Antibodies that bind psma and gamma-delta t cell receptors

Abstract

Provided herein are antibodies capable of binding human PSMA and capable of binding a human Vγ9Vδ2 T cell receptor. In particular, provided herein are pharmaceutical compositions comprising the antibodies capable of binding human PSMA and capable of binding a human Vγ9VΩ T cell receptor and uses of the antibodies for medical treatment.

1 . A multispecific antibody comprising a first antigen-binding region capable of binding human PSMA and a second antigen-binding region capable of binding a human Vγ9Vβ2 T cell receptor. 
     
     
         2 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody is a bispecific antibody. 
     
     
         3 . The multispecific antibody according to  claim 1 , wherein the first antigen-binding region is a single-domain antibody. 
     
     
         4 . The multispecific antibody according to  claim 1 , wherein the second antigen-binding region is a single-domain antibody. 
     
     
         5 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody competes for binding to human PSMA with an antibody having the sequence set forth in SEQ ID NO:2. 
     
     
         6 . The multispecific antibody according to a  claim 1 , wherein the first antigen-binding region comprises the VH CDR1 sequence set forth in SEQ ID NO:14, the VH CDR2 sequence set forth in SEQ ID NO:15 and the VH CDR3 sequence set forth in SEQ ID NO:16. 
     
     
         7 . The multispecific antibody according to  claim 1 , wherein the first antigen-binding region is humanized, and wherein the first antigen-binding region comprises the sequence set forth in SEQ ID NO:2, or a sequence having at least 90% sequence identity to the sequence set forth in SEQ ID NO:2. 
     
     
         8 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody is able to activate human Vγ9Vβ2 T cells. 
     
     
         9 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody is capable of binding to human Vβ2. 
     
     
         10 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody competes for binding to human Vβ2 with an antibody having the sequence set forth in SEQ ID NO:5 or competes for binding to human Vβ2 with an antibody having the sequence set forth in SEQ ID NO:20. 
     
     
         11 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody binds the same epitope on human Vβ2 as an antibody having the sequence set forth in SEQ ID NO:5 or binds the same epitope on human Vβ2 as an antibody having the sequence set forth in SEQ ID NO:20. 
     
     
         12 . The multispecific antibody according to  claim 1 , wherein the second antigen-binding region comprises the VH CDR1 sequence set forth in SEQ ID NO:17, the VH CDR2 sequence set forth in SEQ ID NO:18 and the VH CDR3 sequence set forth in SEQ ID NO:19 or comprises the VH CDR1 sequence set forth in SEQ ID NO:21, the VH CDR2 sequence set forth in SEQ ID NO:22 and the VH CDR3 sequence set forth in SEQ ID NO:23. 
     
     
         13 . The multispecific antibody according to  claim 1 , wherein the second antigen-binding region is humanized, and wherein the second antigen-binding region comprises the sequence set forth in SEQ ID NO:5, or a sequence having at least 90% sequence identity to the sequence set forth in SEQ ID NO:5. 
     
     
         14 . The multispecific antibody according to  claim 1 , wherein the first antigen-binding region comprises the VH CDR1 sequence set forth in SEQ ID NO:14, the VH CDR2 sequence set forth in SEQ ID NO:15 and the VH CDR3 sequence set forth in SEQ ID NO:16 and wherein the second antigen-binding region comprises the VH CDR1 sequence set forth in SEQ ID NO:15, the VH CDR2 sequence set forth in SEQ ID NO:18 and the VH CDR3 sequence set forth in SEQ ID NO:19. 
     
     
         15 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody is capable of binding to human Vg9. 
     
     
         16 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody is capable of mediating killing of PSMA-expressing cells by Vγ9Vβ2 T cells. 
     
     
         17 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody is capable of mediating killing of human PSMA-expressing cells from a prostate cancer patient. 
     
     
         18 . The multispecific antibody according to  claim 1 , wherein the first antigen-binding region and second antigen-binding region are covalently linked via a peptide linker. 
     
     
         19 . The multispecific antibody according to  claim 18 , wherein the peptide linker comprises the sequence set forth in SEQ ID NO:6. 
     
     
         20 . The multispecific antibody according to  claim 1 , wherein the first antigen-binding region capable of binding human PSMA is located N-terminally of the second antigen-binding region capable of binding a human Vγ9Vβ2 T cell receptor. 
     
     
         21 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody further comprises a half-life extension domain. 
     
     
         22 . The multispecific antibody according to  claim 20 , wherein the multispecific antibody has a terminal half-life that is longer than about 168 hours when administered to a human subject. 
     
     
         23 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody comprises an Fc region. 
     
     
         24 . The multispecific antibody according to  claim 23 , wherein the Fc region is a heterodimer comprising two Fc polypeptides, wherein the first antigen-binding region is fused to the first Fc polypeptide and the second antigen-binding region is fused to the second Fc polypeptide and wherein the first and second Fc polypeptides comprise asymmetric amino acid mutations that favor the formation of heterodimers over the formation of homodimers. 
     
     
         25 . The multispecific antibody according to  claim 24 , wherein the CH3 regions of the Fc polypeptides comprise said asymmetric amino acid mutations, wherein the first Fc polypeptide comprises a T366W substitution and the second Fc polypeptide comprises T366S, L368A and Y407V substitutions, or vice versa, wherein the amino acid positions correspond to human IgG1 according to the EU numbering system. 
     
     
         26 . The multispecific antibody according to  claim 24 , wherein the cysteine residues at position 220 in the first and second Fc polypeptides have been deleted or substituted, and wherein the amino acid positions correspond to human IgG1 according to the EU numbering system. 
     
     
         27 . The multispecific antibody according  claim 24 , wherein the first and second Fc polypeptides further comprise a mutation at position 234 and/or 235, wherein the first and second Fc polypeptide comprise an L234F and an L235E substitution, and wherein the amino acid positions correspond to human IgG1 according to the EU numbering system. 
     
     
         28 . The multispecific antibody according to  claim 24 , wherein the first antigen-binding region comprises the sequence set forth in SEQ ID NO:2, the second antigen-binding region comprises the sequence set forth in SEQ ID NO:5 and wherein
 the first Fc polypeptide comprises the sequence set forth in SEQ ID NO:12 and the second Fc polypeptide comprises the sequence set forth in SEQ ID NO:13, or   the first Fc polypeptide comprises the sequence set forth in SEQ ID NO:12 and the second Fc polypeptide comprises the sequence set forth in SEQ ID NO:13.   
     
     
         29 . A pharmaceutical composition comprising a multispecific antibody according to  claim 1 , and a pharmaceutically-acceptable excipient. 
     
     
         30 . The pharmaceutical composition according to  claim 29 , wherein the pharmaceutical composition comprises a buffer, sucrose, polysorbate 80 and methionine, and wherein the pH of the composition is between 5.4 and 7.4. 
     
     
         31 . The A medicament comprising a multispecific antibody according to  claim 1 . 
     
     
         32 . The A method of treating cancer comprising administration of the multispecific antibody according to  claim 1 . 
     
     
         33 . A method of treating prostate cancer comprising administration of the multispecific antibody according to  claim 1 . 
     
     
         34 . The A method of treating cancers in which PSMA is expressed on the tumor neo-vasculature or tumor-associated endothelial cells of primary or metastatic tumors comprising cancers selected from colorectal cancer, lung cancer, breast cancer, endometrial and ovarian cancer, gastric cancer, renal cell cancer, urothelial cancer, hepatocellular cancer, oral squamous cancer, thyroid tumors and glioblastomas comprising administration of the multispecific antibody according to  claim 1 . 
     
     
         35 . A method of treating an adenoid cystic carcinoma of the head and neck comprising administration of the multispecific antibody according to  claim 1 . 
     
     
         36 . A method of treating a disease comprising administration of a multispecific antibody according to  claim 1 . 
     
     
         37 . The method according to  claim 36 , wherein the disease is cancer. 
     
     
         38 . A nucleic acid construct encoding the multispecific antibody according to  claim 1 . 
     
     
         39 . An expression vector comprising a nucleic acid construct according to  claim 38 . 
     
     
         40 . A host cell comprising a nucleic acid construct according to  claim 38 . 
     
     
         41 . A method for production of the multispecific antibody as defined in  claim 1  comprising (co-)expression of one or more nucleic acid constructs encoding the multispecific antibody in a suitable host cell, followed by purification of the produced recombinant antibody. 
     
     
         42 . The multispecific antibody according to  claim 1 , wherein the multispecific antibody binds the same epitope on human PSMA as an antibody having the sequence set forth in SEQ ID NO:2. 
     
     
         43 . The multispecific antibody according to  claim 16 , wherein the PSMA-expressing cells comprise LNCaP cells. 
     
     
         44 . The pharmaceutical composition according to  claim 30 , wherein the pH of the composition is between 5.4 and 6.1. 
     
     
         45 . A host cell comprising an expression vector according to  claim 39 . 
     
     
         46 . The host cell according to  claim 40 , wherein the host cell is a mammalian host cell. 
     
     
         47 . The host cell according to  claim 46 , wherein the mammalian host cell is a CHO cell.