Antibodies specific to ctla-4 and uses thereof

Abstract

Disclosed herein are anti-CTLA-4 antibodies possessing superior binding and biological activities relative to ipibmumab and tremelimumab, pharmaceutical compositions comprising such. Also provided herein are therapeutic and diagnostic applications of such anti-CTLA-4 antibodies.

1 . A monoclonal antibody binding to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4),
 wherein the antibody comprises a heavy chain variable domain (V H ), which comprises (i) a heavy chain complementary determining region 1 (HC CDR1) set forth as GDYYWX 1  (SEQ ID NO: 3), in which X 1  is G or N, (ii) a heavy chain complementary determining region 2 (HC CDR2) set forth as SIYHX 2 X 3 YTYYNPSX 4 KS (SEQ ID NO: 4), in which X 2  is D or S, X 3  is G or A, and X 4  is L or V; and (iii) a heavy chain complementary determining region 3 (HC CDR3) set forth as DSGWYVIAFX 5 X 6  (SEQ ID NO: 5), in which X 5  is D or A, and X 6  is Y or I; and/or wherein the antibody comprises a light chain variable domain (V L ), which comprises (i) a light chain complementary determining region 1 (LC CDR1) set forth as RASQSX 7 SSNLA (SEQ ID NO: 6), in which X 7  is V or I; (ii) a light chain complementary determining region 2 (LC CDR2) set forth as X 8 AX 9 X 10 RAT (SEQ ID NO: 7), in which X 8  is A or G and each of X 9 , X 10  is independently S or T; and (iii) a light chain complementary determining region 3 (LC CDR3) set forth as QQYNNWPPLT (SEQ ID NO: 8).   
     
     
         2 . A monoclonal antibody binding to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), wherein the antibody binds the same epitope as Ab55h or competes against Ab55h from binding to the CTLA-4. 
     
     
         3 . The monoclonal antibody of  claim 1 , wherein the antibody specifically binds human CTLA-4. 
     
     
         4 . The monoclonal antibody of  claim 1 , wherein the antibody cross-reacts with human CTLA-4 and a non-human CTLA-4. 
     
     
         5 . The monoclonal antibody of  claim 4 , wherein the non-human CTLA-4 is a non-human primate CTLA-4, a pig CTLA-4, or a mouse CTLA-4. 
     
     
         6 . The monoclonal antibody of  claim 1 , wherein the antibody binds CTLA-4 expressed on cell surface. 
     
     
         7 . The monoclonal antibody of  claim 2 , wherein the antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3, which collectively contains no more than 10 amino acid variations as compared with the HC CDR1, HC CDR2, and HC CDR3 of Ab55h; and/or a LC CDR1, a LC CDR2, and a LC CDR3, which collectively contains no more than 10 amino acid variations as compared with the LC CDR1, LC CDR2, and LC CDR3 of Ab55h. 
     
     
         8 . The monoclonal antibody of  claim 7 , wherein the antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3, which collectively contains no more than 8 amino acid variations as compared with the HC CDR1, HC CDR2, and HC CDR3 of Ab55h. 
     
     
         9 . The monoclonal antibody of  claim 8 , wherein the antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3, which collectively contains no more than 5 amino acid variations as compared with the HC CDR1, HC CDR2, and HC CDR3 of Ab55h. 
     
     
         10 . The monoclonal antibody of  claim 7 , wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3, which collectively contains no more than 8 amino acid variations as compared with the LC CDR1, LC CDR2, and LC CDR3 of Ab55h. 
     
     
         11 . The monoclonal antibody of  claim 10 , wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3, which collectively contains no more than 5 amino acid variations as compared with the HC CDR1, HC CDR2, and HC CDR3 of Ab55h. 
     
     
         12 . The monoclonal antibody of  claim 2 , wherein the antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3, at least one of which contains no more than 5 amino acid variations as the counterpart HC CDR of Ab55h; and/or a LC CDR1, a LC CDR2, and a LC CDR3, at least one of which contains no more than 5 amino acid variations as the counterpart LC CDR of Ab55h. 
     
     
         13 . The monoclonal antibody of  claim 12 , wherein the antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3, at least one of which contains no more than 2 amino acid variations as the counterpart HC CDR of Ab55h. 
     
     
         14 . The monoclonal antibody of  claim 12 , wherein the at least one HC CDR is HC CDR3. 
     
     
         15 . The monoclonal antibody of  claim 12 , wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3, at least one of which contains no more than 2 amino acid variations as the counterpart LC CDR of Ab55h. 
     
     
         16 . The monoclonal antibody of  claim 2 , wherein the antibody comprises the same heavy chain complementary determining regions (HC CDRs) and/or the same light chain complementary determining regions (LC CDRs) as Ab55h. 
     
     
         17 . The monoclonal antibody of  claim 16 , wherein the antibody comprises the same heavy chain variable domain as Ab55h and/or the same light chain variable domain as Ab55h. 
     
     
         18 . The monoclonal antibody of  claim 1 , wherein the antibody comprises a heavy chain variable domain that is at least 85% identical to the heavy chain variable domain of Ab55h, and/or a light chain variable domain that is at least 85% identical to the light chain variable domain of Ab55h. 
     
     
         19 . The monoclonal antibody of  claim 1 , wherein the antibody is a human antibody of a humanized antibody. 
     
     
         20 . The monoclonal antibody of  claim 1 , wherein the antibody is a full-length antibody. 
     
     
         21 . The monoclonal antibody of  claim 20 , wherein the full-length antibody is an IgG molecule. 
     
     
         22 . The monoclonal antibody of  claim 20 , wherein the antibody contains an altered Fc fragment relative to a naturally-occurring counterpart, or wherein the antibody contains an afucosylated Fc fragment, or wherein the antibody's antigen binding site is masked to allow protease mediated activation. 
     
     
         23 . The monoclonal antibody of  claim 22 , wherein the antibody contains an altered IgG1 Fc fragment, which comprises K214R. 
     
     
         24 . The monoclonal antibody of  claim 23 , wherein the antibody comprises a heavy chain set forth as SEQ ID NO: 1 and a light chain set forth as SEQ ID NO: 2. 
     
     
         25 . The monoclonal antibody of  claim 1 , wherein the antibody is an antigen-binding fragment. 
     
     
         26 . The monoclonal antibody of  claim 25 , wherein the antigen-binding fragment is Fab, Fab′, F(ab′) 2 , or Fv. 
     
     
         27 . The monoclonal antibody of  claim 1 , wherein the antibody is a single-chain antibody, a bispecific antibody or a nanobody. 
     
     
         28 . The monoclonal antibody of  claim 1 , wherein the antibody is conjugated to a detectable label. 
     
     
         29 . A nucleic acid or a nucleic acid set, which collectively encode an antibody binding to CTLA-4,
 wherein the antibody comprises a heavy chain variable domain (V H ), which comprises (i) a heavy chain complementary determining region 1 (HC CDR1) set forth as GDYYWX 1  (SEQ ID NO: 3), in which X 1  is G or N, (ii) a heavy chain complementary determining region 2 (HC CDR2) set forth as SIYHX 2 X 3 YTYYNPSX4KS (SEQ ID NO: 4), in which X2 is D or S, X3 is G or A, and X 4  is L or V; and (iii) a heavy chain complementary determining region 3 (HC CDR3) set forth as DSGWYVIAFX 5 X 6  (SEQ ID NO: 5), in which X 5  is D or A, and X 6  is Y or I; and/or   wherein the antibody comprises a light chain variable domain (V L ), which comprises (i) a light chain complementary determining region 1 (LC CDR1) set forth as RASQSX 7 SSNLA (SEQ ID NO: 6), in which X 7  is V or I; (ii) a light chain complementary determining region 2 (LC CDR2) set forth as X 8 AX 9 X 10 RAT (SEQ ID NO: 7), in which X 8  is A or G and each of X 9 , X 10  is independently S or T; and (iii) a light chain complementary determining region 3 (LC CDR3) set forth as QQYNNWPPLT (SEQ ID NO: 8).   
     
     
         30 .- 33 . (canceled) 
     
     
         34 . A genetically engineered immune cell, which expresses a chimeric receptor comprising an extracellular domain and at least one cytoplasmic signaling domain, wherein the extracellular domain is a single chain antibody derived from a CTLA-4-binding antibody,
 wherein the antibody comprises a heavy chain variable domain (V H ), which comprises (i) a heavy chain complementary determining region 1 (HC CDR1) set forth as GDYYWX 1  (SEQ ID NO: 3), in which X 1  is G or N, (ii) a heavy chain complementary determining region 2 (HC CDR2) set forth as SIYHX 2 X 3 YTYYNPSX 4 KS (SEQ ID NO: 4), in which X 2  is D or S, X 3  is G or A, and X 4  is L or V; and (iii) a heavy chain complementary determining region 3 (HC CDR3) set forth as DSGWYVIAFX 5 X 6  (SEQ ID NO: 5), in which X 5  is D or A, and X 6  is Y or I; and/or   wherein the antibody comprises a light chain variable domain (V L ), which comprises (i) a light chain complementary determining region 1 (LC CDR1) set forth as RASQSX 7 SSNLA (SEQ ID NO: 6), in which X 7  is V or I; (ii) a light chain complementary determining region 2 (LC CDR2) set forth as X 8 AX 9 X 10 RAT (SEQ ID NO: 7), in which X 8  is A or G and each of X 9 , X 10  is independently S or T; and (iii) a light chain complementary determining region 3 (LC CDR3) set forth as QQYNNWPPLT (SEQ ID NO: 8).   
     
     
         35 - 48 . (canceled)