Anti-B7-H1 antibodies for tumor treatment

Abstract

Provided herein are methods for treating tumors expressing B7-H1 comprising administering an effective amount of MEDI4736 or an antigen-binding fragment thereof.

Description

[0001] background

[0002] Cancer remains a major global health burden. Despite advances in the treatment of cancer, there remains an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancer that is resistant to existing therapeutics.

[0003] The immune system is able to identify tumor-associated antigens and eliminate cancerous cells that express them. This process of tumor immune surveillance or tumor immunoediting plays an important role in preventing and resisting tumor growth, and the level of tumor-infiltrating lymphocytes (and more precisely cytotoxic T cells) is associated with improved prognosis in many cancers. Therefore, enhancing the immune response can provide a means of controlling tumors.

[0004] B7-H1 (also known as programmed death ligand 1 (PD-L1) or CD274) is part of a complex system involving receptors and ligands that control T-cell activation. In normal tissues, B7-H1 is expressed on T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, and various non-hematopoietic cells. The normal function of B7-H1 is to regulate the balance between T-cell activation and tolerance by interacting with its two receptors: programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1).

[0005] B7-H1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system. B7-H1 is expressed at high frequencies in a wide range of cancers. In some cancers, the expression of B7-H1 is associated with decreased survival and unfavorable prognosis. Antibodies that block the interaction between B7-H1 and its receptors can relieve B7-H1-dependent immunosuppression in vitro and enhance the cytotoxic activity of anti-tumor T cells.

[0006] MEDI4736 is a human monoclonal antibody against human B7-H1 that blocks the binding of B7-H1 to both PD-1 and CD80 receptors. Therefore, given the high unmet need for treating tumors, including those with high morbidity and uncommon types with limited treatment options and poor outcomes, the effect of MEDI4736 on tumors was examined in human patients.

[0007] Brief Overview

[0008] Provided herein are methods of administering MEDI4736 to human patients and methods of using MEDI4736 to treat tumors in human patients.

[0009] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering MEDI4736 or an antigen-binding fragment thereof to the patient, wherein the administration reduces tumor size.

[0010] In certain aspects, a method of minimizing anti-drug antibodies produced by a human patient having a tumor expressing B7-H1 comprises administering MEDI4736 or an antigen-binding fragment thereof to the patient, wherein the patient is being treated with an anti-B7-H1 antibody or antigen-binding fragment thereof.

[0011] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering MEDI4736 or an antigen-binding fragment thereof to the patient, wherein the administration produces an AUC(τ) of about 100 d·μg / mL to about 2,500 d·μg / mL.

[0012] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering MEDI4736 or an antigen-binding fragment thereof to the patient, wherein the administration produces a Cmax of about 15 μg / mL to about 350 μg / mL.

[0013] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering to the patient MEDI4736 or an antigen-binding fragment thereof, wherein the half-life of MEDI4736 or an antigen-binding fragment thereof is about 5 days to about 25 days.

[0014] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering MEDI4736 or an antigen-binding fragment thereof to the patient, wherein the clearance rate of MEDI4736 or an antigen-binding fragment thereof is about 1-10 mL / day / kg.

[0015] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering to the patient a dose of about 3 mg / kg MEDI4736 or an antigen-binding fragment thereof.

[0016] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering to the patient a dose of about 15 mg / kg MEDI4736 or an antigen-binding fragment thereof.

[0017] In certain aspects, a method of treating a tumor expressing B7-H1 in a human patient comprises administering MEDI4736 or an antigen-binding fragment thereof, wherein administration of 1 mg / kg of the MEDI4736 or an antigen-binding fragment thereof is sufficient to reduce tumor size.

[0018] In some embodiments, at least two doses of MEDI4736 or an antigen-binding fragment thereof are administered. In some embodiments, at least 3 doses of MEDI4736 or an antigen-binding fragment thereof are administered. In some embodiments, at least 5 doses of MEDI4736 or an antigen-binding fragment thereof are administered.

[0019] In some embodiments, the administration reduces tumor growth. In some embodiments, the administration reduces tumor size. In some embodiments, the administration reduces tumor size by at least 25%. In some embodiments, the administration reduces tumor size by at least 50%. In some embodiments, the administration reduces tumor size by at least 75%.

[0020] In some embodiments, the administration minimizes the likelihood of anti-drug antibodies produced by the patient. In some embodiments, no more than 10% of patients treated with MEDI4736 produce anti-drug antibodies. In some embodiments, no more than 9% of patients treated with MEDI4736 produce anti-drug antibodies. In some embodiments, no more than 8% of patients treated with MEDI4736 produce anti-drug antibodies. In some embodiments, no more than 7% of patients treated with MEDI4736 produce anti-drug antibodies.

[0021] In some embodiments, the administration produces a median range of AUC (τ) measurements. Thus, for example, in some embodiments, the administration produces an AUC (τ) of about 100 d μg / mL to about 2,500 d μg / mL. In some embodiments, the administration produces a median range of Cmax measurements. Thus, for example, in some embodiments, the administration produces a Cmax of about 15 μg / mL to about 350 μg / mL. In some embodiments, the administration produces a median range of half-life measurements. Thus, for example, in some embodiments, the half-life of the MEDI4736 or its antigen-binding fragment is about 5 days to about 25 days. In some embodiments, the administration produces a median range of clearance rate measurements. Thus, for example, in some embodiments, the clearance rate of the MEDI4736 or its antigen-binding fragment is about 1-10 ml / day / kg.

[0022] In some embodiments, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 15 mg / kg of MEDI4736 or an antigen-binding fragment thereof is administered. In some embodiments, about 1 mg / kg of MEDI4736 or an antigen-binding fragment thereof is administered. In some embodiments, about 3 mg / kg of MEDI4736 or an antigen-binding fragment thereof is administered. In some embodiments, about 10 mg / kg of MEDI4736 or an antigen-binding fragment thereof is administered. In some embodiments, about 15 mg / kg of MEDI4736 or an antigen-binding fragment thereof is administered.

[0023] In some embodiments, the administration is repeated about every 14 to 21 days. In some embodiments, the administration is repeated about every 14 days. In some embodiments, the administration is repeated about every 21 days.

[0024] In some embodiments, the tumor size is reduced or tumor growth is reduced, and MEDI4736 or an antigen-binding fragment thereof is subsequently administered as a maintenance therapy approximately every 2 months.

[0025] In some embodiments, the tumor size is reduced by at least 25% in about 6 weeks. In some embodiments, the administration reduces the size of the tumor by at least 50%. In some embodiments, the tumor size is reduced by at least 50% in about 10 weeks. In some embodiments, the administration reduces the size of the tumor by at least 75%. In some embodiments, the tumor size is reduced by at least 75% in about 10 weeks.

[0026] In some embodiments, the administration produces a partial response. In some embodiments, the administration produces a complete response. In some embodiments, the administration increases progression-free survival (PFS). In some embodiments, the administration increases overall survival (OS).

[0027] In some embodiments, the administration can reduce free B7-H1 levels by at least 80%. In some embodiments, the administration can reduce free B7-H1 levels by at least 90%. In some embodiments, the administration can reduce free B7-H1 levels by at least 95%. In some embodiments, the administration can reduce free B7-H1 levels by at least 99%. In some embodiments, the administration can reduce the growth rate of B7-H1 levels.

[0028] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is a melanoma, a renal cell carcinoma, a non-small cell lung cancer, or a colorectal cancer. In some embodiments, the tumor is a melanoma. In some embodiments, the tumor is a renal cell carcinoma. In some embodiments, the tumor is a non-small cell lung cancer. In some embodiments, the tumor is a colorectal cancer.

[0029] In some embodiments, the tumor is NSCLC (squamous cell carcinoma), hepatocellular carcinoma (HCC), triple negative breast cancer (TNBC), pancreatic cancer, GI cancer, melanoma, uveal melanoma, or squamous cell carcinoma of the head and neck (SCCHN). In some embodiments, the tumor is NSCLC (squamous cell carcinoma). In some embodiments, the tumor is HCC. In some embodiments, the tumor is TNBC. In some embodiments, the tumor is pancreatic cancer. In some embodiments, the tumor is GI cancer. In some embodiments, the tumor is melanoma. In some embodiments, the tumor is uveal melanoma. In some embodiments, the tumor is SCCHN.

[0030] In some embodiments, the tumor is melanoma, renal cell carcinoma, non-small cell lung cancer (squamous cell), non-small cell lung cancer (non-squamous cell), colorectal cancer, HCC, TNBC, pancreatic cancer, GI cancer, uveal melanoma, or SCCHN.

[0031] In some embodiments, the tumor is refractory to at least one chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin, Bevacizumab, Erlotinib or Pemetrexed.

[0032] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0033] In some embodiments, the administration is by intravenous infusion. In some embodiments, the administration occurs within about one hour.

[0034] In certain aspects of the methods provided herein, administering MEDI4736 or an antigen-binding fragment thereof produces Figure 4-Figure 6 The pharmacokinetic curves are shown in .

[0035] In certain aspects of the provided methods, administration of MEDI4736 or an antigen-binding fragment thereof produces a pharmacokinetic profile as obtained in Example 2.

[0036] In certain aspects of the methods provided herein, administering MEDI4736 or an antigen-binding fragment thereof produces Figure 7-Figure 9 Tumor treatment as shown in .

[0037] In certain aspects of the provided methods, administration of MEDI4736 or an antigen-binding fragment thereof results in tumor treatment as shown in Example 2.

[0038] The present invention also provides a method for quantifying soluble B7-H1 as shown in Example 3.

[0039] In another aspect, the invention provides a method of treating a patient identified as having a tumor expressing B7-H1, the method involving administering MEDI4736 or an antigen-binding fragment thereof to the human patient, wherein the patient is identified by detecting B7-H1 expression in one or more tumor cells.

[0040] In another aspect, the invention provides a method of increasing the efficacy of a MEDI4736 cancer treatment, the method involving administering MEDI4736 to a human patient identified as having tumor cells that express B7-H1.

[0041] In various embodiments of the previous aspects, B7-H1 is detected using immunohistochemistry, for example, in formalin-fixed and paraffin-embedded tumor samples. In other embodiments, at least 25% of these tumor cells contain B7-H1-membrane staining. In other embodiments, there is a 40% or 50% objective response rate in patients identified as having tumors expressing B7-H1. In other embodiments, the tumor is melanoma, renal cell carcinoma, non-small cell lung cancer, pancreatic cancer, gastroesophageal cancer, uveal melanoma, triple-negative breast cancer, hepatocellular carcinoma, squamous cell carcinoma, or colorectal cancer. In other embodiments, the tumor is non-small cell lung cancer (e.g., squamous cell carcinoma or non-squamous cell carcinoma). In other embodiments, the tumor is head and neck squamous cell carcinoma. In other embodiments, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 15 mg / kg MEDI4736 or its antigen-binding fragment is administered. In specific embodiments, the administration is repeated approximately every 14 days or 21 days. In other embodiments, at least two, three, four or five doses of MEDI4736 are administered.

[0042] Brief description of the attached drawings / figures

[0043] Figure 1 A timeline of treatment with MEDI4736 administered intravenously (IV) every two weeks (Q2W) is shown. Immune-related response criteria (irRC) were measured after weeks 6, 12, and 16 and then every 8 weeks.

[0044] Figure 2AThe study flow chart for the dose-expansion and dose-escalation portions of the study is shown. The dose-expansion portion of the study was conducted using a two-week dosing schedule (Q2W) and a three-week dosing schedule (Q3W). Patients with non-small cell lung cancer (NSCLC), melanoma, and other tumors were evaluated in the escalation portion of the study; Figure 2B Expanding tumor types are shown.

[0045] Figure 3 Baseline demographics for subjects treated with 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, or 15 mg / kg of MED4736 in the dose-escalation study are shown.

[0046] Figure 4 Shown is a summary of the pharmacokinetic data obtained following dosing of MEDI4736 at 0.1 mg / kg or 0.3 mg / kg (Q2W) during the dose-escalation phase of the study. "AUC" = Area Under the Curve; "Cmax" = Maximum Observed Concentration (Panel A).

[0047] Figure 5 Shown are the concentrations of MEDI4736 observed over time in patients receiving 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg of MEDI4736 (Q2W) during the dose-escalation phase of the study.

[0048] Figure 6 Shown is target binding observed over time in patients receiving 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg or 10 mg / kg MEDI4736 (Q2W) during the dose-escalation phase of the study. "LLOQ" = lower limit of quantitation.

[0049] Figure 7 The clinical activity of MEDI4736 observed in patients with non-small cell lung cancer (NSCLC), melanoma, or colorectal cancer (CRC) who received 0.1 mg / kg, 0.3 mg / kg, or 1 mg / kg of MEDI4736 is shown. Best response was characterized as stable disease (SD), progressive disease (PD), partial response (PR), or not evaluable (NE).

[0050] Figure 8 The effect of MEDI4736 on tumor size is shown in patients receiving 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 10 mg / kg or 15 mg / kg of MEDI4736.

[0051] Fig. 9Shown are the effects of 10 mg / kg MEDI4736 on NSCLC tumors.

[0052] Fig.10 The percent change in tumor size from baseline is shown for all dose levels for NSCLC (non-squamous and squamous).

[0053] Fig.11 The percent change in tumor size from baseline is shown for all dose levels for advanced cutaneous melanoma.

[0054] Fig.12 Shown are the percent change in tumor size from baseline for SCCHN patients treated with 10 mg / kg MEDI4736 2QW.

[0055] Fig.13 The percent change in tumor size from baseline is shown for pancreatic cancer patients treated with 10 mg / kg MEDI4736 2QW (Panel A); the best change in tumor size from baseline is shown in Panel B.

[0056] Fig.14 A and Fig.14 B shows the percent change in tumor size from baseline for gastroesophageal cancer patients treated with 10 mg / kg MEDI4736 2QW ( Fig.14 A) The best change in tumor size from baseline is shown in Fig.14 In B.

[0057] Fig.15 The percent change in tumor size from baseline is shown for hepatocellular carcinoma (HCC) patients treated with 10 mg / kg MEDI4736 2QW. The best change in tumor size from baseline is shown in panel B.

[0058] Fig.16 Shown is the percent change in tumor size from baseline for triple-negative breast cancer (TNBC) patients treated with 10 mg / kg MEDI4736 2QW.

[0059] Fig.17 Shown is the percent change in tumor size from baseline for uveal melanoma patients treated with 10 mg / kg MEDI4736 2QW.

[0060] Fig.18A shows a comparison of the percentage change in tumor size relative to baseline for NSCLC patients treated with 10 mg / kg MEDI4736 2QW for 2 scans assessable. The graph shows patients with PD-L1 positive tumors, PD-L1 negative tumors, and patients whose PD-L1 tumor status is unavailable. Patients identified as smokers are shown with asterisks. The ORR (confirmed CR+PR) for all patients was 3.7%. The ORR rate for PD-L1+ patients was 10%.

[0061] Fig.18 B shows a comparison of the percentage change in tumor size relative to baseline for NSCLC patients treated with MEDI47362QW at all dose levels that can be evaluated for 1 scan. The graph shows patients with PD-L1 positive tumors, PD-L1 negative tumors, and patients whose PD-L1 tumor status is unavailable. Patients identified as smokers are shown with asterisks. The ORR (confirmed CR+PR) for all confirmed patients was 4.3% (the ORR for all unconfirmed patients was 8.5%). The ORR rate for PD-L1+ patients was 8.3%.

[0062] Fig.19 Shown are changes in tumor size for the six tumor types in increasing stages.

[0063] Fig. 20 Shown is the response of a pancreatic cancer patient treated with 10 mg / kg Q2W MEDI4736. Panel A shows the initial screening and Panel B shows the subject at Week 6.

[0064] Fig.21 Shown are responses in a female patient with SCCHN before (Panel A) and after (Panel B) treatment with 2 infusions of 10 mg / kg MEDI4736.

[0065] Fig. 22 Shown is staining of PD-L1 in tissue (fresh biopsy) from a subject with NSCLC.

[0066] Fig.23 Shown is staining of PD-L1 in subject tissue (fresh biopsy) indicative of neoplastic and immune cells.

[0067] Fig.24 Shown is staining of PD-L1 in subject tissue indicative of neoplastic and immune cells as well as endothelial cells.

[0068] Figures 25A-25C Shown is the response to MEDI4736 treatment in patients relative to their PD-L1 tumor status. Fig.25Ais a spider web curve showing tumor size after MEDI4736 treatment in non-squamous NSCLC and squamous NSCLC. Fig.25B is a spider web curve showing tumor size after MEDI4736 treatment in PD-L1 positive and PD-L1 negative NSCLC tumors. Fig.25C is a waterfall curve showing the change in tumor size in PD-L1 positive and PD-L1 negative NSCLC patients.

[0069] Detailed description

[0070] It should be noted that the term "a" or "an" entity refers to one or more of the entity; for example, "an anti-B7-H1 antibody" is understood to mean one or more anti-B7-H1 antibodies. Therefore, the terms "a" (or "an"), "one or more (one or more)", and "at least one (at least one)" can be used interchangeably herein.

[0071] Methods for treating cancer are provided herein. The methods provided include administering an effective amount of MEDI4736 or an antigen-binding fragment thereof.

[0072] Information about MEDI4736 (or a fragment thereof) for use in the methods provided herein can be found in International Application Publication No. WO 2011 / 066389 A1, the disclosure of which is incorporated herein by reference in its entirety. The fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to complement component C1q and Fcγ receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC). MEDI4736 is selective for B7-H1 and blocks binding of B7-H1 to PD-1 and CD80 receptors. MEDI4736 can relieve B7-H1-mediated inhibition of human T-cell activation in vitro and inhibit tumor growth in a xenograft model through a T-cell-dependent mechanism.

[0073] MEDI4736 and its antigen-binding fragments used in the methods provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a specific aspect, MEDI4736 or its antigen-binding fragments used in the methods provided herein comprise a light chain variable region and a heavy chain variable region, the light chain variable region comprises an amino acid sequence of SEQ ID NO: 1, and the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 2. In a specific aspect, MEDI4736 or its antigen-binding fragments used in the methods provided herein comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1, CDR2, and CDR3 sequence defined by Kabat of SEQ ID NO: 3-5, and wherein the light chain variable region comprises a CDR1, CDR2, and CDR3 sequence defined by Kabat of SEQ ID NO: 6-8. Those skilled in the art will be able to easily identify Chothia's definition, Abm's definition, or other CDR definitions known to those skilled in the art. In specific aspects, MEDI4736 or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as disclosed in WO 2011 / 066389A1, which is incorporated herein by reference in its entirety.

[0074] In certain aspects, patients presenting with tumors are given MEDI4736 or an antigen-binding fragment thereof. MEDI4736 or an antigen-binding fragment thereof can be given only once or occasionally, and still provide benefits to the patient. In other aspects, the patient is given additional subsequent doses. Subsequent doses may be given at different time intervals depending on the patient's age, weight, clinical evaluation, tumor load, and / or other factors (including the judgment of the attending physician).

[0075] The intervals between doses can be every two weeks. The intervals between doses can be every three weeks. The intervals between doses can be every two months (e.g., during a maintenance phase).

[0076] The dosing interval can also be about every 14 days or about every 21 days. In some embodiments, "about" every 14 days or "about" every 21 days indicates 14 days + / - 2 days or 21 days + / - 2 days. In some embodiments, MEDI4736 is administered about every 14 to 21 days.

[0077] In some embodiments, at least two doses of MEDI4736 or an antigen binding fragment thereof are administered to the patient. In some embodiments, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, or at least fifteen doses or more may be administered to the patient. In some embodiments, MEDI4736 or an antigen binding fragment thereof is administered within a two-week treatment cycle, within a four-week treatment cycle, within a six-week treatment cycle, within an eight-week treatment cycle, within a twelve-week treatment cycle, within a twenty-four-week treatment cycle, or within a year or more treatment cycle. In some embodiments, MEDI4736 or an antigen binding fragment thereof is administered within a three-week treatment cycle, within a six-week treatment cycle, within a nine-week treatment cycle, within a twelve-week treatment cycle, within a twenty-four-week treatment cycle, or within a year or more treatment cycle. In some embodiments, MEDI4736 or an antigen binding fragment thereof is administered within a two-month treatment cycle, within a four-month treatment cycle, or within a six-month or more treatment cycle (e.g., during the maintenance phase).

[0078] The amount of MEDI4736 or an antigen-binding fragment thereof to be administered to the patient will depend on various parameters, such as the patient's age, weight, clinical evaluation, tumor burden and / or other factors, including the judgment of the attending physician.

[0079] In certain aspects, the patient is given one or more doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 0.1 mg / kg. In certain aspects, the patient is given one or more doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 0.3 mg / kg. In certain aspects, the patient is given one or more doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 1 mg / kg. In certain aspects, the patient is given one or more doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 3 mg / kg. In certain aspects, the patient is given one or more doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 10 mg / kg. In certain aspects, the patient is given one or more doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 15 mg / kg.

[0080] In certain aspects, the patient is given at least two doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 0.1 mg / kg. In certain aspects, the patient is given at least two doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 0.3 mg / kg. In certain aspects, the patient is given at least two doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 1 mg / kg. In certain aspects, the patient is given at least two doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 3 mg / kg. In certain aspects, the patient is given at least two doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 10 mg / kg. In certain aspects, the patient is given at least two doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 15 mg / kg. In some embodiments, the at least two doses are given about two weeks apart. In some embodiments, the at least two doses are given about three weeks apart.

[0081] In certain aspects, the patient is given at least three doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 0.1 mg / kg. In certain aspects, the patient is given at least three doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 0.3 mg / kg. In certain aspects, the patient is given at least three doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 1 mg / kg. In certain aspects, the patient is given at least three doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 3 mg / kg. In certain aspects, the patient is given at least three doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 10 mg / kg. In certain aspects, the patient is given at least three doses of MEDI4736 or its antigen binding fragment, wherein the dose is about 15 mg / kg. In some embodiments, the at least three doses are given about two weeks apart. In some embodiments, the at least three doses are given about three weeks apart.

[0082] In certain aspects, administration of MEDI4736 or an antigen-binding fragment thereof according to the methods provided herein is by parenteral administration. For example, MEDI4736 or an antigen-binding fragment thereof can be administered by intravenous infusion or by subcutaneous injection. In some embodiments, the administration is by intravenous infusion.

[0083] In certain aspects, MEDI4736 or an antigen-binding fragment thereof is administered in combination or in conjunction with additional cancer therapies according to the methods provided herein. Such therapies include, but are not limited to, chemotherapeutic agents such as vemurafenib, erlotinib, afatinib, cetuximab, carboplatin, bevacizumab, erlotinib or pemetrexed or other chemotherapeutic agents, as well as radiation or any other anti-cancer treatment.

[0084] These methods provided herein can reduce tumor size, delay tumor growth or maintain a stable state. In certain aspects, based on appropriate statistical analysis, the reduction of the tumor size can be significant. The reduction of tumor size can be measured by comparing the size of the patient's tumor at baseline, for the expected tumor size, for the expected tumor size based on a large patient population, or for the tumor size of a control population. In certain aspects provided herein, giving MEDI4736 can reduce tumor size by at least 25%. In certain aspects provided herein, giving MEDI4736 can reduce tumor size by at least 25% within about 6 weeks of the first treatment. In certain aspects provided herein, giving MEDI4736 can reduce tumor size by at least 50%. In certain aspects provided herein, giving MEDI4736 can reduce tumor size by at least 50% within about 10 weeks of the first treatment. In certain aspects provided herein, giving MEDI4736 can reduce tumor size by at least 75%. In certain aspects provided herein, giving MEDI4736 can reduce tumor size by at least 75% within about 10 weeks of the first treatment.

[0085] In certain aspects, use of the methods provided herein, i.e., administration of MEDI4736 or an antigen-binding fragment thereof, can reduce tumor size within 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks of the first treatment.

[0086] In some embodiments, administration of 1 mg / kg of MEDI4736 or an antigen-binding fragment thereof (e.g., at least one dose, at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses or more every two weeks or three weeks) can be sufficient to reduce tumor size. However, as provided herein, larger doses can also be administered, for example, in order to optimize efficacy, the number of doses required, or certain pharmacokinetic parameters.

[0087] These methods provided herein can reduce or delay tumor growth. In some aspects, the reduction or delay can be statistically significant. The reduction of tumor growth can be measured by comparing with the growth of the patient's tumor at baseline, for expected tumor growth, for expected tumor growth based on a large patient population, or for the tumor growth of a control population.

[0088] In certain aspects, the patient achieves disease control (DC).Disease control can be a complete response (CR), a partial response (PR), or stable disease (SD).

[0089] A "complete response" (CR) is the disappearance of all lesions, whether measurable or non-measurable, and the absence of new lesions. Confirmation can be obtained using repeated serial assessments no less than four weeks from the date of the first record. New non-measurable lesions exclude CR.

[0090] A "partial response" (PR) is a ≥50% reduction in tumor burden relative to baseline. Confirmation can be obtained using serial repeated assessments for at least 4 weeks from the date of first documentation.

[0091] "Progressive disease" (PD) is defined as an increase in tumor burden of ≥ 25% relative to the lowest recorded value (nadir). Confirmation can be obtained by serial repeat assessments at least 4 weeks from the date of first record. New non-measurable lesions do not define PD.

[0092] “Stable disease” (SD) means not meeting the criteria for CR, PR, or PD.

[0093] In certain aspects, administration of MEDI4736 or an antigen-binding fragment thereof can increase progression-free survival (PFS).

[0094] In certain aspects, administration of MEDI4736 or an antigen-binding fragment thereof can increase overall survival (OS).

[0095] In certain aspects, the patient has a specific type of tumor. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a melanoma, a renal cell carcinoma, a non-small cell lung cancer (e.g., a squamous or adenocarcinoma), or a colorectal cancer. In some embodiments, the tumor is a melanoma, a non-small cell lung cancer (e.g., a squamous or adenocarcinoma), or a colorectal cancer. In some embodiments, the tumor is a melanoma. In some embodiments, the tumor is a renal cell carcinoma. In some embodiments, the tumor is a non-small cell lung cancer. In some embodiments, the tumor is a colorectal cancer.

[0096] In some embodiments, the tumor is NSCLC (squamous cell carcinoma), hepatocellular carcinoma (HCC), triple negative breast cancer (TNBC), pancreatic cancer, GI cancer, melanoma, uveal melanoma, or squamous cell carcinoma of the head and neck (SCCHN). In some embodiments, the tumor is NSCLC (squamous cell carcinoma). In some embodiments, the tumor is HCC. In some embodiments, the tumor is TNBC. In some embodiments, the tumor is pancreatic cancer. In some embodiments, the tumor is GI cancer. In some embodiments, the tumor is melanoma. In some embodiments, the tumor is uveal melanoma. In some embodiments, the tumor is SCCHN.

[0097] In some embodiments, the tumor is melanoma, renal cell carcinoma, non-small cell lung cancer (squamous cell), non-small cell lung cancer (non-squamous cell), colorectal cancer, HCC, TNBC, pancreatic cancer, GI cancer, uveal melanoma, or SCCHN.

[0098] In some embodiments, the patient has previously received treatment with at least one chemotherapeutic agent. In some embodiments, the patient has previously received treatment with at least two chemotherapeutic agents. The chemotherapeutic agent can be, for example and without limitation, vemurafenib, erlotinib, afatinib, cetuximab, carboplatin, bevacizumab, erlotinib, and / or pemetrexed.

[0099] In some embodiments, the tumor is refractory to at least one chemotherapeutic agent or the tumor is resistant to at least one chemotherapeutic agent. In some embodiments, the tumor is refractory to at least two chemotherapeutic agents or the tumor is resistant to at least two chemotherapeutic agents. The tumor may be refractory to or resistant to one or more of the following: for example and without limitation, vemurafenib, erlotinib, afatinib, cetuximab, carboplatin, bevacizumab, erlotinib, and / or pemetrexed.

[0100] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) (Oken MM et al., Am. J. Clin. Oncol. 5:649–55 (1982)) performance status of 0 or 1 prior to administration of MEDI4736 or an antigen-binding fragment thereof.

[0101] According to the methods provided herein, administration of MEDI4736 or its antigen-binding fragment can produce desired pharmacokinetic parameters. The "area under the curve" (AUC) can be used to assess total drug exposure. "AUC (τ)" refers to the AUC until the end of the dosing cycle, and "AUC (inf)" refers to the AUC until infinite time. The administration can produce an AUC (τ) of about 100 d·μg / mL to about 2,500 d·μg / mL. The administration can produce an observed maximum concentration (Cmax) of about 15μg / mL to about 350μg / mL. The half-life of the MEDI4736 or its antigen-binding fragment can be about 5 days to about 25 days. In addition, the clearance rate of the MEDI4736 or its antigen-binding fragment can be about 1-10 ml / day / kg.

[0102] As provided herein, MEDI4736 or its antigen binding fragment can also reduce the level of free B7-H1. Free B7-H1 refers to B7-H1 that is not bound (e.g., by MEDI4736). In some embodiments, the level of B7-H1 is reduced by at least 80%. In some embodiments, the level of B7-H1 is reduced by at least 90%. In some embodiments, the level of B7-H1 is reduced by at least 95%. In some embodiments, the level of B7-H1 is reduced by at least 99%. In some embodiments, after administering MEDI4736 or its antigen binding fragment, the level of B7-H1 is eliminated. In some embodiments, for example, administering MEDI4736 or its antigen binding fragment reduces the growth rate of B7-H1 levels compared to the growth rate of B7-H1 levels before administering MEDI4736 or its antigen binding fragment.

[0103] Advantageously, the methods of administration provided herein also minimize the anti-drug antibody response provided herein. Thus, in some embodiments, administration of MEDI4736 or an antigen-binding fragment thereof to a patient in need of treatment with anti-B7-H1, anti-B7-1 or anti-PD-1 minimizes the anti-drug antibodies produced by the patient. In some embodiments, in patients treated with MEDI4736, anti-drug antibodies do not affect MEDI4736 exposure.

[0104] Examples

[0105] Example 1: Patients and Methods

[0106] (a) Subjects

[0107] Subjects in this study are required to be 18 years of age or older and have advanced malignant melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), or colorectal cancer (CRC) that is refractory to standard therapy or for which there is no standard therapy. Subjects in the dose-expansion phase of the study will be adults with advanced malignant melanoma, NSCLC, or CRC that is refractory to standard therapy or for which there is no standard therapy. Additional subjects in the dose-expansion phase have NSCLC (squamous cell carcinoma), hepatocellular carcinoma (HCC), triple-negative breast cancer (TNBC), pancreatic cancer, GI cancer, melanoma, uveal melanoma, or squamous cell carcinoma of the head and neck (SCCHN). These cancers must be confirmed histologically or cytologically. These subjects are required to have an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and adequate organ and bone marrow function. Adequate organ and bone marrow function is defined as: hemoglobin ≥9g / dL; absolute neutrophil count ≥1,500 / mm 3 ; Lymphocyte count ≥800 / mm 3 ; Platelet count ≥100,000 / mm 3 ; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × conventional upper limit of normal (ULN); Bilirubin ≤ 1.5 × ULN, except in cases where the subject has documented or suspected Gilbert's disease (for these subjects, bilirubin must be ≤ 5 × ULN); Creatinine clearance ≥ 50 mL / min as determined by the Cockcroft-Gault equation or by a 24-hour urine collection for determination of creatinine clearance.

[0108] Subjects could not participate if they had active autoimmune disease, prior anti-PD-1 or anti-PD-L1 therapy, or prior severe or persistent immune-related adverse events (irAEs). Subjects were not allowed to have any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment, but concurrent use of hormones for non-cancer related conditions was allowed (e.g., insulin for diabetes and hormone replacement therapy).

[0109] (b) Research design

[0110] The study was a multicenter, open-label, Phase 1, first-in-human dose-escalation and dose-expansion study in which multiple doses of MEDI4736 were administered by intravenous (IV) infusion to cancer patients. MEDI4736 was administered at doses of 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, and 15 mg / kg. The study flow chart is shown in Figure 1The first day of dosing was considered Day 1, and disease assessments occurred after 6, 12, and 16 weeks, and then every 8 weeks.

[0111] Dose-escalation was performed using administration of 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg and 10 mg / kg doses, administered every 2 weeks (Q2W) (+ / - 2 days) to different groups.

[0112] A single dose-escalation was performed by administration at 15 mg / kg every 3 weeks (Q3W). An expansion phase was then performed using the maximum tolerated dose (MTD) or optimal biological dose (OBD) identified in this dose-escalation.

[0113] A dose of 15 mg / kg Q2W can also be given.

[0114] Dose escalation

[0115] In this dose-escalation phase, all subjects in the first group were given a first dose of MEDI4736 as a 0.1 mg / kg infusion given over 4 hours. Subsequent infusions (second and third doses, etc.) of the first group were given Q2W within 60 minutes. The dose of the subsequent group was 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg or 10 mg / kg given as a 60-minute IV infusion Q2W. An overview of the dose groups for the initial dose escalation is provided in Table 1 below. An additional dose of 15 mg / kg was also given at Q3W.

[0116] Table 1: Q2W dosing schedule

[0117]

[0118] With the completion of all groups in the Q2W dose escalation regimen, a separate dose escalation using the Q3W regimen was initiated and proceeded to a dose of up to 15 mg / kg Q3W based on available safety, PK / pharmacokinetics and clinical data. The starting dose in the Q3W escalation was the equivalent dosing rate (in average mg / kg / week) for the optimal biological dose (OBD) (or the highest dose tested if no OBD was identified).

[0119] Subjects in this dose-escalation phase continue treatment until confirmed PD, start of alternative cancer therapy, unacceptable toxicity or other reasons for interrupting treatment. In those subjects who achieve confirmed disease control (DC), treatment can continue until 6 months after the date of DC confirmation. DC will include stable disease (SD), partial response (PR) and complete response (CR) with a duration of 3 months or more.

[0120] Dose expansion

[0121] After completing the dose escalation under Q2W and Q3W, the dosage regimen for the expansion phase is selected. The subjects registered in the dose expansion group will receive the maximum tolerated dose (MTD), the best biological dose (OBD) or if the MTD or OBD is not determined, the MEDI4736 at the highest dose evaluated during the dose escalation process will be given as an IV infusion under the selected dose and frequency. The subjects who achieve disease control (DC) will continue treatment and then enter the maintenance cycle. When there is a sign of progressive disease (PD) at any time during the maintenance cycle, MEDI4736 will be re-administered as an IV infusion until there is a confirmed PD or other reasons for interrupting MEDI4736.

[0122] Maintenance cycle

[0123] Subjects who achieve disease control (DC) during this escalation or expansion phase enter a maintenance period in which treatment may continue until six months after the date of DC confirmation.

[0124] During the maintenance cycle, MEDI4736 is administered as an IV infusion every 2 months for 6 months. Physical examinations of the subjects will be performed at 2 months, 4 months, and 6 months. After a 6-month cycle of every 2 months dosing, MEDI4736 is interrupted. Upon signs of progressive disease (PD), MEDI4736 is reinstituted as an IV infusion on a Q2W or Q3W schedule until confirmed PD, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of informed consent, or other reasons for interrupting treatment occur, for up to 2 years.

[0125] (c) Pharmacokinetics, anti-tumor and safety evaluation

[0126] MEDI4736 concentrations in serum were measured using a validated immunoassay during the Q2W dose-escalation phase. Blood samples for pharmacokinetic evaluations and for soluble B7-H1 (sB7-H1) concentrations were collected during the Q2W dose-escalation phase according to the following schedule:

[0127] • First dose: Day 1 Predose, end of infusion (EOI) and 3 hours after EOI, and Days 2, 3, 5, and 10 (+ / - 1 day). An additional sample was obtained during the initial 4 hour infusion for first-time study subjects at 2 hours after the start of the infusion.

[0128] Second dose: before drug administration, 3 hours after EOI, and on Day 8.

[0129] • Subsequent even-numbered doses only: pre-dose and EOI.

[0130] • Upon interruption or last dose, pharmacokinetic (PK) samples should be drawn at 14 days, 30 days, 2 months, and 3 months after the last dose.

[0131] For Q3W administration, pharmacokinetic evaluation was performed under the same schedule as Q2W administration, except that blood samples were collected at the 15th day after the first dose. During the dose-expansion phase, pharmacokinetic evaluation was performed every two months (before the 1st day administration and EOI). In addition, when interrupting or the last dose, pharmacokinetic (PK) samples were extracted at 14 days, 30 days, 2 months and 3 months after the last dose. During the maintenance phase, pharmacokinetic evaluation and assessment of sB7-H1 were performed at the 14th day and the 30th day (+ / -3 days) and at the 2nd month, the 4th month and the 6th month (+ / -1 week).

[0132] The presence of anti-drug antibodies (ADA) was evaluated (and will continue to be evaluated) on Day 1 (pre-infusion) and at all doses after Dose 2 during the Q2W Dose-Escalation Phase. ADA will be evaluated according to the same schedule as in the Q3W Dose-Escalation and Dose-Expansion Phases. During the Maintenance Phase, ADA will be evaluated at Month 6 (+ / - 1 week).

[0133] In the Q2W dose-escalation phase, tumor evaluations were performed (and will continue) during screening (-28 days to -1 days) and at week 7. Tumor evaluations were performed with the same schedule as in the Q3W dose-escalation phase and the dose-expansion phase. Tumor evaluations may include the following assessments: physical examination (using photos and measurements of skin lesions if applicable), CT or MRI scans of the chest, abdomen, and pelvis, and CT or MRI scans of the brain. Only during screening or if the subject is neurologically symptomatic, computed tomography or MRI scans of the brain were performed. During the maintenance phase, tumor evaluations were performed at the 2nd, 4th, and 6th months (+ / -1 week).

[0134] Tumor biopsies were also performed during Screening (Day -28 to Day -1) and at Week 7 during the Extension Phase.

[0135] The evaluation of antitumor activity is based on immune-related objective response rate (ORR), immune-related disease control rate (DCR), immune-related response duration (DR), immune-related progression-free survival (PFS) and overall survival (OS). Immune-related response criteria (Wolchok et al., Clinical Cancer Research (Clin Cancer Res.) 15:7412-20 (2009)) are used to determine tumor response.

[0136] The ORR is defined as the proportion of subjects with confirmed complete response (CR) or confirmed partial response (PR). The confirmed response is to continue to repeat imaging studies ≥4 weeks after the initial record response. The DCR is defined as the proportion of subjects with CR, PR or stable disease (SD) (the subjects who achieve SD will be included in the DCR if they maintain SD ≥3 months). The 95% confidence interval (CI) of ORR and DCR is evaluated using the exact probability method. The response duration (DR) is the duration from the first record of objective response to the first record of disease progression. Progression-free survival (PFS) is measured from the start of treatment with MEDI4736 until the record of confirmed immune-related disease progression or death (regardless of which occurs first) caused by any reason. Overall survival (OS) is the time from the start of treatment with MEDI4736 until death.

[0137] Adverse events were monitored following administration of MEDI4736. Other evaluations included physical examinations, vital sign monitoring, and laboratory measurements.

[0138] Example 2: Results

[0139] (a) Enrollment and baseline characteristics

[0140] Baseline characteristics of subjects dosed with 0.1 mg / kg, 0.3 mg / kg or 1 mg / kg MEDI4736 in the Q2W dose-escalation phase are provided below in Table 2. Additionally, 245 patients were treated with 10 mg / kg Q2W and 6 patients were treated with 15 mg / kg Q3W.

[0141] Table 2: Demographics for Q2W Dosing

[0142]

[0143]

[0144] Baseline characteristics of subjects dosed with 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, or 15 mg / kg of MEDI4736 in the Q2W and Q3W dose-escalation phases are provided in Figure 3middle.

[0145] (b) Pharmacokinetics

[0146] The pharmacokinetic data from MEDI4736 administered at 0.1 mg / kg and 0.3 mg / kg in the Q2W dose-escalation phase are summarized in Figure 4 MEDI4736 exhibited nonlinear PK at lower doses but was linear for doses ≥1.0 mg / kg Q2W. Figure 5 MEDI4736 also showed dose-dependent increases in target binding ( Figure 6 ), which is consistent with the binding of MEDI4736 to B7-H1. Based on calculations using pK data and measurements of soluble B7-H1, significant target occupancy was achieved with doses ≥ 0.3 mg / kg Q2W, and near complete saturation is expected at doses ≥ 3 mg / kg Q2W. Figure 6 .

[0147] (c) Efficacy

[0148] Tumor shrinkage was observed at all dose levels, including in healthy pre-treated patients and in patients with massive tumor burden. Activity was evident rapidly (6 weeks) and durable. Partial responses (PR) and stable disease (SD) were observed in patients receiving as little as 0.1 mg / kg Q2W. Figure 7 and Table 3 below.

[0149]

[0150]

[0151] Additionally, in patients receiving up to 10 mg / kg Q2W, tumor burden was reduced by up to 83%. Figure 7-Figure 9 For example, one NSCLC adenocarcinoma patient (1351901004) receiving 0.3 mg / kg showed a 31% reduction in tumor burden after 6 weeks and a 71% reduction in tumor burden after 23 weeks. Prophylactic steroids were used in one subject and did not appear to affect clinical activity.

[0152] In the dose-expansion phase, clinical activity was initially observed in subjects with non-small cell lung cancer, melanoma, and pancreatic cancer. Stable disease (at 12 weeks) was observed in subjects with non-small cell lung cancer (non-squamous), pancreatic cancer, GI cancer, melanoma, and head and neck squamous cell carcinoma.

[0153] exist Fig.10 The percent change in tumor size from baseline for all dose levels for NSCLC (non-squamous and squamous) is shown in .

[0154] exist Fig.11 The percent change in tumor size from baseline is shown for all dose levels for advanced cutaneous melanoma.

[0155] exist Fig.12 The percent change in tumor size from baseline for SCCHN patients treated with 10 mg / kg MEDI4736 2QW is shown in FIG.

[0156] exist Fig.13 The percentage change in tumor size relative to baseline for pancreatic cancer patients treated with 10 mg / kg MEDI4736 2QW is shown in Figure 2. There were 8 patients with SD [41-108 days] or better results. Of these patients, 6 patients had ≥2L therapy prior to study enrollment. Seven of the 8 patients with SD or better results were PD-L1 (-) (the PD-L1 status of the other patients was unknown).

[0157] exist Fig.14 The percentage change in tumor size relative to baseline for gastroesophageal cancer patients treated with 10 mg / kg MEDI4736 2QW is shown in Figure 2. There were 9 patients with SD [35-174 days] or better results. Of these patients, 6 had ≥2L therapy prior to study enrollment. Three patients with SD or better results were PD-L1 (-), 2 were PD-L1 (+) and the rest were unknown.

[0158] exist Fig.15 The percentage change in tumor size relative to baseline for hepatocellular carcinoma (HCC) patients treated with 10 mg / kg MEDI4736 2QW is shown in Figure . Of the 17 patients enrolled, all had previously received Sorafenib. 3 were HBV(+), 2 were HCV(+) and the rest were HBV(-) & HCV(-). There were 5 patients with SD[33-76 days] or better results. Among these patients, 4 of them had received ≥2L therapy before enrollment; 1 was HBV(+); 4 were HBV(-) & HCV(-). 3 patients with SD or better results were PD-L1(-), and PD-L1 status was unknown in the remaining patients.

[0159] exist Fig.16 Shown in FIG. 5 is the percent change in tumor size from baseline for triple-negative breast cancer (TNBC) patients treated with 10 mg / kg MEDI4736 2QW.

[0160] exist Fig.17Shown in FIG. 5 is the percent change in tumor size from baseline for uveal melanoma patients treated with 10 mg / kg MEDI4736 2QW.

[0161] exist Fig.18 A shows a comparison of the percentage change in tumor size relative to baseline for NSCLC patients treated with 10 mg / kg MEDI4736 2QW for 2 scans assessable. The graph shows patients with PD-L1 positive tumors, PD-L1 negative tumors, and patients whose PD-L1 tumor status is unavailable. Patients identified as smokers are shown with asterisks. The ORR (confirmed CR+PR) for all patients was 3.7%. The ORR rate for PD-L1+ patients was 10%.

[0162] exist Fig.18 B shows a comparison of the percentage change in tumor size relative to baseline for NSCLC patients treated with MEDI4736 2QW at all dose levels that can be evaluated for 1 scan. The graph shows patients with PD-L1 positive tumors, PD-L1 negative tumors, and patients whose PD-L1 tumor status is not available. Patients identified as smokers are shown with asterisks. The ORR (confirmed CR+PR) for all confirmed patients was 4.3% (the ORR for all unconfirmed patients was 8.5%). The ORR rate for PD-L1+ patients was 8.3%.

[0163] exist Fig.19 Shown in Figure 3 are changes in tumor size for the six tumor types in increasing stages.

[0164] exist Fig. 20 The response of one patient in the expansion phase treated with 10 mg / kg MEDI4736 Q2W is shown in FIG. In the upper left panel, the patient's tumor is marked. After week 6, the tumor shrank as shown in the upper right panel.

[0165] exist Fig.21 Figure 2 shows that after only two infusions of MEDI4736 (10 mg / kg Q2W), in patients with SCCHN (PD-L1 + ) played a significant role in tumor regression.

[0166] PD-L1 staining

[0167] PD-L1 staining in tumor tissues from a panel of tumors was performed to evaluate PD-L1 levels in different tumors by IHC. The results are shown in Table 4.

[0168] Table 4

[0169]

[0170]

[0171] The 10 mg / kg Q2W dose (N=245) was well tolerated. The most common SAEs are shown in Table 5 below:

[0172] Table 5

[0173]

[0174]

[0175] (d) Safety and anti-drug antibodies

[0176] MEDI4736 was generally well tolerated. No pneumonia, colitis (of any grade) or hyperglycemia were observed. In addition, no treatment-related grade ≥3 events were observed in the 0.1 mg / kg to 3 mg / kg groups. No dose-limiting toxicity was observed. An overview of adverse events for the 6 groups is shown in Table 6 below:

[0177] Table 6: Summary of Safety-Adverse Events Review

[0178]

[0179] Very low rates of ADA were observed over the dose range of 0.1 mg / kg to 3 mg / kg. Specifically, only 1 of 15 patients dosed over the 0.1 mg / kg to 1 mg / kg dose range tested positive for ADA, with PK / PD implications. Over the 0.1 mg / kg to 1.0 mg / kg dose range, there were no significant effects on drug exposure or target inhibition.

[0180] (e) Discussion

[0181] This study demonstrates that MEDI4736 has favorable pK properties and is generally well tolerated. In addition, MEDI4736 is effective in treating solid tumors (including, but not limited to melanoma, non-small cell lung cancer, pancreatic cancer, uveal melanoma, head and neck squamous cell carcinoma, gastroesophageal cancer and hepatocellular carcinoma), while producing a low ADA incidence. Clinical benefits were observed at all dose levels tested, with activity reported as early as 6 weeks.

[0182] Example 3: Quantification of soluble B7-H1

[0183] Soluble B7-H1 (not bound to MED4736) was measured using an electrochemiluminescence (ECL) based assay.The specific procedure used to measure soluble B7-H1 in human serum is shown below.

[0184] (a) Plate preparation

[0185] I-Blocking Buffer (IBB) (MedImmune) was equilibrated to room temperature (RT) and transferred to a reagent reservoir (Fisher Scientific #07-200-127). 150 μl of IBB was pipetted into each well of a streptavidin coated plate (Meso Scale Discovery ("MSD") catalog L11SA / L15SA). The plates were covered and incubated at room temperature for a minimum of one hour (no more than four hours) on an orbital plate shaker with shaking at approximately 450 rpm.

[0186] The capture antibody working solution (WS) was prepared immediately before use using IBB at room temperature. The capture antibody was a biotinylated anti-human B7-H1 IgG1 TM antibody clone 2.7A4 as described in US 2013 / 0034559. First, at least 100 μL of the capture antibody stock solution was pre-diluted to a concentration of 1000 μg / ml in IBB as shown in Table 7 below. Then, 250 μg / mL capture antibody WS was prepared in a polypropylene tube in IBB using the volumes indicated in Table 8 below. The capture antibody WS was then transferred to a reagent storage tank.

[0187] Table 7: Pre-dilutions of capture antibody stock solution assuming a stock concentration of 10 mg / mL

[0188]

[0189] Table 8: Preparation of Capture Antibody WS from Capture Antibody PD

[0190]

[0191] Plate blocking was completed by washing the plate with 3×300 μL 1× ELISA wash buffer (1× PBS, 0.05% Tween 20) using a plate washer. The plate was blotted dry and immediately coated with 35 μL of capture antibody WS per well. The plate was sealed and incubated for 1 hour at room temperature while shaking at approximately 450 rpm on an orbital plate shaker.

[0192] (b) Preparation of test samples, reference samples and quality control samples

[0193] The human serum samples to be tested were thawed at room temperature and mixed gently until homogenous. These samples were used without dilution.

[0194] As indicated in Table 9 below, a reference standard stock solution (RS stock solution) of recombinant B7-H1 was pre-diluted to a concentration of 47 μg / mL in an assay matrix (AM): Neal calf serum (Lonza, Catalog 14-401F). As indicated in Table 10 below, the RS pre-dilutions were serially diluted in AM for final reference standard concentrations of 2000 (S1), 1000 (S2), 500 (S3), 250 (S4), 125 (S5), 62.5 (S6), 31.3 (S7), 15.6 (S8), 7.8 (S9), and 3.9 (S10) pg / mL. AM-only samples were also included. Dilutions were prepared in polypropylene burettes or equivalent.

[0195] Table 9: Pre-dilutions of reference standard stock solutions assuming RS stock concentration of 470 μg / mL.

[0196]

[0197] Table 10: Preparation of reference standard dilutions

[0198]

[0199] Prepare quality control (QC) sample pre-dilutions in AM and high, mid and low QC samples in polypropylene tubes or equivalent as indicated below in Table 11. The QC stock solution used was recombinant B7-H1 protein in 90% calf serum (Lonza, Catalog 14-401F).

[0200] Table 11: Preparation of QC sample dilutions

[0201]

[0202] (c) Detection of soluble B7-H1

[0203] The prepared plate was washed with 3×300 μL 1×ELISA wash buffer and blotted. Test samples, reference standards, quality control and only assay matrix were transferred to duplicate wells on the plate (35 μl each). The plate was sealed and incubated at room temperature for 30 minutes with shaking at approximately 450 rpm on an orbital plate shaker.

[0204] The primary detection antibody working solution (WS) was prepared in IBB (1 μg / mL) in a polypropylene tube as indicated in Table 12 below. The primary detection antibody was mouse anti-human B7-H1 IgG1 antibody clone 130021 (R&D Systems, catalog MAB1561) (0.5 mg / ml).

[0205] Table 12: Preparation of the first detection antibody working solution (WS)

[0206]

[0207] Remove the plate from the shaker and wash with 3×300 μL 1× ELISA wash buffer and blot dry. Transfer the first detection antibody WS to the reagent reservoir and then pipette 35 μl into each plate well. Seal the plates again and incubate at room temperature for one hour on an orbital plate shaker with shaking at approximately 450 rpm.

[0208] As indicated in Table 13 below, a secondary detection antibody working solution (WS) was prepared in IBB (1 μg / mL) in a polypropylene tube. The secondary detection antibody was a ruthenium-labeled goat anti-mouse B7-H1 polyclonal antibody (MSD, catalog R32AC-1) (0.5 mg / ml). The secondary detection antibody WS was protected from light.

[0209] Table 13: Preparation of Secondary Detection Antibody Working Solution (WS)

[0210]

[0211] Remove the plate from the shaker and wash with 3×300 μL 1× ELISA wash buffer and blot dry. Transfer the second detection antibody WS to the reagent reservoir and then pipette 35 μl into each plate well. Seal the plates again and incubate on an orbital plate shaker with shaking at approximately 450 rpm for one hour at room temperature while protecting from light.

[0212] Read Buffer T (1X) was prepared by diluting Read Buffer T (4X) (MSD Catalog R92TC-1) reagent in cell culture grade water in a polypropylene tube as indicated in Table 14 below.

[0213] Table 14: Preparation of Secondary Detection Antibody Working Solution (WS)

[0214]

[0215] Remove the plate from the shaker and wash with 3×300 μL 1× ELISA Wash Buffer. Cover the plate and blot dry just before adding 1× Reading Buffer T. Transfer Reading Buffer T (1×) to the reagent reservoir. Do not cover the assay plate for reading and blot dry. Pipette Reading Buffer T (1×) into all wells of the assay plate (150 μl) and read the plate within 5 minutes.

[0216] (d) Data analysis

[0217] Send data to Pro GxP v.5.2 software (Molecular Devices, USA) was used for analysis, and 1 / y 2 A weighted 4-parameter logistic curve fitting model was used to plot the reference standard concentration versus the ECL signal value.

[0218] (Backward) Calculate the pg / ml of sB7-H1 for all reference standards and QC sample dilutions. The coefficient of variation (%CV) of duplicate wells for each reference standard and QC sample dilution was also calculated. These data were used to determine whether the plate met the acceptance criteria. If the following acceptance criteria were met, the plate was considered valid:

[0219] 1- The average % recovery for reference standards levels S2 to S7 is within ±25%, and level S8 is within ±30% of the nominal concentration;

[0220] 2- the %CV for each back-calculated concentration of reference standards levels S2 to S7 is ≤ 25%, and level S8 ≤ 30%;

[0221] 3- The average % recovery for each QC level is within ±25% of the nominal concentration; and

[0222] 4- The %CV of the back-calculated concentrations for at least 2 of the 3 QC levels is ≤ 25%.

[0223] For valid plates, the reference standard was used to calculate the pg / ml of sB7-H1 in each sample. Because the test samples were tested pure, the dilution factor for each test sample was 1.0 and no dilution correction was required. The data obtained represent the sB7-H1 concentration in 100% serum.

[0224] The test sample data is also reviewed to determine if it meets the acceptance criteria. The test sample reading is considered valid if the following acceptance criteria are met:

[0225] 1- The back-calculated concentrations of both replicates are within the assay working range;

[0226] 2- The %CV of the mean back-calculated concentration of the test samples is ≤ 25%.

[0227] In case the back-calculated concentration of one of the test samples is within the assay working range and the other is below the assay lower limit of quantitation (LLOQ) or above the assay upper limit of quantitation ULOQ, the following criteria apply:

[0228] - If the %CV of the mean back-calculated concentration is >25%, the test sample is considered invalid.

[0229] - If the %CV of the mean back-calculated concentration is ≤ 25% and the mean back-calculated concentration is within the assay working range, the test sample is considered valid and the mean back-calculated concentration of the test sample is reported.

[0230] - If the %CV of the mean back-calculated concentration is ≤ 25%, the test sample is considered valid and reported as below or above the limit of quantitation.

[0231] In cases where the back-calculated concentrations of both test sample replicates were below the assay LLOQ, the test sample was considered valid and reported as being below the limit of quantitation.

[0232] In the event that the back-calculated concentration of one of the test sample replicates is below the assay working range and the other replicate is outside the range, the following criteria apply:

[0233] - If the ECL values ​​of the out-of-range replicates are below the assayed mean LLOQ ECL, the test sample is considered valid and reported as below the limit of quantitation.

[0234] - If the ECL value of the out-of-range replicates is above the determined average ULOQ ECL, the test sample is considered invalid.

[0235] In cases where the back-calculated concentrations of both test sample replicates were above the assay ULOQ, the test sample was considered valid and reported as above the limit of quantitation.

[0236] In the event that the back-calculated concentration of one of the test sample replicates is above the assay working range and the other replicate is outside the range, the following criteria apply:

[0237] - If the ECL value of the out-of-range replicates is above the assay's average ULOQ ECL, the test sample is considered valid and reported as above the limit of quantitation.

[0238] - If the ECL values ​​of the out-of-range replicates are below the determined average LLOQ ECL, the test sample is considered invalid.

[0239] In the event that the back-calculated concentration of one of the test sample replicates was within the assay working range and the other replicate was outside the range, the test sample was considered invalid.

[0240] In the event that the back-calculated concentrations of both test sample replicates are outside of the range, the following criteria apply.

[0241] - If both ECL values ​​are below the assayed mean LLOQ ECL, the test sample is considered valid and reported as below the limit of quantitation.

[0242] - If both ECL values ​​are above the assayed mean ULOQ ECL, the test sample is considered valid and reported as above the limit of quantitation.

[0243] - If the ECL value of one replicate is below the assayed average LLOQ ECL and the ECL value of another replicate is above the ULOQ ECL, the test sample is considered invalid.

[0244] These procedures were used to determine soluble B7-H1 in human serum samples as provided above in Examples 1 and 2.

[0245] Example 4: PD-L1 expression drives patient response rate

[0246] The PDL1 expression of subject tissues of NSCLC patients was characterized by immunohistochemistry in formalin-fixed and paraffin-embedded tissue samples. A sample was determined to be "PD-L1 positive" if it contained 25% or more tumor cells with PDL1 membrane staining. The prevalence of such samples in the NSCLC population was 20%-40% using the PDL1 assay.

[0247] The cutoff value and scoring algorithm were determined by evaluating samples from approximately 60 patients in a Phase I trial (CP1108). For the cutoff value established in the Phase 3 trial, approximately 40% of NSCLC patients were PD-L1 positive (Table 15 below).

[0248] Table 15: PD-L1 expression is a key driver of response

[0249] Reagents PDL1+ PDL1- PDL1+ group-NSCLC MEDI4736 39％*(5 / 13) 5％*(1 / 19) 39％*(24 / 62)

[0250] *Patients treated for < 12 weeks before data correction

[0251] Patients identified as having tumors expressing PDL1 were more likely to respond to MEDI4736 treatment than unselected patients (Table 16 below). In PDL1-positive NSCLC patients treated with 10 mg / kg MEDI4736, there was an objective response rate of 50% that lasted for greater than 16-24 weeks (Table 16). This significant response rate was not observed in PDL1-negative or unselected patients (Table 16). These results indicate that PDL1 expression is a key driver of response in NSCLC.

[0252] Table 16

[0253] Objective response over time

[0254]

[0255] Complete or partial responses (CR / PR) to MEDI4736 were observed in 50% of PDL1-positive NSCLC patients treated with 10 mg / kg MEDI4736, lasting for greater than 16-24 weeks (Table 17 below). Early responses to MEDI4736 treatment can be observed in just 6-12 weeks (Table 17).

[0256] Table 17

[0257] PDL1 + Response Rate in NSCLC Patients (MEDI4736, 10 mg / kg)

[0258]

[0259] The key driver of response to MEDI4736 is PD-L1 + state

[0260] Unselected patients did not show the same high response rate to MEDI4736 (Table 18 below).

[0261] Table 18

[0262] Response Rates in Unselected NSCLC Patients (MEDI4736, All Doses)

[0263]

[0264] An overview of disease responses is provided in Table 19.1 (10 mg / kg Q2W). When tumor samples met the criteria for being PDL1 positive, i.e., containing 25% or more tumor cells with PDL1 membrane staining (MSCORE>25%), a 40% response rate was observed in patients treated for at least 16 to 24 weeks or more. In subjects with squamous cell carcinoma of the head and neck (SCCHN) treated with 10 mg / kg Q2W for at least 16 to 24 weeks or more, a 33% complete or partial response rate was observed.

[0265] The summary of disease response at all dose levels is shown in Table 19.2. In patients meeting the criteria for PDL1 positive NSCLC, complete or partial response rates were the highest (Table 19.2). Under longer treatment times, greater benefits were seen in NSCLC and SCCHN (Table 19.2). Table 19.3 shows an overview of disease response in subjects with dose escalation (Q2W and Q3W).

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] Additional patient response rates are shown in Figures 25A-25C The responses of non-squamous NSCLC patients and squamous NSCLC patients to MEDI4736 treatment are shown in Fig.25A The response rates relative to tumor PD-L1 status (positive, negative, or unavailable) are shown in Fig.25B and Fig.25C The data demonstrated an increased response rate in patients with PD-L1-positive tumors.

[0272] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation numerous equivalents to the specific aspects of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims.

[0273] Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0274] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

[0275] Sequence Listing

[0276] SEQ ID NO: 1

[0277] >PCT / US2010 / 058007_77 Sequence from PCT / US2010 / 058007 Organism: Homo sapiens 77 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK SEQ ID NO: 2

[0278] > PCT / US2010 / 058007_72 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 72EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS

[0279] SEQ ID NO:3—VH CDR1

[0280] > PCT / US2010 / 058007_73 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 73GFTFSRYWMS

[0281] SEQ ID NO:4—VH CDR2

[0282] >PCT / US2010 / 058007_74 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 74NIKQDGSEKYYVDSVKG

[0283] SEQ ID NO:5—VH CDR3

[0284] > PCT / US2010 / 058007_75 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 75EGGWFGELAFDY

[0285] SEQ ID NO:6—VL CDR1

[0286] >PCT / US2010 / 058007_78 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 78RASQRVSSSYLA

[0287] SEQ ID NO:7—VL CDR2

[0288] > PCT / US2010 / 058007_79 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 79DASSRAT

[0289] SEQ ID NO:8—VL CDR3

[0290] >PCT / US2010 / 058007_80 from PCT / US2010 / 058007 Organism: Homo sapiens sequence 80QQYGSLPWT Sequence Listing <110> MEDIMMUNE, LLC <120> Anti-B7-H1 antibodies for tumor treatment <130> B7H1-200WO1 <140> PCT / EP2014 / 069425 <141> 2014-09-11 <150> 62 / 003,349 <151> May 27, 2014 <150> 61 / 978,401 <151> April 11, 2014 <150> 61 / 971,212 <151> March 27, 2014 <150> 61 / 876,509 <151> September 11, 2013 <160> 8 <170> PatentIn Version 3.5 <210> 1 <211> 108 <212> PRT <213> Homo sapiens <400> 1 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 2 <211> 121 <212> PRT <213> Homo sapiens <400> 2 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> 10 <212> PRT <213> Homo sapiens <400> 3 Gly Phe Thr Phe Ser Arg Tyr Trp Met Ser 1 5 10 <210> 4 <211> 17 <212> PRT <213> Homo sapiens <400> 4 Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly <210> 5 <211> 12 <212> PRT <213> Homo sapiens <400> 5 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr 1 5 10 <210> 6 <211> 12 <212> PRT <213> Homo sapiens <400> 6 Arg Ala Ser Gln Arg Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 7 <211> 7 <212> PRT <213> Homo sapiens <400> 7 Asp Ala Ser Ser Arg Ala Thr 1 5 <210> 8 <211> 9 <212> PRT <213> Homo sapiens <400> 8 Gln Gln Tyr Gly Ser Leu Pro Trp Thr 1 5

Claims

1. Use of an antibody or an antigen-binding fragment thereof for the preparation of a medicament for treating a patient identified as having squamous cell carcinoma of the head and neck (SCCHN), the treatment comprising administering to the patient 10 mg / kg of an isolated antibody or an antigen-binding fragment thereof that specifically binds to PD-L1, the isolated antibody or antigen-binding fragment thereof comprising: VH CDR1 consisting of the amino acid sequence of SEQ ID NO:3; VH CDR2 consisting of the amino acid sequence of SEQ ID NO:4; a VH CDR3 consisting of the amino acid sequence of SEQ ID NO: 5; VL CDR1 consisting of the amino acid sequence of SEQ ID NO:6; a VL CDR2 consisting of the amino acid sequence of SEQ ID NO:7; and A VL CDR3 consisting of the amino acid sequence SEQ ID NO: 8, At least 25% of SCCHN tumor cells are PD-L1 positive.

2. The use as claimed in claim 1, wherein the administration is repeated every 14 to 21 days.

3. The use as claimed in claim 1, wherein the administration is repeated every 14 days.

4. The use of claim 1, wherein the SCCHN is refractory to at least one chemotherapeutic agent.

5. The use of claim 4, wherein the chemotherapeutic agent is Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin, Bevacizumab or Pemetrexed. The use according to claim 1 , wherein the PD-L1 status is detected using immunohistochemistry.

7. The use of the antibody or antigen-binding fragment thereof according to claim 1, wherein the isolated antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence of SEQ ID NO: 1; and a VH having an amino acid sequence of SEQ ID NO:

2.

8. Use of an antibody or antigen-binding fragment thereof for the preparation of a medicament for treating a patient identified as having squamous cell carcinoma of the head and neck (SCCHN), the treatment comprising administering to the patient 15 mg / kg of an isolated antibody or antigen-binding fragment thereof that specifically binds to PD-L1, the isolated antibody or antigen-binding fragment thereof comprising: VH CDR1 consisting of the amino acid sequence of SEQ ID NO:3; VH CDR2 consisting of the amino acid sequence of SEQ ID NO:4; a VH CDR3 consisting of the amino acid sequence of SEQ ID NO: 5; VL CDR1 consisting of the amino acid sequence of SEQ ID NO:6; a VL CDR2 consisting of the amino acid sequence of SEQ ID NO:7; and A VL CDR3 consisting of the amino acid sequence SEQ ID NO: 8, At least 25% of SCCHN tumor cells are PD-L1 positive.

9. The use of claim 8, wherein the administration is repeated every 14 to 21 days.

10. The use as claimed in claim 8, wherein the administration is repeated every 14 days.

11. The use of claim 8, wherein the SCCHN is refractory to at least one chemotherapeutic agent.

12. The method of claim 11, wherein the SCCHN is refractory to at least one chemotherapeutic agent selected from Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin, Bevacizumab or Pemetrexed.

13. The use according to claim 8, wherein the PD-L1 status is detected using immunohistochemistry.

14. The use according to claim 8, wherein the antibody or fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO: 1 and a VH comprising the amino acid sequence of SEQ ID NO:

2.

15. Use of an antibody or an antigen-binding fragment thereof for the preparation of a medicament for treating a patient identified as having squamous cell carcinoma of the head and neck (SCCHN), the treatment comprising administering to the patient 8 mg / kg of an isolated antibody or an antigen-binding fragment thereof that specifically binds to PD-L1, wherein the antibody or fragment thereof comprises a VL having an amino acid sequence of SEQ ID NO: 1 and a VH having an amino acid sequence of SEQ ID NO: 2, wherein at least 25% of the SCCHN tumor cells are PD-L1 positive.

16. Use of an antibody or an antigen-binding fragment thereof for the preparation of a medicament for treating a patient identified as having squamous cell carcinoma of the head and neck (SCCHN), the treatment comprising administering to the patient 15 mg / kg of an isolated antibody or an antigen-binding fragment thereof that specifically binds to PD-L1, wherein the antibody or fragment thereof comprises a VL having an amino acid sequence of SEQ ID NO: 1 and a VH having an amino acid sequence of SEQ ID NO: 2, wherein at least 25% of the SCCHN tumor cells are PD-L1 positive.

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