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.

1 - 17 . (canceled) 
     
     
         18 . A method of treating a tumor derived from a melanoma in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody and a BRAF inhibitor; wherein the anti-PD-1 antibody is administered by intravenous infusion. 
     
     
         19 . The method of  claim 18 , wherein at least 10% of tumor cells in the tumor exhibit membrane PD-L1 expression. 
     
     
         20 . The method of  claim 18 , wherein the therapeutically effective amount of the anti-PD-1 antibody is administered once every 4 weeks. 
     
     
         21 . The method of  claim 18 , wherein the anti-PD-1 antibody is formulated in a pharmaceutical composition. 
     
     
         22 . The method of  claim 21 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable salt, an anti-oxidant, an aqueous carrier, a non-aqueous carrier, or any combination thereof. 
     
     
         23 . The method of  claim 22 , wherein the salt comprises a sodium salt. 
     
     
         24 . The method of  claim 22 , wherein the salt comprises sodium chloride. 
     
     
         25 . The method of  claim 18 , wherein the BRAF inhibitor inhibits mutated B-RAF protein. 
     
     
         26 . The method of  claim 25 , wherein the mutated B-RAF protein comprises V600E-BRAF. 
     
     
         27 . The method of  claim 19 , wherein the membranous PD-L1 expression on the tumor cells is measured prior to administering the anti-PD-1 antibody. 
     
     
         28 . The method of  claim 27 , wherein the measuring comprises an immunohistochemistry. 
     
     
         29 . The method of  claim 28 , wherein the immunohistochemistry is performed using an antibody comprising:
 (a) a heavy chain (HC) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 35;   (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 35;   (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 35;   (d) a light chain (LC) CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 36;   (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQ ID NO: 36; and   (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 36.   
     
     
         30 . A method of treating a tumor derived from a melanoma in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody and a BRAF inhibitor;
 wherein the anti-PD-1 antibody is administered by intravenous infusion once every 4 weeks;   wherein at least 10% of tumor cells in the tumor exhibit membrane PD-L1 expression, as determined using an immunohistochemistry.   
     
     
         31 . The method of  claim 30 , wherein the anti-PD-1 antibody is formulated in a pharmaceutical composition. 
     
     
         32 . The method of  claim 31 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable salt, an anti-oxidant, an aqueous carrier, a non-aqueous carrier, or any combination thereof. 
     
     
         33 . The method of  claim 32 , wherein the salt comprises a sodium salt. 
     
     
         34 . The method of  claim 32 , wherein the salt comprises sodium chloride. 
     
     
         35 . The method of  claim 18 , wherein the BRAF inhibitor inhibits mutated B-RAF protein. 
     
     
         36 . The method of  claim 35 , wherein the mutated B-RAF protein comprises V600E-BRAF. 
     
     
         37 . The method of  claim 30 , wherein the immunohistochemistry is performed using an antibody comprising:
 (a) a heavy chain (HC) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 35;   (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 35;   (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 35;   (d) a light chain (LC) CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 36;   (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQ ID NO: 36; and   (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 36.