Anti-pd-l1 antibodies and their use as therapeutics and diagnostics

Abstract

Provided are antibodies that specifically bind to Programmed Death-1 (PD1, Pdcd-1, or CD279) ligand (PD-L1) and inhibit PD-L1-mediated cellular signaling and activities in immune cells, antibodies binding to a set of amino acid residues required for its ligand binding, and uses of these antibodies to treat or diagnose cancer, infectious diseases or other pathological disorders modulated by PD-L1-mediated functions.

What is claimed is: 
     
         1 - 12 . (canceled) 
     
     
         13 . A mutant IgG1 Fc-containing molecule having a decreased binding affinity to one or more Fcγ receptors and/or human C1q protein as compared to wild type human IgG1, comprising a mutated human IgG1 constant region comprising (i) E233P, L234A, L235A and P329A mutations in wild type human IgG1, as defined by the EU numbering system, or (ii) E233P, L234A, L235A, G237A and P329A mutations in wild type human IgG1, as defined by the EU numbering system. 
     
     
         14 . The mutant IgG1 Fc-containing molecule of  claim 13 , wherein the mutated human IgG1 constant region comprises E233P, L234A, L235A and P329A mutations in wild type human IgG1, as defined by the EU numbering system. 
     
     
         15 . The mutant IgG1 Fc-containing molecule of  claim 13 , wherein the mutated human IgG1 constant region comprises E233P, L234A, L235A, G237A and P329A mutations in wild type human IgG1, as defined by the EU numbering system. 
     
     
         16 . A mutant IgG1 Fc-containing molecule comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:29. 
     
     
         17 . The mutant IgG1 Fc-containing molecule of  claim 16 , which comprises the amino acid sequence of SEQ ID NO:28. 
     
     
         18 . The mutant IgG1 Fc-containing molecule of  claim 16 , which comprises the amino acid sequence of SEQ ID NO:29. 
     
     
         19 . An antibody comprising a mutated human IgG1 constant region comprising (i) E233P, L234A, L235A and P329A mutations in wild type human IgG1, as defined by the EU numbering system, or (ii) E233P, L234A, L235A, G237A and P329A mutations in wild type human IgG1, as defined by the EU numbering system; wherein the antibody has a decreased binding affinity to one or more Fcγ receptors and/or human C1q protein as compared to wild type human IgG1. 
     
     
         20 . The antibody of  claim 19 , wherein the mutated human IgG1 constant region comprises E233P, L234A, L235A and P329A mutations in wild type human IgG1, as defined by the EU numbering system. 
     
     
         21 . The antibody of  claim 19 , wherein the mutated human IgG1 constant region comprises E233P, L234A, L235A, G237A and P329A mutations in wild type human IgG1, as defined by the EU numbering system. 
     
     
         22 . An antibody comprising a mutated human IgG1 constant region comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:29. 
     
     
         23 . The antibody of  claim 22 , which comprises the amino acid sequence of SEQ ID NO:28. 
     
     
         24 . The antibody of  claim 22 , which comprises the amino acid sequence of SEQ ID NO:29. 
     
     
         25 . The antibody of  claim 19 , wherein the antibody is an antibody that specifically binds to human PD-L1. 
     
     
         26 . The antibody of  claim 22 , wherein the antibody is an antibody that specifically binds to human PD-L1. 
     
     
         27 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody which binds human PD-L1, wherein the IgG Fc region of the antibody is an IgG1 Fc region containing E233P, L234A, L235A amino acid mutations and at least one additional amino acid mutation, wherein the at least one additional mutation causes the antibody to exhibit reduced binding to at least one Fcγ receptor relative to Fc binding of a reference IgG1 antibody which binds human PD-L1 having E233P, L234A, L235A amino acid mutations and no other Fc region mutation, and wherein the numbering of the residues in the IgG1 Fc region is that of the EU numbering system. 
     
     
         28 . The method of  claim 27 , wherein the at least one additional amino acid mutation in the IgG1 Fc region is P329A mutation, as defined by the EU numbering system. 
     
     
         29 . The method of  claim 27 , wherein the at least one additional amino acid mutation in the IgG1 Fc region are G237A and P329A mutations, as defined by the EU numbering system. 
     
     
         30 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody which binds human PD-L1, wherein the IgG Fc region of the antibody comprises the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:29. 
     
     
         31 . The method of  claim 30 , wherein the IgG Fc region of the antibody comprises the amino acid sequence of SEQ ID NO:28. 
     
     
         32 . The method of  claim 30 , wherein the IgG Fc region of the antibody comprises the amino acid sequence of SEQ ID NO:29.