CROSS-SPECIES-SPECIFIC PSMAxCD3 BISPECIFIC SINGLE CHAIN ANTIBODY

Abstract

The present invention relates to a bispecific single chain antibody molecule comprising a first binding domain capable of binding to an epitope of human and non-chimpanzee primate CD3 epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs. 2, 4, 6, and 8, and a second binding domain capable of binding to prostate-specific membrane antigen (PSMA). The invention also provides nucleic acids encoding said bispecific single chain antibody molecule as well as vectors and host cells and a process for its production. The invention further relates to pharmaceutical compositions comprising said bispecific single chain antibody molecule and medical uses of said bispecific single chain anti-body molecule.

1 . A bispecific single chain antibody molecule comprising a first binding domain capable of binding to an epitope of human CD3epsilon (CD3ε) chain and non-chimpanzee primate-CD3ε chain, wherein the epitope is part of the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, or 8, and comprises at least the amino sequence Gln-Asp-Gly-Asn-Glu (QDGNE) (SEQ ID NO: 1050), and a second binding domain capable of binding to prostate-specific membrane antigen (PSMA). 
     
     
         2 . The bispecific single chain antibody molecule of  claim 1 , wherein at least one of said first or second binding domain is CDR-grafted, humanized or human. 
     
     
         3 . The bispecific single chain antibody molecule according to  claim 1 , wherein the first binding domain comprises a VL region selected from the group consisting of:
 (a) a VL region comprising a CDR-L1 as depicted in SEQ ID NO: 27, a CDR-L2 as depicted in SEQ ID NO: 28, and a CDR-L3 as depicted in SEQ ID NO: 29;   (b) a VL region comprising a CDR-L1 as depicted in SEQ ID NO: 117, a CDR-L2 as depicted in SEQ ID NO: 118, and a CDR-L3 as depicted in SEQ ID NO: 119; and   (c) a VL region comprising a CDR-L1 as depicted in SEQ ID NO: 153, a CDR-L2 as depicted in SEQ ID NO: 154, and a CDR-L3 as depicted in SEQ ID NO: 155.   
     
     
         4 . The bispecific single chain antibody molecule according to  claim 1 , wherein the first binding domain comprises a VH region selected from the group consisting of:
 (a) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 12, a CDR-H2 as depicted in SEQ ID NO: 13, and a CDR-H3 as depicted in SEQ ID NO: 14;   (b) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 30, a CDR-H2 as depicted in SEQ ID NO: 31, and a CDR-H3 as depicted in SEQ ID NO: 32;   (c) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 48, a CDR-H2 as depicted in SEQ ID NO: 49 1  and a CDR-H3 as depicted in SEQ ID NO: 50;   (d) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 66, a CDR-H2 as depicted in SEQ ID NO: 67, and a CDR-H3 as depicted in SEQ ID NO: 68;   (e) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 84, a CDR-H2 as depicted in SEQ ID NO: 85, and a CDR-H3 as depicted in SEQ ID NO: 86;   (f) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 102, a CDR-H2 as depicted in SEQ ID NO: 103, and a CDR-H3 as depicted in SEQ ID NO: 104;   (g) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 120, a CDR-H2 as depicted in SEQ ID NO: 121, and a CDR-H3 as depicted in SEQ ID NO: 122;   (h) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 138, a CDR-H2 as depicted in SEQ ID NO: 139, and a CDR-H3 as depicted in SEQ ID NO: 140;   (i) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 156, a CDR-H2 as depicted in SEQ ID NO: 157, and a CDR-H3 as depicted in SEQ ID NO: 158; and   (j) a VH region comprising a CDR-H1 as depicted in SEQ ID NO: 174, a CDR-H2 as depicted in SEQ ID NO: 175, and a CDR-H3 as depicted in SEQ ID NO: 176.   
     
     
         5 . The bispecific single chain antibody molecule according to  claim 1 , wherein the first binding domain comprises a VL region as depicted in SEQ ID NO: 35, 39, 125, 129, 161 or 165. 
     
     
         6 . The bispecific single chain antibody molecule according to  claim 1 , wherein the first binding domain comprises a VH region as depicted in SEQ ID NO: 15, 19, 33, 37, 51, 55, 69, 73, 87, 91, 105, 109, 123, 127, 141, 145, 159, 163, 177 or 181. 
     
     
         7 . The bispecific single chain antibody molecule according to  claim 1 , wherein the first binding domain is selected from the group consisting of:
 (a) a first binding domain comprising a VL region as depicted in SEQ ID NO: 17 or 21 and a VH region as depicted in SEQ ID NO: 15 or 19;   (b) a first binding domain comprising a VL region as depicted in SEQ ID NO: 35 or 39 and a VH region as depicted in SEQ ID NO: 33 or 37;   (c) a first binding domain comprising a VL region as depicted in SEQ ID NO: 53 or 57 and a VH region as depicted in SEQ ID NO: 51 or 55;   (d) a first binding domain comprising a VL region as depicted in SEQ ID NO: 71 or 75 and a VH region as depicted in SEQ ID NO: 69 or 73;   (e) a first binding domain comprising a VL region as depicted in SEQ ID NO: 89 or 93 and a VH region as depicted in SEQ ID NO: 87 or 91;   (f) a first binding domain comprising a VL region as depicted in SEQ ID NO: 107 or 111 and a VH region as depicted in SEQ ID NO: 105 or 109;   (g) a first binding domain comprising a VL region as depicted in SEQ ID NO: 125 or 129 and a VH region as depicted in SEQ ID NO: 123 or 127;   (h) a first binding domain comprising a VL region as depicted in SEQ ID NO: 143 or 147 and a VH region as depicted in SEQ ID NO: 141 or 145;   (i) a first binding domain comprising a VL region as depicted in SEQ ID NO: 161 or 165 and a VH region as depicted in SEQ ID NO: 159 or 163; and   (j) a first binding domain comprising a VL region as depicted in SEQ ID NO: 179 or 183 and a VH region as depicted in SEQ ID NO: 177 or 181.   
     
     
         8 . The bispecific single chain antibody molecule according to  claim 1 , wherein the first binding domain comprises the amino acid sequence set forth in SEQ ID NO: 23, 25, 41, 43, 59, 61, 77, 79, 95, 97, 113, 115, 131, 133, 149, 151, 167, 169, 185 or 187. 
     
     
         9 . The bispecific single chain antibody molecule according to  claim 1 , wherein the PSMA is human PSMA and/or a non-chimpanzee primate PSMA. 
     
     
         10 . The bispecific single chain antibody molecule according to  claim 9 , wherein the the second binding domain is selected from the group consisting of:
 a) a second binding domain comprising CDR H1-3 of SEQ ID NO: 394-396 and CDR L1-3 of SEQ ID NO: 389-391;   b) a second binding domain comprising CDR H1-3 of SEQ ID NO: 408-410 and CDR L1-3 of SEQ ID NO: 403-405;   c) a second binding domain comprising CDR H1-3 of SEQ ID NO: 422-424 and CDR L1-3 of SEQ ID NO: 417-419;   d) a second binding domain comprising CDR H1-3 of SEQ ID NO: 436-438 and CDR L1-3 of SEQ ID NO: 431-433;   e) a second binding domain comprising CDR H1-3 of SEQ ID NO: 445-447 and CDR L1-3 of SEQ ID NO: 450-452;   f) a second binding domain comprising CDR H1-3 of SEQ ID NO: 464-466 and CDR L1-3 of SEQ ID NO: 459-461;   g) a second binding domain comprising CDR H1-3 of SEQ ID NO: 478-480 and CDR L1-3 of SEQ ID NO: 473-475;   h) a second binding domain comprising CDR H1-3 of SEQ ID NO: 492-494 and CDR L1-3 of SEQ ID NO: 487-489;   i) a second binding domain comprising CDR H1-3 of SEQ ID NO: 506-508 and CDR L1-3 of SEQ ID NO: 501-503;   j) a second binding domain comprising CDR H1-3 of SEQ ID NO: 520-522 and CDR L1-3 of SEQ ID NO: 515-517;   k) a second binding domain comprising CDR H1-3 of SEQ ID NO: 534-536 and CDR L1-3 of SEQ ID NO: 529-531;   l) a second binding domain comprising CDR H1-3 of SEQ ID NO: 548-550 and CDR L1-3of SEQ ID NO: 543-545;   m) a second binding domain comprising CDR H1-3 of SEQ ID NO: 562-564 and CDR L1-3 of SEQ ID NO: 557-559;   n) a second binding domain comprising CDR H1-3 of SEQ ID NO: 576-578 and CDR L1-3 of SEQ ID NO: 571-573;   o) a second binding domain comprising CDR H1-3 of SEQ ID NO: 590-592 and CDR L1-3 of SEQ ID NO: 585-587;   p) a second binding domain comprising CDR H1-3 of SEQ ID NO: 604-606 and CDR L1-3 of SEQ ID NO: 599-601;   q) a second binding domain comprising CDR H1-3 of SEQ ID NO: 618-620 and CDR L1-3 of SEQ ID NO: 613-615;   r) a second binding domain comprising CDR H1-3 of SEQ ID NO: 632-634 and CDR L1-3 of SEQ ID NO: 627-629;   s) a second binding domain comprising CDR H1-3 of SEQ ID NO: 646-648 and CDR L1-3 of SEQ ID NO: 641-643;   t) a second binding domain comprising CDR H1-3 of SEQ ID NO: 660-662 and CDR L1-3 of SEQ ID NO: 655-657;   u) a second binding domain comprising CDR H1-3 of SEQ ID NO: 674-676 and CDR L1-3 of SEQ ID NO: 669-671;   v) a second binding domain comprising CDR H1-3 of SEQ ID NO: 688-690 and CDR L1-3 of SEQ ID NO: 683-685;   w) a second binding domain comprising CDR H1-3 of SEQ ID NO: 702-704 and CDR L1-3 of SEQ ID NO: 697-699;   x) a second binding domain comprising CDR H1-3 of SEQ ID NO: 716-718 and CDR L1-3 of SEQ ID NO: 711-713;   y) a second binding domain comprising CDR H1-3 of SEQ ID NO: 729-731 and CDR L1-3 of SEQ ID NO: 724-726;   z) a second binding domain comprising CDR H1-3 of SEQ ID NO: 788-790 and CDR L1-3 of SEQ ID NO: 793-795;   aa) a second binding domain comprising CDR H1-3 of SEQ ID NO: 806-808 and CDR L1-3 of SEQ ID NO: 811-813;   ab) a second binding domain comprising CDR H1-3 of SEQ ID NO: 852-854 and CDR L1-3 of SEQ ID NO: 857-859;   ac) a second binding domain comprising CDR H1-3 of SEQ ID NO: 838-840 and CDR L1-3 of SEQ ID NO: 843-845;   ad) a second binding domain comprising CDR H1-3 of SEQ ID NO: 824-826 and CDR L1-3 of SEQ ID NO: 829-831;   ae) a second binding domain comprising CDR H1-3 of SEQ ID NO: 774-776 and CDR L1-3 of SEQ ID NO: 779-781;   af) a second binding domain comprising CDR H1-3 of SEQ ID NO: 688-690 and CDR L1-3 of SEQ ID NO. 683-685;   ag) a second binding domain comprising CDR H1-3 of SEQ ID NO: 870-872 and CDR L1-3 of SEQ ID NO: 875-877;   ah) a second binding domain comprising CDR H1-3 of SEQ ID NO: 888-890 and CDR L1-3 of SEQ ID NO: 893-895;   ai) a second binding domain comprising CDR H1-3 of SEQ ID NO: 924-926 and CDR L1-3 of SEQ ID NO: 929-931;   aj) a second binding domain comprising CDR H1-3 of SEQ ID NO: 1019-1021 and CDR L1-3 of SEQ ID NO: 1025-1027;   ak) a second binding domain comprising CDR H1-3 of SEQ ID NO: 1006-1008 and CDR L1-3 of SEQ ID NO: 1011-1013;   al) a second binding domain comprising CDR H1-3 of SEQ ID NO: 906-908 and CDR L1-3 of SEQ ID NO: 911-913;   am) a second binding domain comprising CDR H1-3 of SEQ ID NO: 992-994 and CDR L1-3 of SEQ ID NO: 997-999;   an) a second binding domain comprising CDR H1-3 of SEQ ID NO: 942-944 and CDR L1-3 of SEQ ID NO: 947-949;   ao) a second binding domain comprising CDR H1-3 of SEQ ID NO: 960-962 and CDR L1-3 of SEQ ID NO: 965-967; and   ap) a second binding domain comprising CDR H1-3 of SEQ ID NO: 978-980 and CDR L1-3 of SEQ ID NO: 983-985.   
     
     
         11 . The bispecific single chain antibody molecule of  claim 10 , wherein the binding domains are arranged in the order VH PSMA-VL PSMA-VH CD3-VL CD3 or VL PSMA-VH CD3-VL CD3. 
     
     
         12 . The bispecific single chain antibody molecule according to  claim 11 , wherein the bispecific single chain antibody molecule comprises an amino acid sequence selected from the group consisting of:
 (a) an amino acid sequence as depicted in any of SEQ ID NO: 399, 413, 427, 441, 455, 469, 483, 497, 511, 525, 539, 553, 567, 581, 595, 609, 623, 637, 651, 665, 679, 693, 707, 721, 734, 799, 817, 863, 849, 835, 785, 899, 935, 1017, 1031, 917, 1003, 953, 971, or 989;   (b) an amino acid sequence encoded by a nucleic acid sequence as depicted in any of SEQ ID NO: 400, 414, 428, 442, 456, 470, 484, 498, 512, 526, 540, 554, 568, 582, 596, 610, 624, 638, 652, 666, 680, 694, 708, 736, 735, 818, 864, 850, 836, 786, 882, 900, 936, 1018, 1032, 918, 1004, 954, 972, 990, 804, 822, 868, 886, 904, 940, 922, 958, or 976; and   (c) an amino acid sequence at least 90% identical to the amino acid sequence of (a) or (b).   
     
     
         13 . A nucleic acid comprising a nucleotide sequence encoding the bispecific single chain antibody molecule of  claim 1 . 
     
     
         14 . A vector comprising the nucleic acid of  claim 13 . 
     
     
         15 - 16 . (canceled) 
     
     
         17 . A host transformed or transfected with the vector of  claim 14 . 
     
     
         18 . A process for producing a bispecific single chain antibody molecule comprising culturing the host of  claim 17  under conditions suitable to express the bispecific single chain antibody molecule and, optionally recovering the bispecific single chain antibody molecule from the culture. 
     
     
         19 . A pharmaceutical composition comprising the bispecific single chain antibody molecule according to  claim 1 . 
     
     
         20 - 27 . (canceled) 
     
     
         28 . A method for preventing, treating, or ameliorating a disease in a subject in the need thereof, said method comprising the step of administering an effective amount of the pharmaceutical composition of  claim 19 . 
     
     
         29 . The method of  claim 28 , wherein said disease is cancer. 
     
     
         30 . The method or use of  claim 29 , wherein said cancer is a solid tumor, preferably a carcinoma or prostate cancer. 
     
     
         31 . The method of  claim 28 , wherein said pharmaceutical composition is administered in combination with an additional drug. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The method of  claim 28 , wherein said subject is a human. 
     
     
         35 . A kit comprising the bispecific single chain antibody molecule of  claim 1 .