Human monoclonal anti-pd-l1 antibodies and methods of use

Abstract

The present invention comprises human monoclonal antibodies that bind to PD-L1 (also known as programmed death ligand 1 or B7H1). Binding of the invented antibody to PD-L1 inhibits binding to its receptor, PD1 (programmed death 1), and ligand-mediated activities and can be used to treat cancer and chronic viral infections.

What is claimed is: 
     
         1 . An isolated humanized monoclonal antibody having:
 a. a heavy chain with three CDRs comprising the amino acid sequences SYGIS (SEQ ID NO:57), WISAYNGNTNYAQKLED (SEQ ID NO:70), and ALPSGTILVGGWFDP (SEQ ID NO:86) respectively and a light chain with three CDRs comprising the amino acid sequences TRSSGNIASNYVQ (SEQ ID NO:101), EDNQRPS (SEQ ID NO:115), and QSYDSSNLWV (SEQ ID NO:127) respectively;   b. a heavy chain with three CDRs comprising the amino acid sequences SYALS (SEQ ID NO:58), AISGGGGSTYYADSVKD (SEQ ID NO:71), and DVFPETFSMNYGMDV (SEQ ID NO:87) respectively and a light chain with three CDRs comprising the amino acid sequences QGDSLRSYYAS (SEQ ID NO:102), GKNNRPS (SEQ ID NO:116), and NSRDSSGNHYV (SEQ ID NO:128) respectively;   c. a heavy chain with three CDRs comprising the amino acid sequences DYAMH (SEQ ID NO:60), LISGDGGSTYYADSVKD (SEQ ID NO:73), and VLLPCSSTSCYGSVGAFDI (SEQ ID NO:88) respectively and a light chain with three CDRs comprising the amino acid sequences GGSDIGRKSVH (SEQ ID NO:103), SDRDRPS (SEQ ID NO:117), and QVWDNNSDHYV (SEQ ID NO:129) respectively;   d. a heavy chain with three CDRs comprising the amino acid sequences NYDMS (SEQ ID NO:61), RVNWNGGSTTYADAVKD (SEQ ID NO:74), and EFVGAYDL (SEQ ID NO:89) respectively and a light chain with three CDRs comprising the amino acid sequences TGTSSDVGGYNYVS (SEQ ID NO:104), DVSNRPS (SEQ ID NO:118), and SSYTSSTLP (SEQ ID NO:130) respectively;   e. a heavy chain with three CDRs comprising the amino acid sequences GLYIH (SEQ ID NO:62), WIIPIFGTANYAQKFED (SEQ ID NO:75), and GLRWGIWGWFDP (SEQ ID NO:90) respectively and a light chain with three CDRs comprising the amino acid sequences RASQSIGNSLA (SEQ ID NO:105), GASSRAT (SEQ ID NO:119), and QQHTIPTFS (SEQ ID NO:131) respectively;   f. a heavy chain with three CDRs comprising the amino acid sequences DNAIS (SEQ ID NO:63), WIIPIFGKPNYAQKFED (SEQ ID NO:76), and TMVRGFLGVMDV (SEQ ID NO:91) respectively and a light chain with three CDRs comprising the amino acid sequences RASQGIGSYLA (SEQ ID NO:106), AASTLQS (SEQ ID NO:120), and QQLNNYPIT (SEQ ID NO:132) respectively;   g. a heavy chain with three CDRs comprising the amino acid sequences SYAMS (SEQ ID NO:64), AISGSGGSTYYADSVKD (SEQ ID NO:77), and DQFVTIFGVPRYGMDV (SEQ ID NO:92) respectively and a light chain with three CDRs comprising the amino acid sequences SGDKLGNKYAY (SEQ ID NO:107), QDIKRPS (SEQ ID NO:121), and QTWDNSVV (SEQ ID NO:133) respectively;   h. a heavy chain with three CDRs comprising the amino acid sequences SYAIS (SEQ ID NO:57), WIIPIFGTANYAQKFED (SEQ ID NO:78), and GRQMFGAGIDF (SEQ ID NO:93) respectively and a light chain with three CDRs comprising the amino acid sequences TRSSGSIDSNYVQ (SEQ ID NO:108), EDNQRPS (SEQ ID NO:115), and QSYDSNNRHVI (SEQ ID NO:134) respectively;   i. a heavy chain with three CDRs comprising the amino acid sequences TYALN (SEQ ID NO:65), RIVPLIGLVNYAHNFED (SEQ ID NO:79), and EVYGGNSDY (SEQ ID NO:94) respectively and a light chain with three CDRs comprising the amino acid sequences TRSSGNIGTNYVQ (SEQ ID NO:109), EDYRRPS (SEQ ID NO:122), and QSYHSSGWE (SEQ ID NO:135) respectively;   j. a heavy chain with three CDRs comprising the amino acid sequences SHGIT (SEQ ID NO:66), WISAHNGHASNAQKVED (SEQ ID NO:80), and VHAALYYGMDV (SEQ ID NO:95) respectively and a light chain with three CDRs comprising the amino acid sequences GGNNIGSKGVH (SEQ ID NO:110), DDSDRPS (SEQ ID NO:123), and QVWDSSSDHWV (SEQ ID NO:136) respectively;   k. a heavy chain with three CDRs comprising the amino acid sequences RHGMH (SEQ ID NO:67), VISHDGSVKYYADSMKD (SEQ ID NO:81), and GLSYQVSGWFDP (SEQ ID NO:96) respectively and a light chain with three CDRs comprising the amino acid sequences TRSSGSIASNYVQ (SEQ ID NO:111), EDNQRPS (SEQ ID NO:115), and QSYDSTTPSV (SEQ ID NO:137) respectively;   l. a heavy chain with three CDRs comprising the amino acid sequences SYGIS (SEQ ID NO:58), WTSPHNGLTAFAQILED (SEQ ID NO:82), and VHPVFSYALDV (SEQ ID NO:97) respectively and a light chain with three CDRs comprising the amino acid sequences TRSSGSIASNYVQ (SEQ ID NO:112), EDNQRPS (SEQ ID NO:115), and QSYDGITVI (SEQ ID NO:138) respectively;   m. a heavy chain with three CDRs comprising the amino acid sequences TYAFS (SEQ ID NO:68), RIIPILGIANYAQKFED (SEQ ID NO:83), and DGYGSDPVL (SEQ ID NO:98) respectively and a light chain with three CDRs comprising the amino acid sequences TRSSGSIASHYVQ (SEQ ID NO:113), EDNKRPS (SEQ ID NO:124), and QSYDSSNRWV (SEQ ID NO:139) respectively; or   n. a heavy chain with three CDRs comprising the amino acid sequences NYGIS (SEQ ID NO:69), WISAYNGNTNYAQKVED (SEQ ID NO:84), and GDFRKPFDY (SEQ ID NO:99) respectively and a light chain with three CDRs comprising the amino acid sequences TLRSGLNVGSYRIY (SEQ ID NO:114), YKSDSNKQQAS (SEQ ID NO:125), and MIWYSSAVV (SEQ ID NO:140) respectively;   
       wherein said antibody binds human PD-L1. 
     
     
         2 . The antibody of  claim 1 , wherein said antibody is monovalent or bivalent. 
     
     
         3 . The antibody of  claim 1 , wherein said antibody is a single chain antibody. 
     
     
         4 . A single chain antibody comprising:
 a. a V H  nucleotide sequence comprising SEQ ID NO: 1 and a V L  nucleotide sequence comprising SEQ ID NO: 3;   b. a V H  nucleotide sequence comprising SEQ ID NO: 5 and a V L  nucleotide sequence comprising SEQ ID NO:7;   c. a V H  nucleotide sequence comprising SEQ ID NO: 9 and a V L  nucleotide sequence comprising SEQ ID NO: 11;   d. a V H  nucleotide sequence comprising SEQ ID NO: 13 and a V L  nucleotide sequence comprising SEQ ID NO: 15;   e. a V H  nucleotide sequence comprising SEQ ID NO: 17 and a V L  nucleotide sequence comprising SEQ ID NO:19;   f. a V H  nucleotide sequence comprising SEQ ID NO: 21 and a V L  nucleotide sequence comprising SEQ ID NO:23;   g. a V H  nucleotide sequence comprising SEQ ID NO: 25 and a V L  nucleotide sequence comprising SEQ ID NO:27;   h. a V H  nucleotide sequence comprising SEQ ID NO: 29 and a V L  nucleotide sequence comprising SEQ ID NO:31;   i. a V H  nucleotide sequence comprising SEQ ID NO: 33 and a V L  nucleotide sequence comprising SEQ ID NO:35;   j. a V H  nucleotide sequence comprising SEQ ID NO: 37 and a V L  nucleotide sequence comprising SEQ ID NO:39;   k. a V H  nucleotide sequence comprising SEQ ID NO: 41 and a V L  nucleotide sequence comprising SEQ ID NO:43;   l. a V H  nucleotide sequence comprising SEQ ID NO: 45 and a V L  nucleotide sequence comprising SEQ ID NO:47;   m. a V H  nucleotide sequence comprising SEQ ID NO: 49 and a V L  nucleotide sequence comprising SEQ ID NO:51; or   n. a V H  nucleotide sequence comprising SEQ ID NO: 53 and a V L  nucleotide sequence comprising SEQ ID NO:55.   
     
     
         5 . A single chain antibody comprising
 a. a V H  amino acid sequence comprising SEQ ID NO: 2 and a V L  amino acid sequence comprising SEQ ID NO: 4;   b. a V H  amino acid sequence comprising SEQ ID NO: 6 and a V L  amino acid sequence comprising SEQ ID NO: 8;   c. a V H  amino acid sequence comprising SEQ ID NO: 10 and a V L  amino acid sequence comprising SEQ ID NO: 12;   d. a V H  amino acid sequence comprising SEQ ID NO: 14 and a V L  amino acid sequence comprising SEQ ID NO: 16;   e. a V H  amino acid sequence comprising SEQ ID NO: 18 and a V L  amino acid sequence comprising SEQ ID NO: 20;   f. a V H  amino acid sequence comprising SEQ ID NO: 22 and a V L  amino acid sequence comprising SEQ ID NO: 24;   g. a V H  amino acid sequence comprising SEQ ID NO: 26 and a V L  amino acid sequence comprising SEQ ID NO: 28;   h. a V H  amino acid sequence comprising SEQ ID NO: 30 and a V L  amino acid sequence comprising SEQ ID NO: 32;   i. a V H  amino acid sequence comprising SEQ ID NO: 34 and a V L  amino acid sequence comprising SEQ ID NO: 36;   j. a V H  amino acid sequence comprising SEQ ID NO: 38 and a V L  amino acid sequence comprising SEQ ID NO: 40;   k. a V H  amino acid sequence comprising SEQ ID NO: 42 and a V L  amino acid sequence comprising SEQ ID NO: 44;   l. a V H  amino acid sequence comprising SEQ ID NO: 46 and a V L  amino acid sequence comprising SEQ ID NO: 48;   m. a V H  amino acid sequence comprising SEQ ID NO: 50 and a V L  amino acid sequence comprising SEQ ID NO: 52; or   n. a V H  amino acid sequence comprising SEQ ID NO: 54 and a V L  amino acid sequence comprising SEQ ID NO: 56.   
     
     
         6 . The antibody of  claim 1 , wherein said antibody has a binding affinity within the range of 10 −5  M to 10 −12  M. 
     
     
         7 . The antibody according to  claim 1  wherein said antibody is a bi-specific antibody that also binds to a tumor-associated antigen, a cytokine or a cell surface receptor. 
     
     
         8 . The antibody according to  claim 7  wherein said tumor-associated antigen is CAIX. 
     
     
         9 . The antibody according to  claim 7 , wherein said cytokine is IL-10. 
     
     
         10 . The antibody according to  claim 7 , wherein said cell surface receptor is CCR4, IL21R, BTLA, HVEM or TIM3. 
     
     
         11 . The antibody according to any one of  claims 1 - 8  linked to a therapeutic agent. 
     
     
         12 . The antibody of  claim 9 , wherein said therapeutic agent is a toxin, a radiolabel, a siRNA, a small molecule, or a cytokine. 
     
     
         13 . A cell producing the antibody of any one of  claims 1 - 12 . 
     
     
         14 . A method of selectively killing a tumor cell comprising contacting said cell with the antibody of any one of  claims 1 - 12 . 
     
     
         15 . The method of  claim 14 , wherein said selective killing occurs by antibody-dependent cellular toxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody dependent cellular phagocytosis (ADCP). 
     
     
         16 . The method of  claim 14 , wherein said tumor cell expresses PD-L1. 
     
     
         17 . A method of preventing or reversing T cell exhaustion comprising administering to a subject in need thereof a composition comprising an antibody of any one of  claims 1 - 12 . 
     
     
         18 . A method of augmenting an immune response to an antigen comprising administering to a subject in need thereof a composition comprising an antibody of any one of  claims 1 - 12 . 
     
     
         19 . The method of  claim 18 , wherein said antigen is a viral antigen, a bacterial antigen or a tumor associated antigen. 
     
     
         20 . The method of  claim 19 , wherein said viral antigen is HIV. 
     
     
         21 . The method of  claim 19 , wherein said tumor associated antigen is CAIX. 
     
     
         22 . The method of  claim 18 , wherein said antibody is administered prior to or after exposure to the antigen. 
     
     
         23 . The method of  claim 17  or  18 , wherein said administration of said antibody causes an increase in antigen specific T cell activity. 
     
     
         24 . The method of  claim 23 , wherein said T-cell is an effector T cell. 
     
     
         25 . A method of treating or alleviating a symptom of cancer, comprising administering to a subject in need thereof a composition comprising an antibody according to any one of  claims 1 - 12 . 
     
     
         26 . The method of  claim 25 , wherein said cancer is renal cell carcinoma or breast cancer. 
     
     
         27 . The method of  claim 25 , wherein said cancer is a cancer in which PD-L1 is overexpressed. 
     
     
         28 . The method of  claim 25 , wherein said cancer is a cancer that induces T cell exhaustion. 
     
     
         29 . A method of treating or alleviating a symptom of a chronic viral infection, comprising administering to a subject in need thereof a composition comprising an antibody according to any one of  claims 1 - 12 . 
     
     
         30 . The method of  claim 29 , wherein said chronic viral infection is an HIV infection. 
     
     
         31 . The method of  claim 29 , wherein said chronic viral infection is a viral infection that induces T cell exhaustion. 
     
     
         32 . A nucleic acid sequence comprising the nucleic acid sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13. 15. 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53 or 55. 
     
     
         33 . A nucleic acid sequence encoding the polypeptide of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54 or 56. 
     
     
         34 . A polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54 or 56. 
     
     
         35 . A vector comprising the nucleic acid  claim 32  or  33 . 
     
     
         36 . A cell comprising the vector of  claim 35 .