Novel bispecific polypeptides against cd137

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.

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 1618/1619 (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 3034/3035 (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).

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).

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.

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).

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.

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).

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).

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.

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).

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).

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.

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.

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.

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.

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).