the response rate after administration of the standard of care therapy.

Immunocheckpoint inhibitors suitable for use in the disclosed methods include anti-PD-L1 antibodies that bind PD-L1 with high specificity and affinity, block binding of PD-L1, and inhibit immunosuppression of the PD-1 signaling pathway. In any of the therapeutic methods disclosed herein, an anti-PD-1 or anti-PD-L1 "antibody" includes an antigen-binding portion that binds to PD-1 or PD-L1 receptor, respectively, and exhibits functional properties similar to those of an intact antibody in inhibiting ligand binding and up-regulating the immune system. In some embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or portion thereof. In certain embodiments relating to treating a human subject, the antibody is a humanized antibody. In other embodiments regarding treatment of a human subject, the antibody is a human antibody. Antibodies of the IgG1, igG2, igG3 or IgG4 isotype may be used.

In certain embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof comprises a heavy chain constant region of a human IgG1 or IgG4 isotype. In certain other embodiments, the sequence of the IgG4 heavy chain constant region of an anti-PD-1 antibody, an anti-PD-L1 antibody, or an antigen-binding portion thereof contains an S228P mutation that replaces a serine residue in the hinge region with a proline residue typically found at the corresponding position of an IgG1 isotype antibody. This mutation, present in the mab, prevents Fab arm exchange with endogenous IgG4 antibodies while retaining low affinity for activation of Fc receptors associated with wild-type IgG4 antibodies (Wang et al 2014Cancer Immunol Res.2 (9): 846-56). In other embodiments, the antibody comprises a light chain constant region that is a human kappa or lambda constant region. In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is a mAb or antigen-binding portion thereof.

anti-PD-L1 antibodies have been disclosed in WO2016022630 as having a high affinity for PD-L1, being capable of significantly inhibiting the interaction of PD-L1 and PD-1 on the cell surface and significantly promoting the secretion of IL-2 and IFN-gamma by T cells.

In certain embodiments, the anti-PD-L1 antibody or fragment thereof cross-competes with 5G11 or 13C5 mab. In other embodiments, the anti-PD-L1 antibody or fragment thereof binds to the same or a similar epitope as 5G11 or 13C5 mab. In certain embodiments, the anti-PD-L1 antibody has the same CDRs as 5G11 or 13C5 mab.

In certain embodiments, the same epitope region on human PD-L1 is cross-competing with 5G11 or 13C5 mab. For administration to a human subject, these cross-competing antibodies are chimeric or humanized or human antibodies. Such chimeric, humanized or human mabs may be prepared and isolated by methods well known in the art.

anti-PD-L1 antibodies useful in the disclosed methods of the invention also include antigen-binding portions of the antibodies described above. It is well established that the antigen binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include: (i) Fab fragments, i.e. monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F (ab ") 2 fragments, i.e., bivalent fragments comprising 2 Fab fragments linked by disulfide bonds at the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; and (iv) Fv fragments consisting of the VL and VH domains of a single arm of an antibody.

anti-PD-L1 antibodies suitable for use in the disclosed compositions are antibodies that bind to PD-L1 with high specificity and affinity, block binding of PD-1, and inhibit immunosuppression of the PD-L1/PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to a PD-L1 ligand and exhibits functional properties similar to those of an intact antibody in inhibiting receptor binding and up-regulating the immune system. In certain embodiments, the anti-PD-L1 antibody, or antigen-binding portion thereof, cross-competes with 5G11 or 13C5 mab for binding to human PD-L1. In other embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or portion thereof. In certain embodiments, the antibody is a humanized antibody. In other embodiments, the antibody is a human antibody. Antibodies of the IgG1, igG2, igG3 or IgG4 isotype may be used.

In certain embodiments, the anti-PD-L1 antibodies used in the methods may be replaced with another PD-1 or anti-PD-L1 antagonist. For example, because anti-PD-L1 antibodies prevent interactions between PD-1 and PD-L1, thereby exerting a similar effect on the signaling pathway of PD-1, anti-PD-1 antibodies may be substituted for the use of anti-PD-L1 antibodies in the methods disclosed herein. Thus, in one embodiment, the invention relates to a method for treating a subject having a tumor that is primary mediastinal large B-cell lymphoma comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody.

In certain embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is a 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 monoclonal antibody or antigen-binding fragment thereof (see WO2016022630 or CN 107001463A).

The present invention provides antigen binding polypeptides or pharmaceutical compositions comprising antigen binding polypeptides for the treatment of cancer or tumors. In some embodiments, the antigen binding polypeptide is an antibody or antigen binding portion thereof that binds to programmed death ligand 1 (PD-L1) and/or inhibits PD-L1 activity. In some embodiments, the antigen binding polypeptide is an anti-PD-L1 antibody.

The present invention provides an isolated antibody or fragment thereof that binds PD-L1, wherein the antibody is produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5, 5G 11. Thus, the invention also includes hybridomas 13C5, 5G11, as well as any hybridomas that produce the antibodies disclosed herein. The invention also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein. The invention also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.

The present invention provides an anti-PD-L1 antibody comprising a heavy chain Complementarity Determining Region (CDR) selected from the group consisting of a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from the group consisting of a 13C5 or 5G11 antibody. In one embodiment, the invention provides an anti-PD-L1 antibody comprising a variable heavy chain selected from the group consisting of a ch5G11-hIgG1, a ch5G11-hIgG4, a ch13C5-hIgG1, a ch13C5-hIgG4 chimeric antibody, and a variable light chain selected from the group consisting of a ch5G11-hIgG1, a ch5G11-hIgG4, a ch13C5-hIgG1, and a ch13C5-hIgG4 chimeric antibody. In one embodiment, the invention provides an anti-PD-L1 antibody comprising a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibody, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibody. Reference may be made to the description of patent document WO2016022630 or CN107001463 a: 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, or hu13C5-hIgG4, the HCDR1 sequence is SYGMS, the HCDR2 sequence is SISSGGSTYYPDSVKG, HCDR, the LCDR1 sequence is ASQSVSTSSSSFMH, LCDR, the YASNLES, the LCDR3 sequence is QHSWEIPYT; the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 is TYGVH, the HCDR2 sequence is VIWRGVTTDYNAAFMS, HCDR sequence is LGFYAMDY, the LCDR1 sequence is KASQSVSNDVA, LCDR sequence is YAANRY, and the LCDR3 sequence is QQDYTSPYT.

In certain embodiments, the immunocheckpoint inhibitor (e.g., an anti-PD-L1 antagonist) used in the present invention is a PD-L1 Fc fusion protein.

In certain embodiments, the invention provides for administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is administered alone. In some embodiments, the separate administration means that the anti-PD-L1 antibody may not be used in combination with other anti-cancer drugs, and/or not be administered simultaneously with other anti-cancer drugs. In some embodiments, the administration alone means that the anti-PD-L1 antibody may not be used in combination with a chemotherapeutic agent, and/or not be administered concurrently with a chemotherapeutic agent. In some embodiments, the separate administration means that the anti-PD-L1 antibody may not be used in conjunction with, and/or administered simultaneously with, other targeted drugs. In some embodiments, the separate administration means that the anti-PD-L1 antibody may not be used in combination with other anti-cancer antibodies, and/or not be administered concurrently with other anti-cancer antibodies. In some embodiments, the administration alone means that the anti-PD-L1 antibody may not be used in conjunction with radiation therapy and/or not be administered concurrently with radiation therapy.

In certain embodiments, the invention provides for administering to a subject a therapeutically effective amount of an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is co-administered.

In certain embodiments, an immunocheckpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered in combination with one or more other anti-cancer agents. In certain embodiments, the one or more anti-cancer agents have been administered to the subject prior to administration of the anti-PD-1 or anti-PD-L1 antibody or prior to combination with the anti-PD-1 or anti-PD-L1 antibody. In certain embodiments, the one or more anticancer agents are not effective in treating the cancer. In certain embodiments, the additional anti-cancer agent is any anti-cancer agent described herein or known in the art.

In certain embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be combined with another immunotherapy. In certain embodiments, the blocking immunotherapy involving an immunocheckpoint is administered as monotherapy. In other embodiments, the blocked immunotherapy involving an immunocheckpoint is administered in combination with other therapies.

The therapeutic agents of the invention may be formulated in a composition, for example, a pharmaceutical composition comprising an antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier for the composition comprising the antibody is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion), while the carrier for the composition comprising the TKI is suitable for parenteral (e.g., oral) administration. The pharmaceutical compositions of the present invention may include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and/or adjuvants such as preserving, wetting, emulsifying and dispersing agents.

The dosage regimen is adjusted to provide the most desirable response, e.g., maximum therapeutic response and/or minimal adverse effects. In certain embodiments, the methods of the invention may be used with a uniform dose or a weight-based dose. In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is administered as a uniform dose. In other embodiments, the anti-PD-1 antibody, anti-PD-L1 antibody, or antigen-binding portion thereof is administered as a weight-based dose. For administration of an anti-PD-L1 antibody (as monotherapy or in combination with another anticancer agent), the dose may be within the following range: about 0.01 to about 40mg/kg, about 0.1 to about 30mg/kg, about 0.1 to about 20mg/kg, about 0.1 to about 15mg/kg, about 0.1 to about 10mg/kg, about 1 to about 15mg/kg, about 1 to about 20mg/kg, about 1 to about 3mg/kg, about 3 to about 10mg/kg, about 3 to about 15mg/kg, about 3 to about 20mg/kg, about 3 to about 30mg/kg, about 10 to about 20mg/kg, or about 15 to about 20mg/kg of body weight, or about 60mg to at least 2400mg, about 90mg to at least about 1800mg, about 120mg to at least about 1500mg, about 300mg to at least about 9000mg, about 600mg to at least about 900mg, about 300mg to at least about 1200mg, about 600mg to at least about 1200mg, or about 900mg to at least about 1200mg. For example, the dosage may be about 0.1, about 1, about 2, about 3, about 5, about 6, about 9, about 10, about 15, about 20, or about 30mg/kg body weight; or about 30mg, about 60mg, about 120mg, about 150mg, about 180mg, about 300mg, about 600mg, about 900mg, about 1200mg, about 1800mg, about 2100mg, or about 2400mg. Dosing schedules are often designed to achieve exposure (based on typical pharmacokinetic properties of antibodies) that results in sustained Receptor Occupancy (RO). An exemplary treatment regimen entails administration about once per week (q 1 w), about once every 2 weeks (q 2 w), about once every 3 weeks (q 3 w), about once every 4 weeks (q 4 w), about once a month (q 1 m), about once every 3-6 months, or longer. In certain embodiments, an anti-PD-L1 antibody, such as 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 mab, is administered to the subject about once every 2 weeks. In other embodiments, the antibody is administered about once every 3 weeks. The dose and schedule may vary during the course of treatment. Considering that IgG4 antibodies typically have a half-life of 2-3 weeks, the dosage regimen of the anti-PD-L1 antibodies of the invention comprises at least about 1 to at least about 30mg/kg body weight, at least about 3 to at least about 20mg/kg body weight, at least about 10 to at least about 15mg/kg body weight, or at least about 300 to at least about 1200mg administered via intravenous administration every about 14-21 days over a period of up to about 6 weeks or about 12 weeks until complete response or demonstration of progressive disease. In certain embodiments, anti-PD-L1 monotherapy is administered at 3mg/kg every 2 weeks until progressive disease or unacceptable toxicity. In other embodiments, anti-PD-L1 monotherapy is administered every 3 weeks at 1200mg until progressive disease or unacceptable toxicity. In certain embodiments, the antibody treatment or any combination treatment disclosed herein lasts for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

When used in combination with other cancer agents, the dose of anti-PD-L1 antibodies may be reduced relative to monotherapy doses. Dosages of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 mab below typically 20mg/kg, but not less than 0.001mg/kg, are sub-therapeutic dosages. The subtherapeutic amount of anti-PD-L1 antibody used in the methods herein is greater than 0.001mg/kg and less than 20mg/kg. In certain embodiments, the sub-therapeutic dose is about 0.001mg/kg to about 3mg/kg, about 0.01mg/kg to about 3mg/kg, about 0.001mg/kg to about 10mg/kg, or about 0.01mg/kg to about 10mg/kg body weight. In certain embodiments, the sub-therapeutic dose is at least about 0.001mg/kg, at least about 0.005mg/kg, at least about 0.01mg/kg, at least about 0.05mg/kg, at least about 0.1mg/kg, at least about 0.5mg/kg, at least about 1.0mg/kg body weight, or at least about 3.0mg/kg body weight. In certain embodiments, the subtherapeutic unit dose is less than about 600mg every 3 weeks, for example about 300mg or about 120mg every 3 weeks. In certain embodiments, 3mg/kg administration may allow for sufficient exposure to result in maximum biological activity.

In certain embodiments, the dose of the anti-PD-L1 antibody or anti-PD-1 antibody is a fixed dose in a pharmaceutical composition. In other embodiments, the methods of the invention may be used in a uniform dose (the dose administered to a patient regardless of the patient's weight). For example, a uniform dose of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 monoclonal antibody may be about 1200mg. In certain embodiments, the anti-PD-L1 antibody, or antigen-binding portion thereof, is administered at a dose of about 1200mg. In certain embodiments, the anti-PD-L1 antibody, or antigen-binding portion thereof, is administered at a dose of about 900 mg. In certain embodiments, the anti-PD-L1 antibody, or antigen-binding portion thereof, is administered at a dose of about 600 mg. In one embodiment, 900mg of the anti-PD-L1 antibody or antigen-binding fragment is administered once every 3 weeks. In another embodiment, 1200mg of the anti-PD-L1 antibody or antigen-binding fragment is administered once every 4 weeks.

For administration of an anti-PD-L1 antibody (as monotherapy or in combination with another anticancer agent), the dose may be within the following range: about 0.01 to about 20mg/kg, about 0.1 to about 10mg/kg, about 0.1 to about 5mg/kg, about 3 to about 10mg/kg, about 3 to about 15mg/kg, or about 0.1 to about 30mg/kg body weight or about 80mg to at least 800mg, about 80mg to at least about 700mg, about 80mg to at least about 600mg, about 80mg to at least about 500mg, about 80mg to at least about 400mg, about 80mg to at least about 300mg, about 100mg to at least about 300mg, or about 200mg to about 300mg. For example, the dosage may be about 0.1, about 0.3, about 1, about 2, about 3, about 5, or about 10mg/kg body weight, or about 0.3, about 1, about 2, about 3, or about 5mg/kg body weight; or about 80mg, about 100mg, about 160mg, about 200mg, about 240mg, about 300mg, about 320mg, about 400mg, about 500mg, about 600mg, about 700mg, or about 800mg. Dosing schedules are often designed to achieve exposure (based on typical pharmacokinetic properties of antibodies) that results in sustained Receptor Occupancy (RO). An exemplary treatment regimen entails administration about once per week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about 1 time per month, about once every 3-6 months, or longer.

In certain embodiments, each cycle of day 1 (D1) receives an intravenous drip of about 3mg/kg to about 30mg/kg body weight dose for about 21 days for 1 cycle until the efficacy is assessed as disease progression, intolerable toxic reactions occur. In certain embodiments, each cycle of day 1 (D1) receives an intravenous drip of about 3mg/kg to about 20mg/kg body weight dose for about 21 days for 1 cycle until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) of each cycle receives 3mg/kg of intravenous infusion for about 21 days for 1 cycle until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) of each cycle receives an intravenous drip of about 10mg/kg body weight dose for about 21 days for 1 cycle until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) of each cycle receives an intravenous drip of about 15mg/kg body weight dose for about 21 days for 1 cycle until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) of each cycle receives an intravenous drip of about 20mg/kg body weight dose for 1 cycle for 21 days until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) of each cycle receives an intravenous drip of about 30mg/kg body weight dose for 1 cycle for 21 days until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) receives intravenous drip at a body weight dose of about 3mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, or 30mg/kg for 1 cycle for about 2 weeks, about 3 weeks, or about 4 weeks until the efficacy is assessed as disease progression, intolerable toxic reactions occur. In certain embodiments, day 1 (D1) of each cycle receives a uniform dose of about 1200mg of intravenous drip for about 1 cycle for about 2 weeks, about 3 weeks, or about 4 weeks until the efficacy is assessed as disease progression, intolerable toxic reactions occur.

In certain embodiments, a uniform dose of about 600mg to about 1200mg is administered intravenously on day 1 (D1) of each cycle for about 21 days for 1 cycle until efficacy is assessed as disease progression, intolerance of toxic response occurs. In certain embodiments, a uniform dose of about 600mg to about 900mg is administered intravenously on day 1 (D1) of each cycle for about 21 days for 1 cycle until efficacy is assessed as disease progression, intolerance of toxic response occurs. In certain embodiments, a 1200mg unified dose intravenous drip is received on day 1 (D1) of each cycle for about 21 days for 1 cycle until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, a uniform dose of about 900mg to about 1200mg is administered intravenously on day 1 (D1) of each cycle for about 21 days for 1 cycle until efficacy is assessed as disease progression, intolerance of toxic response occurs. In certain embodiments, a 600mg bolus intravenous drip is received on day 1 (D1) of each cycle for 1 cycle for 21 days until the efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, a 900mg unified dose intravenous drip is received on day 1 (D1) of each cycle for 1 cycle for 21 days until efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, a 1200mg uniform dose intravenous drip is received on day 1 (D1) of each cycle for 1 cycle for 21 days until efficacy is assessed as disease progression, intolerance of toxic response. In certain embodiments, day 1 (D1) of each cycle receives a uniform dose of about 900mg of intravenous drip for about 2 weeks, about 3 weeks, or about 4 weeks for 1 cycle until the efficacy is assessed as disease progression, intolerable toxic reactions occur. In certain embodiments, day 1 (D1) of each cycle receives a uniform dose of about 1200mg of intravenous drip for about 1 cycle for about 2 weeks, about 3 weeks, or about 4 weeks until the efficacy is assessed as disease progression, intolerable toxic reactions occur.

In certain embodiments, the dose of the anti-PD-L1 antibody or anti-PD-1 antibody is a fixed dose in a pharmaceutical composition.

In certain embodiments, the dose of the anti-PD-L1 antibody or anti-PD-1 antibody is a fixed dose in a pharmaceutical composition that contains a second anti-cancer agent.

The actual dosage level of the one or more active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration without undue toxicity to the patient. The dosage level selected will depend on a variety of pharmacokinetic factors including the activity of the particular composition of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The compositions of the present invention may be administered via one or more routes of administration using one or more of a variety of methods well known in the art. The skilled artisan will appreciate that the route and/or mode of administration will vary with the desired result.

The invention also aims at providing a pharmaceutical composition which is characterized in that: the pharmaceutical composition comprises an antibody and at least one or more of a buffer, an isotonicity adjusting agent, a stabilizing agent and/or a surfactant. In particular, the pharmaceutical composition comprises 1-150mg/ml of an anti-PD-L1 humanized monoclonal antibody (mab), 3-50mM buffer, 2-150mg/ml of an isotonicity modifier/stabilizer and 0.01-0.8mg/ml of a surfactant, and has a pH of about 4.5-6.8.

In some embodiments, the anti-PD-L1 humanized monoclonal antibody concentration is about 5-150mg/ml calculated as w/v; preferably about 10-60mg/ml; more preferably about 10-30mg/ml. In some embodiments, the anti-PD-L1 humanized monoclonal antibody is present in a mass volume concentration of about 10mg/ml, about 20mg/ml, about 30mg/ml, about 40mg/ml, about 50mg/ml, about 60mg/ml, about 70mg/ml, about 80mg/ml, about 90mg/ml, about 100mg/ml, about 110mg/ml, or about 120mg/ml, preferably about 10mg/ml, about 20mg/ml, about 30mg/ml, about 40mg/ml, about 50mg/ml, or about 60mg/ml, more preferably about 10mg/ml, about 20mg/ml, or about 30mg/ml. In some embodiments, the anti-PD-L1 humanized monoclonal antibody is present at a mass-to-volume concentration of about 10mg/ml. In other embodiments, the anti-PD-L1 humanized monoclonal antibody is present at a mass-to-volume concentration of about 30mg/ml. In other embodiments, the anti-PD-L1 humanized monoclonal antibody has a mass-to-volume concentration of about 60mg/ml.

In some embodiments, the buffer is a histidine salt buffer. The histidine salt buffer concentration is about 5-30mM, preferably about 10-25mM, more preferably about 10-20mM, and most preferably about 10-15mM. In some embodiments, the histidine salt buffer is about 5mM, about 10mM, about 15mM, about 20mM, about 25mM, or about 30mM. In some embodiments, the histidine salt buffer is about 10mM. In other embodiments, the histidine salt buffer is about 15mM. In other embodiments, the histidine salt buffer is about 20mM. Wherein the histidine salt buffer comprises histidine and hydrochloric acid.

In some embodiments, the isotonicity modifier/stabilizer is about 20 to 150mg/ml sucrose, preferably about 40 to 100mg/ml sucrose, more preferably about 60 to 80mg/ml sucrose, calculated as w/v. In some embodiments, the sucrose is at a concentration of about 40mg/ml, 50mg/ml, 60mg/ml, 70mg/ml, 80mg/ml, 90mg/ml, or 100mg/ml. In some embodiments, the sucrose is at a concentration of about 60mg/ml. In some embodiments, the sucrose is at a concentration of about 70mg/ml. In some embodiments, the sucrose is at a concentration of about 80mg/ml. In some embodiments, the sucrose is at a concentration of about 90mg/ml.

In some embodiments, the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; preferably polysorbate 80 or polysorbate 20; more preferably polysorbate 80. In some embodiments, the surfactant is present at a concentration of about 0.05 to about 0.6mg/ml, preferably about 0.1 to about 0.4mg/ml, and more preferably about 0.2 to about 0.3mg/ml, calculated as w/v.

In some embodiments, the surfactant is about 0.01 to 0.8mg/ml polysorbate 80 or polysorbate 20 calculated as w/v. In some embodiments, the surfactant is about 0.05 to about 0.6mg/ml polysorbate 80, preferably about 0.1 to about 0.4mg/ml polysorbate 80, more preferably about 0.2 to about 0.3mg/ml polysorbate 80, and most preferably about 0.2mg/ml polysorbate 80. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, or 0.6mg/ml; preferably, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/ml, 0.3mg/ml, 0.4mg/ml or 0.5mg/ml; more preferably, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/ml, 0.3mg/ml or 0.4mg/ml; optimally, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/ml. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.1mg/ml. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/ml. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.3mg/ml. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.4mg/ml. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.5mg/ml.

In some embodiments, the aqueous solution of the pharmaceutical composition has a pH of from 4.0 to 6.8; preferably 4.5 to 6.5; more preferably 5.5 to 6.0; most preferably 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 4.5, about 4.8, about 5.0, about 5.2, about 5.4, about 5.5, about 5.6, about 5.8, or about 6.0, preferably about 5.0, about 5.2, about 5.4, about 5.5, or about 5.6, more preferably about 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.2. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.4. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.6. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.8. In some embodiments, the aqueous pharmaceutical composition has a pH of about 6.0.

The invention provides isolated antibodies or fragments thereof that bind to PD-L1. The anti-PD-L1 humanized monoclonal antibody provided by the invention comprises the following amino acid sequences: a heavy chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 1 or SEQ ID No. 4; a heavy chain CDR2 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 2 or SEQ ID No. 5; a heavy chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 3 or SEQ ID No. 6; a light chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 7 or SEQ ID No. 10; a light chain CDR2 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 8 or SEQ ID No. 11; a light chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 9 or SEQ ID No. 12.

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises the following amino acid sequences: a heavy chain CDR1 region selected from SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region selected from SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region selected from SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region selected from SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region selected from SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region selected from SEQ ID NO. 9 or SEQ ID NO. 12.

Preferably, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises the following amino acid sequences: a heavy chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO. 13 or SEQ ID NO. 14; a light chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO. 15 or SEQ ID NO. 16.

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises the following amino acid sequence, namely a heavy chain variable region shown as SEQ ID NO. 13; the light chain variable region as shown in SEQ ID NO. 15.

In another specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises the following amino acid sequence, namely a heavy chain variable region shown as SEQ ID NO. 14; the light chain variable region as shown in SEQ ID NO. 16.

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises a heavy chain amino acid sequence shown as SEQ ID NO.17 and a light chain amino acid sequence shown as SEQ ID NO. 18.

In another specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises a heavy chain amino acid sequence shown as SEQ ID NO.19 and a light chain amino acid sequence shown as SEQ ID NO. 20.

In another specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided by the invention comprises a heavy chain amino acid sequence shown as SEQ ID NO.21 and a light chain amino acid sequence shown as SEQ ID NO. 18.

The anti-PD-L1 humanized monoclonal antibody provided by the invention can be an IgG1 or IgG4 antibody, preferably, the anti-PD-L1 humanized monoclonal antibody is an IgG1 antibody, and more preferably, a glycosylated IgG1 antibody.

In a specific embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 20mg/mL, (b) sucrose with a mass volume concentration of about 70mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.1mg/mL, (d) histidine with a molar concentration of about 20mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.0.

In another specific embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 10mg/mL, (b) sucrose with a mass volume concentration of about 80mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.2mg/mL, (d) histidine with a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In yet another embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 50mg/mL, (b) sucrose with a mass volume concentration of about 80mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.3mg/mL, (d) histidine with a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In yet a more specific embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 100mg/mL, (b) sucrose with a mass volume concentration of about 80mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.5mg/mL, (d) histidine with a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In yet another embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 30mg/mL, (b) sucrose with a mass volume concentration of about 80mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.2mg/mL, (d) histidine with a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In yet another specific embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 60mg/mL, (b) sucrose with a mass volume concentration of about 80mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.2mg/mL, (d) histidine with a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In yet another embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 10mg/mL, (b) sucrose with a mass volume concentration of about 70mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.4mg/mL, (d) histidine with a molar concentration of about 20mM, (e) optionally an appropriate amount of acetic acid, and adjusting the pH of the composition to about 6.5.

In yet another embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 humanized monoclonal antibody with a mass volume concentration of about 10mg/mL, (b) sucrose with a mass volume concentration of about 80mg/mL, (c) polysorbate 80 with a mass volume concentration of about 0.2mg/mL, (d) histidine with a molar concentration of about 20mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In some embodiments, the pharmaceutical composition is a water-soluble injection, including but not limited to a water-soluble formulation that has not been lyophilized or a water-soluble formulation that has been reconstituted from a lyophilized powder. In other embodiments, the pharmaceutical composition is a lyophilized formulation. The lyophilized preparation means that the aqueous solution is subjected to a lyophilization process to prepare the preparation, and lyophilization is a stabilization process in which a substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process) and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction. The lyophilized formulation of the present invention may also be dried by other methods known in the art, such as spray drying and bubble drying (bubble drying).

The present invention provides formulations which do not exceed 1.1%, preferably not exceed 0.9%, more preferably not exceed 0.5% of the polymer when stored at 2-8 ℃ or 25 ℃ for at least 6 months.

The invention also provides a method for preparing the pharmaceutical composition, which comprises mixing the anti-PD-L1 humanized monoclonal antibody with other reagents, such as one or more of buffer, isotonic regulator/stabilizer and/or surfactant.

The invention also provides a method for treating a neoplasia condition in a subject comprising administering to the subject the aforementioned pharmaceutical composition.

The present invention provides articles of manufacture comprising a container containing a fixed dose of an anti-PD-L1 antibody. The invention also provides the use of an anti-PD-L1 antibody in the manufacture of a preparation for use in the treatment of cancer comprising a fixed dose of a container of an anti-PD-L1 antibody. In some embodiments, the container is a vial. The fixed dose is selected from the group consisting of about 300mg, about 600mg, about 900mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2100mg, and about 2400mg of an anti-PD-L1 antibody. In some embodiments, the article of manufacture further comprises a package insert or pharmaceutical instructions instructing the user to administer the fixed dose to a cancer patient. In some embodiments, the article comprises 1 or more vials containing about 300mg or 600mg of the anti-PD-L1 antibody. In some embodiments, the article comprises 1 vial containing about 300mg of the anti-PD-L1 antibody. In some embodiments, the article of manufacture comprises 1 or more vials, each of the vials containing about 10mL of the pharmaceutical composition comprising the anti-PD-L1 antibody. In some embodiments, the article of manufacture comprises 1 or more vials, each of the vials containing about 20mL of the pharmaceutical composition comprising the anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises 1-150mg/ml of an anti-PD-L1 humanized monoclonal antibody (mab), 3-50mM buffer, 2-150mg/ml of an isotonicity modifier/stabilizer, and 0.01-0.8mg/ml of a surfactant, and has a pH of about 4.5-6.8. In some embodiments, the article of manufacture comprises 1 or more vials, each of the vials containing about 10mL of a pharmaceutical composition comprising an anti-PD-L1 antibody, wherein the pharmaceutical composition comprises 30mg/mL of an anti-PD-L1 humanized monoclonal antibody. In some embodiments, the article of manufacture comprises 1 or more vials, each of the vials containing about 20mL of a pharmaceutical composition comprising an anti-PD-L1 antibody, wherein the pharmaceutical composition comprises 30mg/mL of an anti-PD-L1 humanized monoclonal antibody. In some embodiments, the pharmaceutical composition is any one of the pharmaceutical compositions provided herein.

In some embodiments, the invention comprises:

1. a method of treating mediastinal large B-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody comprises the amino acid sequence of: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.

2. The method of the preceding claim, wherein the anti-PD-L1 antibody is administered at a dose of 1mg/kg, 3mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg body weight for sustained administration.

3. The method of any one of the preceding claims, wherein the anti-PD-L1 antibody is administered in one or more uniform doses effective to treat the mediastinal large B-cell lymphoma.

4. The method of any one of the preceding claims, wherein the uniform dose is in the range of about 20mg to about 2000mg of anti-PD-L1 antibody.

5. The method of any one of the preceding claims, wherein the uniform dose is selected from about 300mg, about 600mg, about 900mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2100mg, or about 2400mg of the anti-PD-L1 antibody.

6. The method of any one of the preceding claims, wherein the uniform dose is selected from about 1200mg of anti-PD-L1 antibody.

7. The method of any one of the preceding claims, wherein the anti-PD-L1 antibody is administered about weekly (q 1 w), about every 2 weeks (q 1 w), about every 3 weeks (q 1 w), or about every 4 weeks (q 1 w).

8. The method of any one of the preceding claims, wherein the anti-PD-L1 antibody is administered at a dose of about 1200mg per patient, about once every 3 weeks, for continued administration.

9. The method of any one of the preceding claims, wherein a uniform dose of anti-PD-L1 antibody is administered to the patient approximately every 3 weeks.

10. The method of any one of the preceding claims, wherein the anti-PD-L1 antibody is administered as an intravenous infusion.

11. The method of any one of the preceding claims, wherein the anti-PD-L1 antibody is administered as a 1-2 hour intravenous infusion, preferably a 1 hour intravenous infusion.

12. The method of any one of the preceding claims, wherein the anti-PD-L1 antibody is a naked antibody, an intact antibody, or an antibody fragment comprising an antigen binding region.

13. The method according to any of the preceding claims, wherein the method results in an objective response, preferably a complete response or a partial response.

14. The method of any one of the preceding claims, wherein the subject has previously received chemotherapy and/or radiation therapy.

15. The method according to any one of the preceding claims, wherein the subject has received autologous stem cell transplantation after receiving chemotherapy and/or radiation therapy.

16. The method according to any one of the preceding claims, wherein the subject is again in disease progression after complete remission following chemotherapy and/or autologous stem cell transplantation.

17. The method of any one of the preceding claims, wherein the subject fails to completely or partially alleviate following chemotherapy and/or autologous stem cell transplantation.

18. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma has progressed following chemotherapy.

19. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma is recurrent and/or refractory mediastinal large B-cell lymphoma.

20. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma is recurrent or refractory mediastinal large B-cell lymphoma.

21. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma is recurrent.

22. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma is refractory.

23. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma treatment is a treatment of recurrent or refractory mediastinal large B-cell lymphoma.

24. The method of any one of the preceding claims, wherein the recurrent or refractory mediastinal large B-cell lymphoma does not progress during or after completion of first-line therapy.

25. The method of any one of the preceding claims, wherein the recurrent or refractory mediastinal large B-cell lymphoma has progressed following chemotherapy.

26. The method of any one of the preceding claims, wherein the mediastinal large B-cell lymphoma is metastatic.

27. The method of any one of the preceding claims, wherein the metastatic mediastinal large B-cell lymphoma does not progress during or after completion of first line therapy.

28. The method of any one of the preceding claims, wherein the metastatic mediastinal large B-cell lymphoma has progressed following first line treatment.

29. The method of any one of the preceding claims, wherein the metastatic large mediastinal B-cell lymphoma is metastatic recurrent and/or refractory large mediastinal B-cell lymphoma.

30. An article of manufacture comprising a container containing a fixed dose of an anti-PD-L1 antibody, wherein the fixed dose is selected from the group consisting of about 300mg, about 600mg, about 900mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2100mg, and about 2400mg of an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.

31. The article of any one of the preceding claims, comprising 1 or more vials containing about 300mg or 600mg of anti-PD-L1 antibody.

32. The article of any one of the preceding claims, comprising 1 vial containing about 300mg of anti-PD-L1 antibody.

33. The article of any one of the preceding claims, comprising 1 vial containing about 600mg of anti-PD-L1 antibody.

Definitions and term interpretations

In order that the invention may be more readily understood, certain terms are defined. As used in this application, each of the following terms shall have the following meanings, except as otherwise expressly provided herein. Additional definitions are set forth in this application.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present invention may be whole antibodies or any fragment thereof. Thus, antibodies and fragments of the invention include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, fab 'fragments, F (ab)' fragments, fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, igG2, igG3 or IgG4 isotype. The term "isotype" refers to the type of antibody encoded by the heavy chain constant region gene. In one embodiment, the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The PD-L1 antibodies and fragments thereof of the invention may be derived from any species including, but not limited to, mice, rats, rabbits, primates, llamas, and humans. The PD-L1 antibody and fragments thereof may be chimeric, humanized or fully human antibodies. In one embodiment, the anti-PD-L1 antibody is an antibody produced by a mouse-derived hybridoma cell line. Thus, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and is humanized.

"humanized antibodies" are the following antibodies: the antibodies contain Complementarity Determining Regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from human antibodies. For example, an anti-PD-L1 antibody provided herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions. Thus, in one embodiment, the humanized antibodies provided herein bind to the same epitope on PD-L1 as the murine antibody from which the CDRs of the antibodies are derived. Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising heavy and light chain CDRs provided herein can be generated using any human framework sequences and are also included in the invention. In one embodiment, framework sequences suitable for use in the present invention include those framework sequences that are similar in structure to the framework sequences provided herein. Additional modifications may be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or to remove T cell epitopes; or reverting the mutation to a residue in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of VH and/or VL of a humanized antibody provided herein are back mutated to corresponding amino acids in a parent murine antibody. For example, for the VH and VL of humanized 5G11 and humanized 13C5, several sites of framework amino acids of the above template human antibodies were back mutated to the corresponding amino acid sequences in the mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are back mutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 light chain variable region. In another embodiment, the amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are back mutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 heavy chain variable region. In one embodiment, the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser (S) to Asp (D) and the amino acid at position 67 is mutated from Ser (S) to Tyr (Y); and a heavy chain variable region wherein the amino acid at position 24 is mutated from Phe (F) to Val (V), the amino acid at position 49 is mutated from Ala (a) to Gly (G), the amino acid at position 73 is mutated from Thr (T) to Asn (N), and the amino acid at position 83 is mutated from Thr (T) to Asn (N). In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region, wherein the amino acid at position 28 is mutated from Thr (T) to Ile (I), the amino acid at position 30 is mutated from Ser (S) to Arg (R), the amino acid at position 49 is mutated from Ser (S) to Ala (a), and the amino acid at position 94 is mutated from Tyr (Y) to Asp (D). Additional or alternative back mutations may be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies. The invention also includes humanized antibodies that bind PD-L1 and comprise framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequence, as well as other framework modifications that otherwise improve the properties of the antibodies.

"isolated antibody" means an antibody that: which is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind antigens other than PD-1). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens (such as PD-1 molecules from different species). In addition, the isolated antibodies may be substantially free of other cellular material and/or chemicals.

The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of antibody molecules of single molecular composition (i.e., antibody molecules whose basic sequences are substantially identical and which exhibit a single binding specificity and affinity for a particular epitope). A mAb is one example of an isolated antibody. Mabs may be produced by hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those skilled in the art.

An "antigen binding portion" of an antibody (also referred to as an "antigen binding fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by the intact antibody.

As used herein, the term "derived" when used in reference to a molecule or polypeptide relative to a reference antibody or other binding protein means a molecule or polypeptide capable of specifically binding the same epitope as the reference antibody or other binding protein.

The antibodies and antigen binding fragments thereof disclosed herein are specific for PD-L1. In one embodiment, the antibody or fragment thereof is specific for PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but do not bind to PD-L1 from any other mammal. In another embodiment, the antibody or fragment thereof does not bind to mouse PD-L1. The terms "human PD-L1", "hPD-L1" and "huPD-L1" and the like are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1. By "specific" is meant that the antibody and fragments thereof bind PD-L1 with greater affinity than any other target.

As used herein, the term "EC50" refers to the effective concentration, 50% of the maximum response of an antibody. As used herein, the term "IC50" refers to the inhibitory concentration, 50% of the maximum response of an antibody. Both EC50 and IC50 may be measured by ELISA or FACS analysis or any other method known in the art.

As used herein, the term "treatment" refers to therapeutic treatment as well as preventive or prophylactic measures. Subjects in need of treatment include those already with the disease or condition, as well as subjects who are likely to have the disease or condition and whose purpose is to prevent, delay or attenuate the disease or condition.

As used herein, the term "subject" refers to mammals, such as rodents, felines, canines, and primates. Preferably, the subject according to the invention is a human.

By "administering" is meant physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of the immunocheckpoint inhibitor (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immunocheckpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route, in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, one, multiple times, and/or over one or more extended periods of time.

As used herein, an "adverse reaction" (AE) is any adverse and often unintended or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the application of medical treatment. For example, an adverse event may be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatments may have one or more associated AEs, and each AE may have the same or different severity levels. References to methods capable of "altering adverse events" refer to treatment regimens that reduce the incidence and/or severity of one or more AEs associated with the application of different treatment regimens.

As used herein, "dosing interval" refers to the amount of time that elapses between multiple doses of the formulation disclosed herein administered to a subject. The dosing interval may thus be indicated as a range.

The term "frequency of administration" as used herein means the frequency of the dosage administered of the formulations disclosed herein in a given time. The dosing frequency may be indicated as the number of doses per given time, e.g. 1 time per week or 1 time per 2 weeks.

The use of the term "flat dose" refers to the dose administered to a patient irrespective of the weight or Body Surface Area (BSA) of the patient. The unified dose is thus provided as a mg/kg dose, rather than as an absolute amount of the agent (e.g., anti-PD-1 antibody). For example, 60kg of humans and 100kg of humans will receive the same dose of antibody (e.g., 240mg of anti-PD-1 antibody).

The use of the term "fixed dose" in relation to the compositions of the invention means that two or more different antibodies in a single composition are present in a specific (fixed) ratio to each other in the composition. In certain embodiments, the fixed dose is based on the weight of the antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg/ml). In certain embodiments, the ratio of the mg first antibody to the mg second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 7:1, about 1:1, about 1:1:1, about 5:1, about 1:1 or about 1:2:1. For example, a 3:1 ratio of primary antibody to secondary antibody may mean that the vial may contain about 240mg primary antibody and 80mg secondary antibody, or about 3mg primary antibody and 1mg secondary antibody per ml.

The term "weight-based dose" as referred to herein refers to the dose calculated based on the weight of the patient that is administered to the patient. For example, when a patient having a body weight of 60kg requires 3mg/kg of anti-PD-1 antibody and 1mg/kg of anti-CTLA-4 antibody, one can withdraw the appropriate amounts of anti-PD-1 antibody (i.e., 180 mg) and anti-CTLA-4 antibody (i.e., 60 mg) at one time from the 3:1 ratio fixed dose formulation of anti-PD-1 antibody and anti-CTLA-4 antibody.

The term "immunotherapy" refers to the treatment of a subject suffering from a disease or at risk of infection or suffering from recurrence of a disease by a method that includes inducing, enhancing, suppressing or otherwise altering an immune response. "treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on the subject, or administration of an active agent to the subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing or preventing the onset, progression, development, severity or recurrence of a symptom, complication or disorder, or a biochemical indicator associated with a disease.

As used herein, "PD-L1 positive" may be used interchangeably with "at least about 1% PD-L1 expression". In one embodiment, PD-L1 expression may be used by any method known in the art. In another embodiment, PD-L1 expression is measured by automated IHC. PD-L1 positive tumors may thus have at least about 1%, at least about 2%, at least about 5%, at least about 10%, or at least about 20% of PD-L1 expressing tumor cells, as measured by automated IHC. In certain embodiments, "PD-L1 positive" means that there are at least 100 cells expressing PD-L1 on the cell surface.

"programmed death receptor-1 (PD-1)" means an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed primarily on previously activated T cells in vivo and binds to two ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes variants, homologs and species of human PD-1 (hPD-1), hPD-1, and analogs having at least one epitope in common with hPD-1.

"programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands (the other is PD-L2) directed against PD-1, which down-regulates T cell activation and cytokine secretion upon binding to PD-1.

"subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject" and "patient" are used interchangeably in certain contexts herein.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from onset of a disease or promotes regression of a disease as evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease-free symptom stages, or prevention of injury or disability caused by affliction of the disease. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems that predict efficacy for humans, or by assaying the activity of the agent in an in vitro assay.

As used herein, a "sub-therapeutic dose" refers to a dose of a therapeutic compound (e.g., an antibody) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).

As an example, an "anticancer agent" promotes cancer regression or prevents further tumor growth in a subject. In certain embodiments, a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer. By "promoting regression of cancer" is meant that administration of an effective amount of the drug, alone or in combination with an anti-neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free stages, or prevention of injury or disability caused by affliction of the disease. Furthermore, the terms "effective" and "effectiveness" in relation to treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote regression of cancer in a patient. Physiological safety means the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ and/or organism level caused by drug administration.

As an example for treating a tumor, a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to an untreated subject, or, in certain embodiments, relative to a patient treated with standard of care therapy. In other embodiments of the invention, tumor regression may be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these final measures of therapeutic effectiveness, the evaluation of immunotherapeutic drugs must also take into account "immune-related" response patterns.

An "immune-related" response pattern refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce an anti-tumor effect by inducing a cancer-specific immune response or by altering the innate immune process. This response pattern is characterized by a beneficial therapeutic effect after an initial increase in tumor burden or the appearance of new lesions, which will be classified as disease progression in the evaluation of traditional chemotherapeutic agents and will be synonymous with drug failure. Thus, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effect of these agents on target disease.

A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the occurrence or recurrence of cancer when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of recurrence of cancer. In certain embodiments, a prophylactically effective amount completely prevents the occurrence or recurrence of cancer. "inhibiting" the occurrence or recurrence of cancer refers to reducing the likelihood of occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer altogether.

The application of alternatives (e.g., "or") should be understood to refer to either, both, or any combination thereof. The indefinite articles "a" or "an" as used herein are to be understood to mean "one or more" of any listed or enumerated ingredient.

The terms "about," "approximately" or "substantially comprise" mean a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or measured, i.e., the limitations of the measurement system. For example, "about" or "substantially comprising" may mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "substantially comprising" may refer to a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3mg may include any number between 2.7mg to 3.3mg (for 10%) or between 2.4mg to 3.6mg (for 20%). Furthermore, in particular with respect to biological systems or processes, the term may refer to up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in the application and claims, unless otherwise indicated, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

The terms "about once a week", "about once every two weeks" or any other similar dosing interval terms as used herein refer to approximations. "about once a week" may include every 7 days + -1 day, i.e., every 6 days to every 8 days. "about once every two weeks" may include every 14 days + -3 days, i.e., every 11 days to every 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, an dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose may be administered on any day of the first week and then the second dose may be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to the administration of a first dose on a particular day of the first week (e.g., monday) and then a second dose on the same day of the sixth or twelfth week (i.e., monday), respectively. Similar principles apply to phrases including, but not limited to, "about 1 every 2 weeks", "about 1 every month", etc. … ….

As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the values of any integer within the recited range, and fractions thereof (such as tenths and hundredths of integers) as appropriate, unless otherwise indicated.

Unless specifically stated otherwise, "about" or "approximately" in the present invention means that the fluctuation is within + -5%, preferably within + -2%, and more preferably within + -1% of the specified numerical range given. For example, a pH of about 5.5 means a pH of 5.5.+ -. 5%, preferably a pH of 5.5.+ -. 2%, more preferably a pH of 5.5.+ -. 1%.

Detailed Description

The invention will be further described with reference to specific examples, which are, however, only intended to illustrate and not limit the scope of the invention. Also, the invention is not limited to any particular preferred embodiment described herein. It should be understood by those skilled in the art that equivalent substitutions and corresponding modifications of the technical features of the present invention are included in the scope of the present invention. The reagents used in the examples below are commercially available products, and the solutions may be formulated using techniques conventional in the art, unless otherwise specified. The anti-PD-L1 humanized monoclonal antibody in the example is prepared by the method described in WO2016022630, and the eluent containing the antibody is obtained by a conventional antibody purification method after affinity chromatography.

TABLE 1 abbreviation form

EXAMPLE 1 preclinical pharmacodynamic test

This example discloses the experimental results of pharmacodynamic studies of anti-PD-L1 antibodies in vitro and in mice.

hu5G11-hIgG1 binds to human PD-L1 protein with an EC50 of 21.3ng/mL; hu5G11-hIgG1 and human PD-L1 significantly induced secretion of IFN-gamma in CD4+ DC MLR, the effect was significantly dose-dependent, and the EC50 was 35.0+ -11.3 ng/mL, indicating that binding of hu5G11-hIgG1 to DC-expressed PD-L1 inhibited the PD-L1/PD-1 signaling pathway, thereby stimulating secretion of IFN-gamma in CD4+ T cells.

The tumor inhibition rate of hu5G11-hIgG1 (15 mg/kg, IP, Q2D X11) on MC-38/H-11 mice was 91.7% (all calculated on the basis of median tumor volume) and the survival time of the mice inoculated with MC-38/H-11 cells in the abdominal cavity was significantly prolonged, the median survival time was >98 days, and the survival rate by the end of the experiment (D98) was 80% (p <0.01 compared with the group of human IgG 15 mg/kg).

From this, in vivo and in vitro pharmacodynamic experiments prove that hu5G11-hIgG1 can prevent PD-L1 from combining with PD-1 and B7.1 receptors on the surface of T cells, so that the T cells can recover activity, and the immune response is enhanced, and the anti-tumor effect is exerted.

EXAMPLE 2 preclinical toxicology testing

This example discloses acute toxicity test and long-term toxicity test results of anti-PD-L1 antibodies in animals.

6 cynomolgus monkeys are used, and are divided into 2 groups, wherein 3 cynomolgus monkeys are used in each group, and both male and female are used. The hu5G11-hIgG 1-containing pharmaceutical composition of the present invention was administered at a dose of 10mg/mL at hu5G11-hIgG1 200 and 400mg/kg, respectively. The day of administration was the day of the test 1. Observing the general condition of each group of cynomolgus monkeys 14 days after administration; body weight was measured before dosing and on days 4, 9, and 14 of the trial; measuring the food intake on test days 2-3, 8-9 and 12-13; measuring body temperature, II-lead electrocardiogram and blood pressure before administration on the same day, about 0-1 hour after administration and on test day 14; carrying out hematology and blood biochemical detection on the 4 th and 14 th days of the test; all cynomolgus monkeys in each group were euthanized on day 15 of the trial and were subjected to anatomic observations. The test results show that: 200 mg/kg of the cynomolgus monkey intravenous injection is administered intravenously once, and no obvious abnormality is seen in general observation, weight, ingestion, body temperature, electrocardiogram, blood pressure, hematology, hematochemistry, urine routine and general anatomy, and the Maximum Tolerated Dose (MTD) is 400mg/kg.

The long-term toxicity test results show that the cynomolgus monkey is intravenous injected with the pharmaceutical composition containing hu5G11-hIgG1 for 4 weeks, and the medicine is stopped and recovered for 4 weeks, and the non-toxic reactant (NOAEL) is 200mg/kg.

Example 3 clinical phase I protocol and safety, tolerability results

This example discloses the pharmacokinetic and tolerogenic primary efficacy results of single-site, open, dose escalating clinical phase I trials.

Clinical phase I tolerability and pharmacokinetic studies incorporate patients with advanced malignancy who are well diagnosed, failed or lacking standard treatment, observing safety and tolerability with pharmaceutical compositions containing hu5G11-hIgG1, determining Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT).

The main end point is: DLT; MTD.

Secondary endpoint: pharmacokinetic evaluation; the anti-tumor treatment effect is primarily examined.

Safety and tolerability results showed that the hu5G11-hIgG 1-containing pharmaceutical compositions were administered to the group of patients 1, 3, 10, 20, 30 mg/kg. The administration was continued every 21 days for a period. The results show that patients currently in the group are well tolerated during continuous dosing, and that none of the adverse drug-related reactions exceed grade II. The current dosage is tolerable; 1-10mg/kg dose group cytokine detection, no cytokine storm was seen; serious adverse reactions associated with immunity were also not found.

Preliminary pharmacokinetic assessments showed that the serum drug exposure levels of the current group of patients, after the first intravenous infusion of the different doses (1, 3, 10 mg/kg) of the drug under test, were significantly dose dependent, exhibiting linear pharmacokinetic profiles.

Example 4 treatment results for patients with classical Hodgkin's lymphoma and primary mediastinum large B cell lymphoma

This example discloses the results of preliminary efficacy assessment of patients with classical hodgkin's lymphoma and primary mediastinal large B-cell lymphoma in the clinical phase I trial.

By 2018, 7 months, 2 classical hodgkin lymphoma subjects, and 1 primary mediastinal large B cell lymphoma patient, comprising: subject No. 3, having been histopathologically diagnosed as a classical hodgkin lymphoma patient, having had a pathological tissue acquisition pathway of surgery, had developed lymph node metastasis, and had previously undergone surgical treatment, radiation treatment, and chemotherapy; subject No. 5, primary mediastinal large B-cell lymphoma patient by histopathological diagnosis; subject 6, with histopathological diagnosis of classical hodgkin's lymphoma, with a pathological tissue acquisition route of tissue biopsy, underwent pleural and local chest wall metastasis, previously undergoing chemotherapy.

In terms of efficacy assessment, subject No. 3 received a dose of 3mg/kg body weight, 1 cycle for 21 days, continued dosing, and after 9 weeks the primary tumor evaluation target lesions were reduced by 73% from baseline, and after 18 weeks the target lesions were reduced by 76% from baseline. Subject No. 5 received a 10mg/kg body weight dose for 1 cycle over 21 days, with continued dosing, to 27 weeks of disease Stabilization (SD). Subject 6 received a dose of 10mg/kg body weight, 1 cycle for 21 days, continued dosing, and after 9 weeks the primary tumor evaluation target lesions were reduced by 55% from baseline, and after 18 weeks the target lesions were reduced by 75% from baseline. Meanwhile, table 2 shows the treatment progress for the cHL and rrPMBCL patients who had entered the group. These results suggest that hu5G11-hIgG1 containing pharmaceutical compositions significantly controlled disease in cHL and rrPMBCL patients.

Table 2 patient treatment progression in group cHL and rrPMBCL

* Lymphoma units are mm ²

In accordance with the present disclosure, while the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention.

The disclosures of all documents cited herein are hereby incorporated by reference to the extent that they provide exemplary, procedural and other details supplementary to those set forth herein.

Sequence listing

<110> the pharmaceutical industry group Co., ltd

CHIA TAI TIANQING PHARMACEUTICAL GROUP NANJING SHUNXIN PHARMACEUTICAL Co.,Ltd.

<120> use of anti-PD-L1 monoclonal antibodies for the treatment of cancer

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Gln Gln Asp Tyr Thr Ser Pro Tyr Thr

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Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

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Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met

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Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu

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Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

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Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

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Thr Val Ser Ser

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Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

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Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys

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Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

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Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala

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Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

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Thr Val Ser Ser

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Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

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Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

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Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

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Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

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Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu

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Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

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Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

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Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

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Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

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Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

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Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

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Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

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Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

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Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

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Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

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Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val

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Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

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Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

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Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

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Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

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Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

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Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

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Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

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Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

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Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

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Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

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Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

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Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

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Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly

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Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

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Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr

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Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

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Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

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Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

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Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

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Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

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Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

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Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

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Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys

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Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

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Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala

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Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

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Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

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Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

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Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

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Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

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Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

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Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

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Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

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Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val

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Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 20

<211> 218

<212> PRT

<213> Synthetic sequence

<400> 20

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser

20 25 30

Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 21

<211> 442

<212> PRT

<213> Synthetic sequence

<400> 21

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr

20 25 30

Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met

50 55 60

Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu

65 70 75 80

Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro

210 215 220

Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

Claims (15)

1. Use of an anti-PD-L1 antibody in the preparation of a medicament for treating primary mediastinal large B-cell lymphoma in a host, wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region as in SEQ ID NO:1, a heavy chain CDR2 region as in SEQ ID NO:2, a heavy chain CDR3 region as in SEQ ID NO:3, a light chain CDR1 region as in SEQ ID NO:7, a light chain CDR2 region as in SEQ ID NO:8, and a light chain CDR3 region as in SEQ ID NO:9. 2. The use according to claim 1, wherein the anti-PD-L1 antibody comprises: the heavy chain variable region shown in SEQ ID NO:13 and the light chain variable region shown in SEQ ID NO:15. 3. The use according to claim 1, wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO:17 and the light chain amino acid sequence shown in SEQ ID NO:18. 4. The use according to claim 1, wherein the subject is a human patient. 5. The use according to claim 1, wherein the anti-PD-L1 antibody is administered at a dose of 1 mg/kg, 3 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, or 30 mg/kg body weight. 6. The use according to claim 1, wherein the anti-PD-L1 antibody is administered in one or more uniform doses, the uniform dose being 1200 mg of anti-PD-L1 antibody. 7. The use according to claim 6, wherein a uniform dose of anti-PD-L1 antibody is administered every 3 weeks. 8. The use according to claim 1, wherein the anti-PD-L1 antibody is administered at a dose of 1200 mg every 3 weeks. 9. The use according to claim 7 or 8, wherein the anti-PD-L1 antibody is administered via intravenous infusion. 10. The use according to claim 9, wherein the anti-PD-L1 antibody is administered as a 1-hour intravenous infusion. 11. The use according to claim 1, wherein the primary mediastinal large B-cell lymphoma is relapsed and/or refractory primary mediastinal large B-cell lymphoma. 12. The use according to claim 11, wherein the primary mediastinal large B-cell lymphoma is recurrent primary mediastinal large B-cell lymphoma. 13. The use according to claim 11, wherein the primary mediastinal large B-cell lymphoma is refractory primary mediastinal large B-cell lymphoma. 14. The use according to claim 1, wherein the primary mediastinal large B-cell lymphoma is a metastatic primary mediastinal large B-cell lymphoma. 15. The use according to claim 14, wherein the metastatic primary mediastinal large B-cell lymphoma is a metastatic relapsed and/or refractory primary mediastinal large B-cell lymphoma.