Cancer immunotherapy by disrupting pd-1/pd-l1 signaling

Patent metadata

Field	Value
Publication number	US-2019153099-A1
Application number	US-201916248215-A
Country	US
Kind code	A1
Filing date	Jan 15, 2019
Priority date	May 15, 2012
Publication date	May 23, 2019
Grant date	—

Abstract

The disclosure provides a method for immunotherapy of a subject afflicted with cancer, comprises administering to the subject a composition comprising a therapeutically effective amount of an antibody that inhibits signaling from the PD-1/PD-L1 signaling pathway. This disclosure also provides a method for immunotherapy of a subject afflicted with cancer comprising selecting a subject that is a suitable candidate for immunotherapy based on an assessment that the proportion of cells in a test tissue sample from the subject that express PD-L1 on the cell surface exceeds a predetermined threshold level, and administering a therapeutically effective amount of an anti-PD-1 antibody to the selected subject. The invention additionally provides rabbit mAbs that bind specifically to a cell surface-expressed PD-L1 antigen in a FFPE tissue sample, and an automated IHC method for assessing cell surface expression in FFPE tissues using the provided anti-PD-L1 Abs.

First claim

What is claimed is:

1 . A method of treating a subject afflicted with a cancer comprising administering to the subject a therapeutically effective amount of an antibody or an antigen-binding portion thereof that disrupts the interaction between Programmed Death-1 (PD-1) and Programmed Death Ligand-1 (PD-L1).

2 . The method of claim 1 , wherein the antibody or antigen-binding portion thereof binds specifically to PD-1.

3 . The method of claim 1 , wherein the antibody or antigen-binding portion thereof binds specifically to PD-L1.

4 . The method of claim 1 , wherein the subject has been pre-treated for the cancer.

5 . The method of claim 1 , wherein the cancer is an advanced, metastatic and/or refractory cancer.

6 . The method of claim 1 , wherein the administration of the antibody or antigen-binding portion thereof induces a durable clinical response in the subject.

7 . The method of claim 3 , wherein the cancer is selected from the group consisting of melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and a hematological malignancy.

8 . The method of claim 1 , wherein the therapeutically effective amount of the antibody or antigen-binding portion thereof comprises a dose ranging from 0.1 to 10.0 mg/kg body weight which is administered at a dosing schedule of once per week, once every two weeks, or once a month.

9 . A method for immunotherapy of a subject afflicted with cancer, which method comprises:
(a) selecting a subject that is a suitable candidate for immunotherapy, the selecting comprising:
(i) providing a test tissue sample obtained from a patient with cancer of the tissue, the test tissue sample comprising tumor cells and tumor-infiltrating inflammatory cells;
(ii) assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface; and
(iii) selecting the subject as a suitable candidate based on an assessment that the proportion of cells in the test tissue sample that express PD-L1 on the cell surface exceeds a predetermined threshold level; and
(b) administering a composition comprising a therapeutically effective amount of an anti-PD-1 antibody to the selected subject.

10 . The method of claim 9 , wherein the proportion of cells that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide on the surface of cells in the test tissue sample.

11 . The method of claim 9 , wherein the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample.

12 . The method of claim 11 , wherein the presence of PD-L1 polypeptide is determined using an automated IHC assay.

13 . The method of claim 12 , wherein the IHC assay is performed using an anti-PD-L1 monoclonal antibody to bind to the PD-L1 polypeptide, wherein the anti-PD-L1 monoclonal antibody is selected from 28-8, 28-1, 28-12, 29-8, and 5H1.

14 . The method of claim 9 , wherein the predetermined threshold level is 1% of tumor cells or a single tumor-infiltrating inflammatory cell expressing cell surface PD-L1 as determined by automated IHC using mAb 28-8.

15 . A monoclonal antibody or an antigen-binding portion thereof that binds specifically to a cell surface-expressed PD-L1 polypeptide in a formalin-fixed, paraffin-embedded (FFPE) tissue sample.

16 . The monoclonal antibody or antigen-binding portion thereof of claim 15 , which antibody or portion thereof comprises the CDR1, CDR2 and CDR3 regions in a heavy chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 35, and the CDR1, CDR2 and CDR3 regions in a light chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 36.

17 . The monoclonal antibody or antigen-binding portion thereof of claim 15 , which antibody or portion thereof comprises a heavy chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 35, and a light chain variable region comprising consecutively linked amino acids having the sequence set forth in SEQ ID NO: 36.

Assignees

• Bristol Myers Squibb Co

Inventors

• Cogswell John P
• Goldberg Stacie M
• Gupta Ashok K
• Jure-Kunkel Maria
• Wang xi-tao
• Wigginton Jon M

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K16/2827

  against B7 molecules, e.g. CD80, CD86 · CPC title