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

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.

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.