Novel bispecific polypeptides against cd137

Abstract

The invention provides bispecific polypeptides comprising a first binding domain, designated B1, which is capable of binding specifically to CD137, and a second binding domain, designated B2, which is capable of specifically binding to a tumour cell-associated antigen. Also provided are pharmaceutical compositions of such bispecific polypeptides and uses of the same in medicine.

1 . A bispecific polypeptide comprising a first binding domain, designated B1, which is capable of binding specifically to CD137, and a second binding domain, designated B2, which is capable of specifically binding to a tumour cell-associated antigen. 
     
     
         2 . A polypeptide according to  claim 1 , wherein the first and/or second binding domains are/is selected from the group consisting of antibodies and antigen-binding fragments thereof. 
     
     
         3 . A polypeptide according to  claim 2  wherein the antigen-binding fragment is selected from the group consisting of: Fv fragments (such as a single chain Fv fragment, or a disulphide-bonded Fv fragment), Fab-like fragments (such as a Fab fragment; a Fab′ fragment or a F(ab) 2  fragment) and domain antibodies. 
     
     
         4 . A polypeptide according to any one of the preceding claims wherein the polypeptide is a bispecific antibody. 
     
     
         5 . A polypeptide according to  claim 4  wherein:
 (a) binding domain B1 and/or binding domain B2 is an intact IgG antibody; 
 (b) binding domain B1 and/or binding domain B2 is an Fv fragment; 
 (c) binding domain B1 and/or binding domain B2 is a Fab fragment; and/or 
 (d) binding domain B1 and/or binding domain B2 is a single domain antibody. 
 
     
     
         6 . A polypeptide according to  claim 4  or  5  wherein the bispecific antibody comprises a human Fc region or a variant of a said region, where the region is an IgG1, IgG2, IgG3 or IgG4 region, preferably an IgG1 or IgG4 Fc region. 
     
     
         7 . A polypeptide according to  claim 6  wherein the Fc exhibits no or very low affinity for FcgR. 
     
     
         8 . A polypeptide according to  claim 6  or  7  wherein the Fc region is a variant of a human IgG1 Fc region comprising a mutation at one or more of the following positions:
 L234, L235, P239, D265, N297 and/or P329. 
 
     
     
         9 . A polypeptide according to  claim 8  wherein alanine is present at the mutated positions(s). 
     
     
         10 . A polypeptide according to  claim 9  wherein the Fc region is a variant of a human IgG1 Fc region comprising the double mutations L234A and L235A. 
     
     
         11 . A polypeptide according to any one of  claims 4  to  10  wherein the bispecific antibody is selected from the groups consisting of:
 (a) bivalent bispecific antibodies, such as IgG-scFv bispecific antibodies (for example, wherein B1 is an intact IgG and B2 is an scFv attached to B1 at the N-terminus of a light chain and/or at the C-terminus of a light chain and/or at the N-terminus of a heavy chain and/or at the C-terminus of a heavy chain of the IgG, or vice versa); 
 (b) monovalent bispecific antibodies, such as a DuoBody® or a ‘knob-in-hole’ bispecific antibody (for example, an scFv-KIH, scFv-KIHr, a BiTE-KIH or a BiTE-KIHr; 
 (c) scFv 2 -Fc bispecific antibodies (for example, ADAPTIR™ bispecific antibodies); 
 (d) BITE/scFv2 bispecific antibodies; 
 (e) DVD-Ig bispecific antibodies or other IgG-FAb, FAb-IgG bispecific antibodies regardless of bivalency or linkers/connectors employed; 
 (f) DART-based bispecific antibodies (for example, DART 2 -Fc, DART 2 -Fc or DART); 
 (g) DNL-Fabs bispecific antibodies; and 
 (h) scFv-HSA-scFv bispecific antibodies. 
 
     
     
         12 . A polypeptide according to  claim 11  wherein the bispecific antibody is an IgG-scFv bispecific antibody. 
     
     
         13 . A polypeptide according to any one of the preceding claims wherein binding domain B1 and binding domain B2 are fused directly to each other. 
     
     
         14 . A polypeptide according to any one of  claims 1  to  12  wherein binding domain B1 and binding domain B2 are joined via a polypeptide linker. 
     
     
         15 . A polypeptide according to  claim 14  wherein the linker is selected from the group consisting of the amino acid sequence SGGGGSGGGGS (SEQ ID NO: 87), SGGGGSGGGGSAP (SEQ ID NO: 88), NFSQP (SEQ ID NO: 89), KRTVA (SEQ ID NO: 90), GGGSGGGG (SEQ ID NO: 91), GGGGSGGGGS (SEQ ID NO: 92), GGGGSGGGGSGGGGS (SEQ ID NO: 93), THTCPPCPEPKSSDK (SEQ ID NO:
 140), GGGS (SEQ ID NO: 141), EAAKEAAKGGGGS (SEQ ID NO: 142), EAAKEAAK (SEQ ID NO: 143), or (SG)m, where m=1 to 7. 
 
     
     
         16 . A polypeptide according to any of the preceding claims, wherein the polypeptide is incapable of inducing antibody dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and/or complement-dependent cytotoxicity (CDC). 
     
     
         17 . A polypeptide according to any of the preceding claims, wherein the polypeptide is capable of inducing tumour immunity. 
     
     
         18 . A polypeptide according to any one of the preceding claims, wherein the polypeptide is capable of inducing:
 (a) activation of cytotoxic T cells, i.e. CD8+ T cells;   (b) activation of helper T cells, i.e. CD4 +  T cells;   (c) activation of dendritic cells; and/or   (d) activation of natural killer cells; and/or   (e) reprograming of Tregs into effector T cells.   
     
     
         19 . A polypeptide according to any of the preceding claims wherein binding domain B1 binds to human CD137 with a K D  of less than 10×10 −9 M, for example less than 4×10 −9 M or less than 1.2×10 −9 M. 
     
     
         20 . A polypeptide according to any of the preceding claims wherein binding domain B1 comprises:
 (a) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1200/1201 (SEQ ID NOs: 54, 55 and 79 and/or SEQ ID NOs: 46, 65 and 72);   (b) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1202/1203 (SEQ ID NOs: 54, 55 and 80 and/or SEQ ID NOs: 60, 66 and 73);   (c) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1204/1205 (SEQ ID NOs: 54, 55 and 81 and/or SEQ ID NOs: 61, 67, 74);   (d) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1214/1215 (SEQ ID NOs: 54, 55 and 82 and/or SEQ ID NOs: 46, 68 and 75);   (e) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 161 8 / 1 619 (SEQ ID NOs: 54, 55 and 83 and/or SEQ ID NOs: 62, 69 and 76);   (f) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1620/1621 (SEQ ID NOs: 54, 55 and 84 and/or SEQ ID NOs: 63, 70, and 77);   (g) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1626/1627 (SEQ ID NOs: 54, 55 and 85 and/or SEQ ID NOs: 64, 71 and 78);   (h) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3012/3013 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 158, 155 and 83);   (i) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3014/3015 (SEQ ID NOs: 62, 69 and 76 and/or SEQ ID NOs: 159, 160 and 83);   (j) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3016/3017 (SEQ ID NOs: 62, 69 and 76 and/or SEQ ID NOs: 159, 155 and 83);   (k) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3018/3019 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 158, 161 and 83);   (l) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3020/3021 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 162, 163 and 83);   (m) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3022/3023 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 159, 155 and 83);   (n) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3024/3025 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 54, 55 and 83);   (o) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3026/3027 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 162, 165 and 83);   (p) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3028/3029 (SEQ ID NOs: 157, 69 and 76 and/or SEQ ID NOs: 159, 166 and 83);   (q) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3030/3031 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 54, 166 and 83);   (r) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3032/3033 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 54, 55 and 83);   (s) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 303 4 / 3 035 (SEQ ID NOs: 62, 69 and 76 and/or SEQ ID NOs: 54, 155 and 83); or   (t) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3036/3037 (SEQ ID NOs: 156, 69 and 76 and/or SEQ ID NOs: 162, 155 and 83).   
     
     
         21 . A polypeptide according to any of the preceding claims wherein binding domain B1 comprises:
 (a) the heavy chain variable region and/or the light chain variable region of antibody 1200/1201 (SEQ ID NO: 19 and/or SEQ ID NO: 17);   (b) the heavy chain variable region and/or the light chain variable region of antibody 1202/1203 (SEQ ID NO: 23 and/or SEQ ID NO: 21);   (c) the heavy chain variable region and/or the light chain variable region of antibody 1204/1205 (SEQ ID NO: 25 and/or SEQ ID NO: 27);   (d) the heavy chain variable region and/or the light chain variable region of antibody 1214/1215 (SEQ ID NO: 31 and/or SEQ ID NO: 29);   (e) the heavy chain variable region and/or the light chain variable region of antibody 1618/1619 (SEQ ID NO: 35 and/or SEQ ID NO: 33);   (f) the heavy chain variable region and/or the light chain variable region of antibody 1620/1621 (SEQ ID NO: 39 and/or SEQ ID NO: 37);   (g) the heavy chain variable region and/or the light chain variable region of antibody 1626/1627 (SEQ ID NO: 43 and/or SEQ ID NO: 41);   (h) the heavy chain variable region and/or the light chain variable region of antibody 3012/3013 (SEQ ID NO: 114 and/or SEQ ID NO: 115);   (i) the heavy chain variable region and/or the light chain variable region of antibody 3014/3015 (SEQ ID NO: 116 and/or SEQ ID NO: 117);   (j) the heavy chain variable region and/or the light chain variable region of antibody 3016/3017 (SEQ ID NO: 118 and/or SEQ ID NO: 119);   (k) the heavy chain variable region and/or the light chain variable region of antibody 3018/3019 (SEQ ID NO: 120 and/or SEQ ID NO: 121);   (l) the heavy chain variable region and/or the light chain variable region of antibody 3020/3021 (SEQ ID NO: 122 and/or SEQ ID NO: 123);   (m)the heavy chain variable region and/or the light chain variable region of antibody 3022/3023 (SEQ ID NO: 124 and/or SEQ ID NO: 125);   (n) the heavy chain variable region and/or the light chain variable region of antibody 3024/3025 (SEQ ID NO: 126 and/or SEQ ID NO: 127);   (o) the heavy chain variable region and/or the light chain variable region of antibody 3026/3027 (SEQ ID NO: 128 and/or SEQ ID NO: 129);   (p) the heavy chain variable region and/or the light chain variable region of antibody 3028/3029 (SEQ ID NO: 130 and/or SEQ ID NO: 131);   (q) the heavy chain variable region and/or the light chain variable region of antibody 3030/3031 (SEQ ID NO: 132 and/or SEQ ID NO: 133);   (r) the heavy chain variable region and/or the light chain variable region of antibody 3032/3033 (SEQ ID NO: 134 and/or SEQ ID NO: 135);   (s) the heavy chain variable region and/or the light chain variable region of antibody 3034/3035 (SEQ ID NO: 136 and/or SEQ ID NO: 137); or   (t) the heavy chain variable region and/or the light chain variable region of antibody 3036/3037 (SEQ ID NO: 138 and/or SEQ ID NO: 139).   
     
     
         22 . A polypeptide according to any of the preceding claims wherein binding domain B1 comprises:
 (a) the heavy chain and/or the light chain of antibody 1200/1201;   (b) the heavy chain and/or the light chain of antibody 1202/1203;   (c) the heavy chain and/or the light chain of antibody 1204/1205;   (d) the heavy chain and/or the light chain of antibody 1214/1215;   (e) the heavy chain and/or the light chain of antibody 1618/1619;   (f) the heavy chain and/or the light chain of antibody 1620/1621;   (g) the heavy chain and/or the light chain of antibody 1626/1627;   (h) the heavy chain and/or the light chain of antibody 3012/3013;   (i) the heavy chain and/or the light chain of antibody 3014/3015;   (j) the heavy chain and/or the light chain of antibody 3016/3017;   (k) the heavy chain and/or the light chain of antibody 3018/3019;   (l) the heavy chain and/or the light chain of antibody 3020/3021;   (m)the heavy chain and/or the light chain of antibody 3022/3023;   (n) the heavy chain and/or the light chain of antibody 3024/3025;   (o) the heavy chain and/or the light chain of antibody 3026/3027;   (p) the heavy chain and/or the light chain of antibody 3028/3029;   (q) the heavy chain and/or the light chain of antibody 3030/3031;   (r) the heavy chain and/or the light chain of antibody 3032/3033;   (s) the heavy chain and/or the light chain of antibody 3034/3035; or   (t) the heavy chain and/or the light chain of antibody 3036/3037.   
     
     
         23 . A polypeptide according to any of the preceding claims wherein binding domain B1 comprises the light chain variable region and the heavy chain variable region of antibody 1200/1201 (SEQ ID NO: 19 and/or SEQ ID NO: 17), or a variant which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO: 19 and/or SEQ ID NO: 17). 
     
     
         24 . A polypeptide according to any one of  claims 1  to  22  wherein binding domain B1 comprises the light chain variable region and the heavy chain variable region of antibody 1618/1619 (SEQ ID NO: 35 and/or SEQ ID NO: 33), ora variant which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO: 35 and/or SEQ ID NO: 33). 
     
     
         25 . A polypeptide according to any of the preceding claims wherein binding domain B2 binds to a tumour cell-associated antigen selected from the group consisting of:
 (a) products of mutated oncogenes and tumour suppressor genes;   (b) overexpressed or aberrantly expressed cellular proteins;   (c) tumour antigens produced by oncogenic viruses;   (d) oncofetal antigens;   (e) altered cell surface glycolipids and glycoproteins;   (f) cell type-specific differentiation antigens;   (g) hypoxia-induced antigens;   (h) tumour peptides presented by MHC class I;   (i) epithelial tumour antigens;   (j) haematological tumour-associated antigens;   (k) cancer testis antigens; and   (l) melanoma antigens.   
     
     
         26 . A polypeptide according to any of the preceding claims wherein the tumour cell-associated antigen is selected from the group consisting of 5T4, CD20, CD19, MUC-1, carcinoembryonic antigen (CEA), CA-125, C017-1A, EpCAM, HER2, EGFR, HER3, GD2, Podocalyxin, TROP-2, DLK-1, Ox1R, Nectin-4, FAP, EphA2, EphA3, mesothelin, E-cadherin, CD24 and VEGFR. 
     
     
         27 . A polypeptide according to any of the preceding claims wherein the tumour cell-associated antigen is an oncofetal antigen. 
     
     
         28 . A polypeptide according to any of the preceding claims wherein the tumour cell-associated antigen is 5T4. 
     
     
         29 . A polypeptide according to any of the preceding claims wherein the tumour cell is a solid tumour cell. 
     
     
         30 . A polypeptide according to  claim 29  wherein the solid tumour is selected from the groups consisting of renal cell carcinoma, colorectal cancer, lung cancer, prostate cancer, breast cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer and sarcomas. 
     
     
         31 . A polypeptide according to any of the preceding claims wherein binding domain B2 binds to the tumour cell-associated antigen with a KD of less than 10×10 −9 M, for example less than 4×10 −9 M or less than 1.2×10 −9 M. 
     
     
         32 . A polypeptide according to any of the preceding claims wherein binding domain B2 comprises:
 (a) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1206/1207 (SEQ ID NOs: 54, 55 and 56 and/or SEQ ID NOs: 45, 47 and 50);   (b) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1208/1135 (SEQ ID NOs: 54, 55 and 57 and/or SEQ ID NOs: 46, 48 and 51);   (c) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1210/1211 (SEQ ID NOs: 54, 55 and 58 and/or SEQ ID NOs: 46, 48 and 52);   (d) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1212/1213 (SEQ ID NOs: 54, 55 and 59 and/or SEQ ID NOs: 46, 49 and 53);   (e) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 2992/2993 (SEQ ID NOs: 144, 48 and 52 and/or SEQ ID NOs: 145, 55 and 58);   (f) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 2994/2995 (SEQ ID NOs: 146, 147 and 52 and/or SEQ ID NOs: 145, 55 and 58);   (g) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 2996/2997 (SEQ ID NOs: 146, 48 and 52 and/or SEQ ID NOs: 148, 55 and 58);   (h) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 2998/2999 (SEQ ID NOs: 146, 48 and 52 and/or SEQ ID NOs: 149, 55 and 58);   (i) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3000/3001 (SEQ ID NOs: 150, 48 and 52 and/or SEQ ID NOs: 148, 151 and 58);   (j) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3002/3003 (SEQ ID NOs: 152, 48 and 52 and/or SEQ ID NOs: 145, 55 and 58);   (k) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3004/3005 (SEQ ID NOs: 146, 48 and 52 and/or SEQ ID NOs: 153, 55 and 58);   (l) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3006/3007 (SEQ ID NOs: 144, 48 and 52 and/or SEQ ID NOs: 154, 155 and 58); or   (m)the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 3008/3009 (SEQ ID NOs: 146, 48 and 52 and/or SEQ ID NOs: 154, 55 and 58).   
     
     
         33 . A polypeptide according to any of the preceding claims wherein binding domain B2 comprises:
 (a) the heavy chain variable region and/or the light chain variable region of antibody 1206/1207 (SEQ ID NO: 3 and/or SEQ ID NO: 1);   (b) the heavy chain variable region and/or the light chain variable region of antibody 1208/1135 (SEQ ID NO: 7 and/or SEQ ID NO: 5);   (c) the heavy chain variable region and/or the light chain variable region of antibody 1210/1211 (SEQ ID NO: 11 and/or SEQ ID NO: 9);   (d) the heavy chain variable region and/or the light chain variable region of antibody 1212/1213 (SEQ ID NO: 15 and/or SEQ ID NO: 13);   (e) the heavy chain variable region and/or the light chain variable region of antibody 2992/2993 (SEQ ID NO: 96 and/or SEQ ID NO: 97);   (f) the heavy chain variable region and/or the light chain variable region of antibody 2994/2995 (SEQ ID NO: 98 and/or SEQ ID NO: 99);   (g) the heavy chain variable region and/or the light chain variable region of antibody 2996/2997 (SEQ ID NO: 100 and/or SEQ ID NO: 101);   (h) the heavy chain variable region and/or the light chain variable region of antibody 2998/2999 (SEQ ID NO: 102 and/or SEQ ID NO: 103);   (i) the heavy chain variable region and/or the light chain variable region of antibody 3000/3001 (SEQ ID NO: 104 and/or SEQ ID NO: 105);   (j) the heavy chain variable region and/or the light chain variable region of antibody 3002/3003 (SEQ ID NO: 106 and/or SEQ ID NO: 107);   (k) the heavy chain variable region and/or the light chain variable region of antibody 3004/3005 (SEQ ID NO: 108 and/or SEQ ID NO: 109);   (l) the heavy chain variable region and/or the light chain variable region of antibody 3006/3007 (SEQ ID NO: 110 and/or SEQ ID NO: 111); or   (m)the heavy chain variable region and/or the light chain variable region of antibody 3008/3009 (SEQ ID NO: 112 and/or SEQ ID NO: 113).   
     
     
         34 . A polypeptide according to any of the preceding claims wherein binding domain B2 comprises:
 (a) the heavy chain and/or the light chain of antibody 1206/1207;   (b) the heavy chain and/or the light chain of antibody 1208/1135;   (c) the heavy chain and/or the light chain of antibody 1210/1211;   (d) the heavy chain and/or the light chain of antibody 1212/1213;   (e) the heavy chain and/or the light chain of antibody 2992/2993;   (f) the heavy chain and/or the light chain of antibody 2994/2995;   (g) the heavy chain and/or the light chain of antibody 2996/2993;   (h) the heavy chain and/or the light chain of antibody 2998/2999;   (i) the heavy chain and/or the light chain of antibody 3000/3001;   (j) the heavy chain and/or the light chain of antibody 3002/3003;   (k) the heavy chain and/or the light chain of antibody 3004/3005;   (l) the heavy chain and/or the light chain of antibody 3006/3007; or   (m) the heavy chain and/or the light chain of antibody 3008/3009.   
     
     
         35 . A polypeptide according to any of the preceding claims wherein binding domain B2 comprises the light chain variable region and the heavy chain variable region of antibody 1208/1135 (SEQ ID NO: 7 and SEQ ID NO: 5), or a variant which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO: 7 and/or SEQ ID NO: 5). 
     
     
         36 . A polypeptide according to any one of  claims 1  to  34  wherein binding domain B2 comprises the light chain variable region and the heavy chain variable region of antibody 1210/1211 (SEQ ID NO: 11 and SEQ ID NO: 9), or a variant which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO: 11 and/or SEQ ID NO: 9). 
     
     
         37 . A polypeptide according to any one of  claims 1  to  34  wherein binding domain B2 comprises the light chain variable region and the heavy chain variable region of antibody 2992/2993 (SEQ ID NO: 96 and SEQ ID NO: 97), or a variant which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO: 96 and/or SEQ ID NO: 97). 
     
     
         38 . A polypeptide according to any one of  claims 1  to  34  wherein binding domain B2 comprises the light chain variable region and the heavy chain variable region of antibody 2994/2995 (SEQ ID NO: 98 and SEQ ID NO: 99), or a variant which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO: 98 and/or SEQ ID NO: 99). 
     
     
         39 . A polypeptide according to any one of the preceding claims wherein binding domain B1 is an IgG and binding domain B2 is an scFv. 
     
     
         40 . A polypeptide according to any one of  claims 1  to  38  wherein binding domain B1 is an scFv and binding domain B2 is an IgG. 
     
     
         41 . A polypeptide according to any one of  claims 1  to  38  wherein binding domain B1 is an scFv and binding domain B2 is an scFv (e.g. in an scFv 2 -Fc format). 
     
     
         42 . A polypeptide according to any one of the preceding claims wherein:
 (a) B1 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1200/1201 (SEQ ID NOs: 54, 55 and 79 and/or SEQ ID NOs: 46, 65 and 72) and B2 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1208/1135 (SEQ ID NOs: 54, 55 and 57 and/or SEQ ID NOs: 46, 48 and 51);   (b) B1 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1200/1201 (SEQ ID NOs: 54, 55 and 79 and/or SEQ ID NOs: 46, 65 and 72) and B2 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1210/1211 (SEQ ID NOs: 54, 55 and 58 and/or SEQ ID NOs: 46, 48 and 52);   (c) B1 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1618/1619 (SEQ ID NOs: 54, 55 and 83 and/or SEQ ID NOs: 62, 69 and 76) and B2 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1208/1135 (SEQ ID NOs: 54, 55 and 57 and/or SEQ ID NOs: 46, 48 and 51); or   (d) B1 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1618/1619 (SEQ ID NOs: 54, 55 and 83 and/or SEQ ID NOs: 62, 69 and 76) and B2 comprises the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1210/1211 (SEQ ID NOs: 54, 55 and 58 and/or SEQ ID NOs: 46, 48 and 52).   
     
     
         43 . A polypeptide according to any one of the preceding claims wherein:
 (a) B1 comprises the light chain variable region and/or the heavy chain variable region of antibody 1200/1201 (SEQ ID NO: 19 and/or SEQ ID NO: 17) and B2 comprises the light chain variable region and/or the heavy chain variable region of antibody 1208/1135 (SEQ ID NO: 7 and/or SEQ ID NO: 5);   (b) B1 comprises the light chain variable region and/or the heavy chain variable region of antibody 1200/1201 (SEQ ID NO: 19 and/or SEQ ID NO: 17) and B2 comprises the light chain variable region and/or the heavy chain variable region of antibody 1210/1211 (SEQ ID NO: 11 and/or SEQ ID NO: 9);   (c) B1 comprises the light chain variable region and/or the heavy chain variable region of antibody 1618/1619 (SEQ ID NO: 35 and/or SEQ ID NO: 33) and B2 comprises the light chain variable region and/or the heavy chain variable region of antibody 1208/1135 (SEQ ID NO: 7 and/or SEQ ID NO: 5); or   (d) B1 comprises the light chain variable region and/or the heavy chain variable region of antibody 1618/1619 (SEQ ID NO: 35 and/or SEQ ID NO: 33) and B2 comprises the light chain variable region and/or the heavy chain variable region of antibody 1210/1211 (SEQ ID NO: 11 and/or SEQ ID NO: 9); or   (e) B1 and/or B2 comprise variants of said light chain variable regions and/or said heavy chain variable regions having at least 90% sequence identity thereto.   
     
     
         44 . A polypeptide according to any one of the preceding claims wherein B1 comprises the light chain variable region and/or the heavy chain variable region of antibody 1200/1201 (SEQ ID NO: 19 and/or SEQ ID NO: 17) and B2 comprises the light chain variable region and/or the heavy chain variable region of antibody 1210/1211 (SEQ ID NO: 11 and/or SEQ ID NO: 9), or variants of said light chain variable regions and/or said heavy chain variable regions (for example, having at least 90% sequence identity thereto), or vice versa. 
     
     
         45 . A polypeptide according to any one of the preceding claims wherein B1 comprises the light chain variable region and/or the heavy chain variable region of antibody 1618/1619 (SEQ ID NO: 35 and/or SEQ ID NO: 33) and B2 comprises the light chain variable region and/or the heavy chain variable region of antibody 1210/1211 (SEQ ID NO: 11 and/or SEQ ID NO: 9), or variants of said light chain variable regions and/or said heavy chain variable regions (for example, having at least 90% sequence identity thereto), or vice versa. 
     
     
         46 . A polypeptide according to any one of the preceding claims comprising a heavy chain constant region having an amino acid sequence of SEQ ID NO:94 or 96 and/or a light chain constant region having an amino acid sequence of SEQ ID NO:95. 
     
     
         47 . A polypeptide according to any one of the preceding claims wherein the polypeptide comprises at least one of the following:
 (a) an Fc region comprising ‘LALA’ mutations;   (b) an scFv comprising mutations in the heavy and light chain variable regions to cysteine residues capable of forming a disulphide bridge; and/or   (c) an scFv comprising mutation in the heavy chain variable region to create one or more N-glycosylation sites.   
     
     
         48 . A polypeptide according to any one of the preceding claims comprising
 (a) a binding domain (B1) comprising a heavy chain variable region of any of SEQ ID NOs: 17, 21, 27, 29, 33, 37, 41, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136 or 138 and a light chain variable region of any of SEQ ID NOs: 19, 23, 25, 31, 35, 39, 43, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135 or  139 ;   (b) a heavy chain constant region comprising an Fc region (for example, SEQ ID NO: 94 or 96);   (c) a binding domain (B2) comprising a heavy chain variable region of any of SEQ ID NOs: 1, 5, 9, 13, 96, 98, 100, 102, 104, 106, 108, 110 or 112 and a light chain variable region of any of SEQ ID NOs: 3, 7, 11, 15, 97, 99, 101, 103, 105, 107, 109, 111 or 113; and   (d) optionally, a light chain constant region (for example SEQ ID NO:95).   
     
     
         49 . An isolated nucleic acid molecule encoding a bispecific polypeptide according to any one of the preceding claims, or a component polypeptide chain thereof. 
     
     
         50 . A nucleic acid molecule according to  claim 49  wherein the molecule is a cDNA molecule. 
     
     
         51 . A nucleic acid molecule according to  claim 49  or  50  encoding an antibody heavy chain or variable region thereof. 
     
     
         52 . A nucleic acid molecule according to any one of  claims 49  to  51  encoding an antibody light chain or variable region thereof. 
     
     
         53 . A vector comprising a nucleic acid molecule according to any one of  claims 49  to  52 . 
     
     
         54 . A vector according to  claim 53  wherein the vector is an expression vector. 
     
     
         55 . A recombinant host cell comprising a nucleic acid molecule according to any one of  claims 49  to  52  or a vector according to  claim 53  or  54 . 
     
     
         56 . A host cell according to  claim 55  wherein the host cell is a bacterial cell. 
     
     
         57 . A host cell according to  claim 55  wherein the host cell is a mammalian cell. 
     
     
         58 . A host cell according to  claim 55  wherein the host cell is a human cell. 
     
     
         59 . A method for producing bispecific polypeptide according to any one of the  claims 1  to  48 , the method comprising culturing a host cell as defined in any of  claims 55  to  58  under conditions which permit expression of the bispecific polypeptide or component polypeptide chain thereof. 
     
     
         60 . A pharmaceutical composition comprising an effective amount of bispecific polypeptide according to any one of the  claims 1  to  48  and a pharmaceutically-acceptable diluent, carrier or excipient. 
     
     
         61 . A pharmaceutical composition according to  claim 60  adapted for parenteral delivery. 
     
     
         62 . A pharmaceutical composition according to  claim 60  adapted for intravenous delivery. 
     
     
         63 . A bispecific polypeptide according to any one of the  claims 1  to  48  for use in medicine. 
     
     
         64 . A bispecific polypeptide according to any one of the  claims 1  to  48  for use in treating or preventing a neoplastic disorder in a subject. 
     
     
         65 . A polypeptide for use according to  claim 64  wherein the neoplastic disorder is associated with the formation of solid tumours within the subject's body. 
     
     
         66 . A polypeptide for use according to  claim 65  wherein the solid tumour is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer and sarcomas. 
     
     
         67 . A polypeptide for use according to  claim 66  wherein the solid tumour is selected from the groups consisting of renal cell carcinoma, colorectal cancer, lung cancer, prostate cancer and breast cancer. 
     
     
         68 . A polypeptide for use according to any one of  claims 64  to  67  wherein the polypeptide is for use in combination with one or more additional therapeutic agents. 
     
     
         69 . A polypeptide for use according to  claim 68  wherein the one or more additional therapeutic agents is/are an immunotherapeutic agent that binds a target selected from the group consisting of PD-1/PD-1L, CTLA-4, OX40, CD40, GITR, LAG3, TIM3, CD27 and KIR. 
     
     
         70 . Use of a bispecific polypeptide according to any one of the  claims 1  to  46  in the preparation of a medicament for treating or preventing a neoplastic disorder in a subject. 
     
     
         71 . A use according to  claim 70  wherein the neoplastic disorder is associated with the formation of solid tumours within the subject's body. 
     
     
         72 . A use according to  claim 71  wherein the solid tumour is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer and sarcomas. 
     
     
         73 . A use according to  claim 72  wherein the solid tumour is selected from the groups consisting of renal cell carcinoma, colorectal cancer, lung cancer, prostate cancer and breast cancer. 
     
     
         74 . A use according to any one of  claims 70  to  73  wherein the polypeptide is for use in combination with one or more additional therapeutic agents. 
     
     
         75 . A polypeptide for use according to  claim 74  wherein the one or more additional therapeutic agents is/are an immunotherapeutic agent that binds a target selected from the group consisting of PD-1/PD-1L, CTLA-4, OX40, CD40, GITR, LAG3, TIM3, CD27 and KIR. 
     
     
         76 . A method for the treatment or diagnosis of a neoplastic disorder in a subject, comprising the step of administering to the subject an effective amount of a bispecific polypeptide according to any one of the  claims 1  to  48 . 
     
     
         77 . A method according to  claim 76  wherein the neoplastic disorder is associated with the formation of solid tumours within the subject's body. 
     
     
         78 . A method according to  claim 77  wherein the solid tumour is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer and sarcomas. 
     
     
         79 . A method according to  claim 78  wherein the solid tumour is selected from the groups consisting of renal cell carcinoma, colorectal cancer, lung cancer, prostate cancer and breast cancer. 
     
     
         80 . A method according to any one of  claims 76  to  79  wherein the subject is human. 
     
     
         81 . A method according to any one of  claims 76  to  80  wherein the method comprises administering the bispecific antibody systemically. 
     
     
         82 . A method according to any one of  claims 76  to  81  further comprising administering to the subject one or more additional therapeutic agents. 
     
     
         83 . A method according to any one of  claims 76  to  82  wherein the one or more additional therapeutic agents is/are an immunotherapeutic agent that binds a target selected from the group consisting of PD-1/PD-1L, CTLA-4, OX40, CD40, GITR, LAG3, TIM3, CD27 and KIR. 
     
     
         84 . A bispecific polypeptide substantially as described herein with reference to the description and figures. 
     
     
         85 . A polynucleotide substantially as described herein with reference to the description and figures. 
     
     
         86 . A pharmaceutical composition substantially as described herein with reference to the description and figures. 
     
     
         87 . Use of a bispecific polypeptide substantially as described herein with reference to the description and figures. 
     
     
         88 . A method of treatment substantially as described herein with reference to the description and figures.