	US 12,077,595 B2
	Single domain antibodies that bind to CD137
Verena Brucklacher-Waldert, Cambridge (GB); Carolyn Edwards, Cambridge (GB); James Legg, Cambridge (GB); Jayesh Majithiya, Cambridge (GB); Brian McGuinness, Cambridge (GB); Christine Rossant, Cambridge (GB); and Yumin Teng, Cambridge (GB)
Assigned to Crescendo Biologics Limited, Cambridge (GB)
Appl. No. 16/763,059
Filed by CRESCENDO BIOLOGICS LIMITED, Cambridge (GB)
PCT Filed Nov. 13, 2018, PCT No. PCT/GB2018/053279 § 371(c)(1), (2) Date May 11, 2020, PCT Pub. No. WO2019/092451, PCT Pub. Date May 16, 2019.
Claims priority of application No. 1718734 (GB), filed on Nov. 13, 2017; application No. 1718735 (GB), filed on Nov. 13, 2017; and application No. 1808589 (GB), filed on May 24, 2018.
Prior Publication US 2020/0362047 A1, Nov. 19, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. C07K 16/28 (2006.01); C07K 16/30 (2006.01); A61K 39/00 (2006.01)

CPC C07K 16/2878 (2013.01) [C07K 16/2896 (2013.01); C07K 16/30 (2013.01); A61K 2039/505 (2013.01); C07K 2317/24 (2013.01); C07K 2317/31 (2013.01); C07K 2317/565 (2013.01); C07K 2317/569 (2013.01); C07K 2317/75 (2013.01); C07K 2317/76 (2013.01); C07K 2317/77 (2013.01); C07K 2317/92 (2013.01)]

15 Claims

1. An isolated single variable heavy chain domain antibody which binds to human CD137 but does not elicit CD137 signalling when bound to CD137 as a monospecific entity, wherein said single variable heavy chain domain antibody comprises a CDR1 as shown in SEQ ID NO: 1, a CDR2 as shown in SEQ ID NO 2, and a CDR3 as shown in SEQ ID NO: 3; a CDR1 as shown in SEQ ID NO: 5, a CDR2 as shown in SEQ ID NO: 6 and a CDR3 as shown in SEQ ID NO: 7; a CDR1 as shown in SEQ ID NO: 9, a CDR2 as shown in SEQ ID NO: 10 and a CDR3 as shown in SEQ ID NO: 11; a CDR1 as shown in SEQ ID NO: 13, a CDR2 as shown in SEQ ID NO: 14 and a CDR3 as shown in SEQ ID NO: 15; a CDR1 as shown in SEQ ID NO: 17, a CDR2 as shown in SEQ ID NO: 18 and a CDR3 as shown in SEQ ID NO: 19; a CDR1 as shown in SEQ ID NO: 21, a CDR2 as shown in SEQ ID NO: 22 and a CDR3 as shown in SEQ ID NO: 23; a CDR1 as shown in SEQ ID NO: 25, a CDR2 as shown in SEQ ID NO: 26 and a CDR3 as shown in SEQ ID NO: 27; a CDR1 as shown in SEQ ID NO: 29, a CDR2 as shown in SEQ ID NO: 30 and a CDR3 as shown in SEQ ID NO: 31; a CDR1 as shown in SEQ ID NO: 33, a CDR2 as shown in SEQ ID NO: 34 and a CDR3 as shown in SEQ ID NO: 35; a CDR1 as shown in SEQ ID NO: 37, a CDR2 as shown in SEQ ID NO: 38 and a CDR3 as shown in SEQ ID NO: 39; a CDR1 as shown in SEQ ID NO: 41, a CDR2 as shown in SEQ ID NO: 42 and a CDR3 as shown in SEQ ID NO: 43; a CDR1 as shown in SEQ ID NO: 45, a CDR2 as shown in SEQ ID NO: 46 and a CDR3 as shown in SEQ ID NO: 47; a CDR1 as shown in SEQ ID NO: 49, a CDR2 as shown in SEQ ID NO: 50 and a CDR3 as shown in SEQ ID NO: 51; a CDR1 as shown in SEQ ID NO: 53, a CDR2 as shown in SEQ ID NO: 54 and a CDR3 as shown in SEQ ID NO: 55; a CDR1 as shown in SEQ ID NO: 57, a CDR2 as shown in SEQ ID NO: 58 and a CDR3 as shown in SEQ ID NO: 59; a CDR1 as shown in SEQ ID NO: 61, a CDR2 as shown in SEQ ID NO: 62 and a CDR3 as shown in SEQ ID NO: 63; a CDR1 as shown in SEQ ID NO: 65, a CDR2 as shown in SEQ ID NO: 66 and a CDR3 as shown in SEQ ID NO: 67; a CDR1 as shown in SEQ ID NO: 69, a CDR2 as shown in SEQ ID NO: 70 and a CDR3 as shown in SEQ ID NO: 71; a CDR1 as shown in SEQ ID NO: 73, a CDR2 as shown in SEQ ID NO: 74 and a CDR3 as shown in SEQ ID NO: 75; a CDR1 as shown in SEQ ID NO: 77, a CDR2 as shown in SEQ ID NO: 78 and a CDR3 as shown in SEQ ID NO: 79; a CDR1 as shown in SEQ ID NO: 81, a CDR2 as shown in SEQ ID NO: 82 and a CDR3 as shown in SEQ ID NO: 83; a CDR1 as shown in SEQ ID NO: 85, a CDR2 as shown in SEQ ID NO: 86 and a CDR3 as shown in SEQ ID NO: 87; a CDR1 as shown in SEQ ID NO: 89, a CDR2 as shown in SEQ ID NO: 90 and a CDR3 as shown in SEQ ID NO: 91; a CDR1 as shown in SEQ ID NO: 93, a CDR2 as shown in SEQ ID NO: 94 and a CDR3 as shown in SEQ ID NO: 95; a CDR1 as shown in SEQ ID NO: 97, a CDR2 as shown in SEQ ID NO: 98 and a CDR3 as shown in SEQ ID NO: 99; a CDR1 as shown in SEQ ID NO: 101, a CDR2 as shown in SEQ ID NO: 102 and a CDR3 as shown in SEQ ID NO: 103; a CDR1 as shown in SEQ ID NO: 105, a CDR2 as shown in SEQ ID NO: 106 and a CDR3 as shown in SEQ ID NO: 107; a CDR1 as shown in SEQ ID NO: 109, a CDR2 as shown in SEQ ID NO: 110 and a CDR3 as shown in SEQ ID NO: 111; a CDR1 as shown in SEQ ID NO: 113, a CDR2 as shown in SEQ ID NO: 114 and a CDR3 as shown in SEQ ID NO: 115; a CDR1 as shown in SEQ ID NO: 117, a CDR2 as shown in SEQ ID NO: 118 and a CDR3 as shown in SEQ ID NO: 119; a CDR1 as shown in SEQ ID NO: 121, a CDR2 as shown in SEQ ID NO: 122 and a CDR3 as shown in SEQ ID NO: 123; a CDR1 as shown in SEQ ID NO: 125, a CDR2 as shown in SEQ ID NO: 126 and a CDR3 as shown in SEQ ID NO: 127; a CDR1 as shown in SEQ ID NO: 129, a CDR2 as shown in SEQ ID NO: 130 and a CDR3 as shown in SEQ ID NO: 131; a CDR1 as shown in SEQ ID NO: 133, a CDR2 as shown in SEQ ID NO: 134 and a CDR3 as shown in SEQ ID NO: 135; a CDR1 as shown in SEQ ID NO: 137, a CDR2 as shown in SEQ ID NO: 138 and a CDR3 as shown in SEQ ID NO: 139; a CDR1 as shown in SEQ ID NO: 141, a CDR2 as shown in SEQ ID NO: 142 and a CDR3 as shown in SEQ ID NO: 143; a CDR1 as shown in SEQ ID NO: 145, a CDR2 as shown in SEQ ID NO: 146 and a CDR3 as shown in SEQ ID NO: 147; a CDR1 as shown in SEQ ID NO: 149, a CDR2 as shown in SEQ ID NO: 150 and a CDR3 as shown in SEQ ID NO: 151; a CDR1 as shown in SEQ ID NO: 153, a CDR2 as shown in SEQ ID NO: 154 and a CDR3 as shown in SEQ ID NO: 155; a CDR1 as shown in SEQ ID NO: 157, a CDR2 as shown in SEQ ID NO: 158 and a CDR3 as shown in SEQ ID NO: 159; a CDR1 as shown in SEQ ID NO: 161, a CDR2 as shown in SEQ ID NO: 162 and a CDR3 as shown in SEQ ID NO: 163; a CDR1 as shown in SEQ ID NO: 165, a CDR2 as shown in SEQ ID NO: 166 and a CDR3 as shown in SEQ ID NO: 167; a CDR1 as shown in SEQ ID NO: 169, a CDR2 as shown in SEQ ID NO: 170 and a CDR3 as shown in SEQ ID NO: 171; a CDR1 as shown in SEQ ID NO: 173, a CDR2 as shown in SEQ ID NO: 174 and a CDR3 as shown in SEQ ID NO: 175; a CDR1 as shown in SEQ ID NO: 177, a CDR2 as shown in SEQ ID NO: 178 and a CDR3 as shown in SEQ ID NO: 179; a CDR1 as shown in SEQ ID NO: 181, a CDR2 as shown in SEQ ID NO: 182 and a CDR3 as shown in SEQ ID NO: 183; a CDR1 as shown in SEQ ID NO: 185, a CDR2 as shown in SEQ ID NO: 186 and a CDR3 as shown in SEQ ID NO: 187; a CDR1 as shown in SEQ ID NO: 189, a CDR2 as shown in SEQ ID NO: 190 and a CDR3 as shown in SEQ ID NO: 191; a CDR1 as shown in SEQ ID NO: 193, a CDR2 as shown in SEQ ID NO: 194 and a CDR3 as shown in SEQ ID NO: 195; a CDR1 as shown in SEQ ID NO: 197, a CDR2 as shown in SEQ ID NO: 198 and a CDR3 as shown in SEQ ID NO: 199; a CDR1 as shown in SEQ ID NO: 201, a CDR2 as shown in SEQ ID NO: 202 and a CDR3 as shown in SEQ ID NO: 203; a CDR1 as shown in SEQ ID NO: 205, a CDR2 as shown in SEQ ID NO: 206 and a CDR3 as shown in SEQ ID NO: 207; a CDR1 as shown in SEQ ID NO: 209, a CDR2 as shown in SEQ ID NO: 210 and a CDR3 as shown in SEQ ID NO: 211; a CDR1 as shown in SEQ ID NO: 213, a CDR2 as shown in SEQ ID NO: 214 and a CDR3 as shown in SEQ ID NO: 215; a CDR1 as shown in SEQ ID NO: 217, a CDR2 as shown in SEQ ID NO: 218 and a CDR3 as shown in SEQ ID NO: 219; a CDR1 as shown in SEQ ID NO: 221, a CDR2 as shown in SEQ ID NO: 222 and a CDR3 as shown in SEQ ID NO: 223; a CDR1 as shown in SEQ ID NO: 225, a CDR2 as shown in SEQ ID NO: 226 and a CDR3 as shown in SEQ ID NO: 227; a CDR1 as shown in SEQ ID NO: 229, a CDR2 as shown in SEQ ID NO: 230 and a CDR3 as shown in SEQ ID NO: 231; a CDR1 as shown in SEQ ID NO: 233, a CDR2 as shown in SEQ ID NO: 234 and a CDR3 as shown in SEQ ID NO: 235; a CDR1 as shown in SEQ ID NO: 237, a CDR2 as shown in SEQ ID NO: 238 and a CDR3 as shown in SEQ ID NO: 239; a CDR1 as shown in SEQ ID NO: 241, a CDR2 as shown in SEQ ID NO: 242 and a CDR3 as shown in SEQ ID NO: 243; a CDR1 as shown in SEQ ID NO: 245, a CDR2 as shown in SEQ ID NO: 246 and a CDR3 as shown in SEQ ID NO: 247; a CDR1 as shown in SEQ ID NO: 249, a CDR2 as shown in SEQ ID NO: 250 and a CDR3 as shown in SEQ ID NO: 251; a CDR1 as shown in SEQ ID NO: 253, a CDR2 as shown in SEQ ID NO: 254 and a CDR3 as shown in SEQ ID NO: 255; a CDR1 as shown in SEQ ID NO: 257, a CDR2 as shown in SEQ ID NO: 258 and a CDR3 as shown in SEQ ID NO: 259; a CDR1 as shown in SEQ ID NO: 261, a CDR2 as shown in SEQ ID NO: 262 and a CDR3 as shown in SEQ ID NO: 263; a CDR1 as shown in SEQ ID NO: 265, a CDR2 as shown in SEQ ID NO: 266 and a CDR3 as shown in SEQ ID NO: 267; a CDR1 as shown in SEQ ID NO: 269, a CDR2 as shown in SEQ ID NO: 270 and a CDR3 as shown in SEQ ID NO: 271; a CDR1 as shown in SEQ ID NO: 273, a CDR2 as shown in SEQ ID NO: 274 and a CDR3 as shown in SEQ ID NO: 275; a CDR1 as shown in SEQ ID NO: 277, a CDR2 as shown in SEQ ID NO: 278 and a CDR3 as shown in SEQ ID NO: 279; a CDR1 as shown in SEQ ID NO: 281, a CDR2 as shown in SEQ ID NO: 282 and a CDR3 as shown in SEQ ID NO: 283; a CDR1 as shown in SEQ ID NO: 285, a CDR2 as shown in SEQ ID NO: 286 and a CDR3 as shown in SEQ ID NO: 287; a CDR1 as shown in SEQ ID NO: 289, a CDR2 as shown in SEQ ID NO: 290 and a CDR3 as shown in SEQ ID NO: 291; a CDR1 as shown in SEQ ID NO: 293, a CDR2 as shown in SEQ ID NO: 294 and a CDR3 as shown in SEQ ID NO: 295; a CDR1 as shown in SEQ ID NO: 297, a CDR2 as shown in SEQ ID NO: 298 and a CDR3 as shown in SEQ ID NO: 299; a CDR1 as shown in SEQ ID NO: 301, a CDR2 as shown in SEQ ID NO: 302 and a CDR3 as shown in SEQ ID NO: 303; a CDR1 as shown in SEQ ID NO: 305, a CDR2 as shown in SEQ ID NO: 306 and a CDR3 as shown in SEQ ID NO: 307; a CDR1 as shown in SEQ ID NO: 309, a CDR2 as shown in SEQ ID NO: 310 and a CDR3 as shown in SEQ ID NO: 311; a CDR1 as shown in SEQ ID NO: 313, a CDR2 as shown in SEQ ID NO: 314 and a CDR3 as shown in SEQ ID NO: 315; a CDR1 as shown in SEQ ID NO: 317, a CDR2 as shown in SEQ ID NO: 318 and a CDR3 as shown in SEQ ID NO: 319; a CDR1 as shown in SEQ ID NO: 321, a CDR2 as shown in SEQ ID NO: 322 and a CDR3 as shown in SEQ ID NO: 323; a CDR1 as shown in SEQ ID NO: 325, a CDR2 as shown in SEQ ID NO: 326 and a CDR3 as shown in SEQ ID NO: 327; a CDR1 as shown in SEQ ID NO: 329, a CDR2 as shown in SEQ ID NO: 330 and a CDR3 as shown in SEQ ID NO: 331; a CDR1 as shown in SEQ ID NO: 333, a CDR2 as shown in SEQ ID NO: 334 and a CDR3 as shown in SEQ ID NO: 335; a CDR1 as shown in SEQ ID NO: 337, a CDR2 as shown in SEQ ID NO: 338 and a CDR3 as shown in SEQ ID NO: 339; a CDR1 as shown in SEQ ID NO: 341, a CDR2 as shown in SEQ ID NO: 342 and a CDR3 as shown in SEQ ID NO: 343; a CDR1 as shown in SEQ ID NO: 345, a CDR2 as shown in SEQ ID NO: 346 and a CDR3 as shown in SEQ ID NO: 347; a CDR1 as shown in SEQ ID NO: 349, a CDR2 as shown in SEQ ID NO: 350 and a CDR3 as shown in SEQ ID NO: 351; a CDR1 as shown in SEQ ID NO: 353, a CDR2 as shown in SEQ ID NO: 354 and a CDR3 as shown in SEQ ID NO: 355; a CDR1 as shown in SEQ ID NO: 357, a CDR2 as shown in SEQ ID NO: 358 and a CDR3 as shown in SEQ ID NO: 359; a CDR1 as shown in SEQ ID NO: 361, a CDR2 as shown in SEQ ID NO: 362 and a CDR3 as shown in SEQ ID NO: 363; a CDR1 as shown in SEQ ID NO: 365, a CDR2 as shown in SEQ ID NO: 366 and a CDR3 as shown in SEQ ID NO: 367; a CDR1 as shown in SEQ ID NO: 369, a CDR2 as shown in SEQ ID NO: 370 and a CDR3 as shown in SEQ ID NO: 371; a CDR1 as shown in SEQ ID NO: 373, a CDR2 as shown in SEQ ID NO: 374 and a CDR3 as shown in SEQ ID NO: 375; a CDR1 as shown in SEQ ID NO: 377, a CDR2 as shown in SEQ ID NO: 378 and a CDR3 as shown in SEQ ID NO: 379; a CDR1 as shown in SEQ ID NO: 381, a CDR2 as shown in SEQ ID NO: 382 and a CDR3 as shown in SEQ ID NO: 383; a CDR1 as shown in SEQ ID NO: 385, a CDR2 as shown in SEQ ID NO: 386 and a CDR3 as shown in SEQ ID NO: 387; a CDR1 as shown in SEQ ID NO: 389, a CDR2 as shown in SEQ ID NO: 390 and a CDR3 as shown in SEQ ID NO: 391; a CDR1 as shown in SEQ ID NO: 393, a CDR2 as shown in SEQ ID NO: 394 and a CDR3 as shown in SEQ ID NO: 395; a CDR1 as shown in SEQ ID NO: 397, a CDR2 as shown in SEQ ID NO: 398 and a CDR3 as shown in SEQ ID NO: 399; a CDR1 as shown in SEQ ID NO: 401, a CDR2 as shown in SEQ ID NO: 402 and a CDR3 as shown in SEQ ID NO: 403; a CDR1 as shown in SEQ ID NO: 405, a CDR2 as shown in SEQ ID NO: 406 and a CDR3 as shown in SEQ ID NO: 407; a CDR1 as shown in SEQ ID NO: 409, a CDR2 as shown in SEQ ID NO: 410 and a CDR3 as shown in SEQ ID NO: 411; a CDR1 as shown in SEQ ID NO: 413, a CDR2 as shown in SEQ ID NO: 414 and a CDR3 as shown in SEQ ID NO: 415; a CDR1 as shown in SEQ ID NO: 417, a CDR2 as shown in SEQ ID NO: 418 and a CDR3 as shown in SEQ ID NO: 419; a CDR1 as shown in SEQ ID NO: 421, a CDR2 as shown in SEQ ID NO: 422 and a CDR3 as shown in SEQ ID NO: 423; a CDR1 as shown in SEQ ID NO: 849, a CDR2 as shown in SEQ ID NO: 850 and a CDR3 as shown in SEQ ID NO: 851; a CDR1 as shown in SEQ ID NO: 853, a CDR2 as shown in SEQ ID NO: 854 and a CDR3 as shown in SEQ ID NO: 855; a CDR1 as shown in SEQ ID NO: 857, a CDR2 as shown in SEQ ID NO: 858 and a CDR3 as shown in SEQ ID NO: 859; a CDR1 as shown in SEQ ID NO: 861, a CDR2 as shown in SEQ ID NO: 862 and a CDR3 as shown in SEQ ID NO: 863; a CDR1 as shown in SEQ ID NO: 865, a CDR2 as shown in SEQ ID NO: 866 and a CDR3 as shown in SEQ ID NO: 867; a CDR1 as shown in SEQ ID NO: 869, a CDR2 as shown in SEQ ID NO: 870 and a CDR3 as shown in SEQ ID NO: 871; a CDR1 as shown in SEQ ID NO: 873, a CDR2 as shown in SEQ ID NO: 874 and a CDR3 as shown in SEQ ID NO: 875; or a CDR1 as shown in SEQ ID NO: 877, a CDR2 as shown in SEQ ID NO: 878 and a CDR3 as shown in SEQ ID NO: 879 sequences as shown for one of the said single variable heavy chain domain antibodies in Table 1.