Antigen-binding molecules

Abstract

Antigen binding molecules comprising a γc-binding moiety and / or a IL-2Rβ-binding moiety are disclosed herein. Also disclosed are compositions comprising such antigen binding molecules, and uses and methods using the same.

Description

[0001] Antigen-Binding Molecules

[0002] This application claims priority from US 63 / 681723 filed 9 August 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0003] Technical Field

[0004] The present disclosure relates to the field of molecular biology, more specifically antibody technology. The present disclosure also relates to methods of medical treatment and prophylaxis.

[0005] Background

[0006] Interleukins play a central role in maintaining T cell homeostasis and mediating proper immune responses. Specifically, interleukins and associated cytokines serve as the means of communication for innate and adaptive immune cells, as well as non-immune cells and tissues. Thus, interleukins have a critical role in cancer development, progression and control (Briukhovetska D. et al. Nat Rev Cancer 21 , 481-499 (2021)).

[0007] The use of interleukins in therapy has shown much promise but has been associated with drawbacks and disappointing results.

[0008] IL-2 was the first interleukin to be approved for cancer treatment, although its use entails major safety concerns. The high dose of IL-2 that is required for effective treatment of certain diseases is highly toxic. Major adverse effects of such therapy include vascular leak syndrome (VLS), which results in accumulation of the intravascular fluid in organs such as lung and liver with subsequent pulmonary edema and liver damage. There is no treatment for VLS except withdrawing therapy.

[0009] The common cytokine receptor gamma chain (common gamma chain, yc, or CD132) is a cytokine receptor polypeptide which forms part of the cytokine receptor complex of the IL-2 receptor. Heterodimerization of yc and the beta chain of the IL-2 receptor (IL-2R0) is necessary for effective IL-2 signal transduction.

[0010] Antigen-binding molecules that bind to yc and IL-2R0 are disclosed e.g. in WO 2017 / 021540 A1 .

[0011] Summary

[0012] In a first aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc.

[0013] In a second aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to IL-2R0.

[0014] In a third aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc and another antigen. In a fourth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to IL-2Rp and another antigen.

[0015] In a fifth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc and IL-2Rp.

[0016] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety.

[0017] In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety.

[0018] In some embodiments, the antigen-binding molecule comprises:

[0019] (i) a yc-binding moiety, and

[0020] (ii) an IL-2Rp-binding moiety.

[0021] In some embodiments, the antigen-binding molecule comprises a VH sequence incorporating the CDR sequences of an antibody disclosed herein.

[0022] In some embodiments, the yc-binding moiety comprises a VHH.

[0023] In some embodiments, the IL-2Rp-binding moiety comprises a VHH.

[0024] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody disclosed herein. In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody presented in Table A. In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody presented in Table C.

[0025] In some embodiments, the yc-binding moiety comprises a VH sequence (e.g., a VHH sequence) incorporating the following CDRs:

[0026] (i) CDR1 having the amino acid sequence of SEQ ID NO:267 CDR2 having the amino acid sequence of SEQ ID NO:268 CDR3 having the amino acid sequence of SEQ ID NO:269;

[0027] (ii) CDR1 having the amino acid sequence of SEQ ID NQ:270 CDR2 having the amino acid sequence of SEQ ID NO:271 CDR3 having the amino acid sequence of SEQ ID NO:272;

[0028] (iii) CDR1 having the amino acid sequence of SEQ ID NO:276 CDR2 having the amino acid sequence of SEQ ID NO:277 CDR3 having the amino acid sequence of SEQ ID NO:278;

[0029] (iv) CDR1 having the amino acid sequence of SEQ ID NO:273 CDR2 having the amino acid sequence of SEQ ID NO:274 CDR3 having the amino acid sequence of SEQ ID NO:275;

[0030] (v) CDR1 having the amino acid sequence of SEQ ID NO:279 CDR2 having the amino acid sequence of SEQ ID NO:280

[0031] CDR3 having the amino acid sequence of SEQ ID NO:281 ;

[0032] (vi) CDR1 having the amino acid sequence of SEQ ID NO:282 CDR2 having the amino acid sequence of SEQ ID NO:283 CDR3 having the amino acid sequence of SEQ ID NO:284;

[0033] (vi) CDR1 having the amino acid sequence of SEQ ID NO:285 CDR2 having the amino acid sequence of SEQ ID NO:286 CDR3 having the amino acid sequence of SEQ ID NO:287;

[0034] (viii) CDR1 having the amino acid sequence of SEQ ID NO:288 CDR2 having the amino acid sequence of SEQ ID NO:289 CDR3 having the amino acid sequence of SEQ ID NQ:290;

[0035] (ix) CDR1 having the amino acid sequence of SEQ ID NO:291 CDR2 having the amino acid sequence of SEQ ID NO:292 CDR3 having the amino acid sequence of SEQ ID NO:293;

[0036] (x) CDR1 having the amino acid sequence of SEQ ID NO:294 CDR2 having the amino acid sequence of SEQ ID NO:295 CDR3 having the amino acid sequence of SEQ ID NO:296; or

[0037] (xi) CDR1 having the amino acid sequence of SEQ ID NO:297 CDR2 having the amino acid sequence of SEQ ID NO:298 CDR3 having the amino acid sequence of SEQ ID NO:299.

[0038] In some embodiments, the yc-binding moiety comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NQ:501 ; SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178.

[0039] In some embodiments, the yc-binding moiety comprises a VH sequence (e.g., a VHH sequence) incorporating the following FRs:

[0040] (i) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:400 FR3 having the amino acid sequence of SEQ ID NO:463 FR4 having the amino acid sequence of SEQ ID NO:475

[0041] (ii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:400 FR3 having the amino acid sequence of SEQ ID NO:462 FR4 having the amino acid sequence of SEQ ID NO:475;

[0042] (iii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:401 FR3 having the amino acid sequence of SEQ ID NO:465 FR4 having the amino acid sequence of SEQ ID NO:473;

[0043] (iv) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:403 FR3 having the amino acid sequence of SEQ ID NO:466 FR4 having the amino acid sequence of SEQ ID NO:474;

[0044] (V) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:400 FR3 having the amino acid sequence of SEQ ID NO:425 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0045] (vi) FR1 having the amino acid sequence of SEQ ID NO:378 FR2 having the amino acid sequence of SEQ ID NQ:401 FR3 having the amino acid sequence of SEQ ID NO:426 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0046] (vii) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NQ:403 FR3 having the amino acid sequence of SEQ ID NO:428 FR4 having the amino acid sequence of SEQ ID NO:472;

[0047] (viii) FR1 having the amino acid sequence of SEQ ID NO:379 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:427 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0048] (ix) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NO:392 FR3 having the amino acid sequence of SEQ ID NO:429 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0049] (x) FR1 having the amino acid sequence of SEQ ID NO:395 FR2 having the amino acid sequence of SEQ ID NO:392 FR3 having the amino acid sequence of SEQ ID NO:429 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0050] (xi) FR1 having the amino acid sequence of SEQ ID NO:393 FR2 having the amino acid sequence of SEQ ID NQ:404 FR3 having the amino acid sequence of SEQ ID NQ:430 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0051] (xii) FR1 having the amino acid sequence of SEQ ID NO:382 FR2 having the amino acid sequence of SEQ ID NQ:405 FR3 having the amino acid sequence of SEQ ID NO:431 ; FR4 having the amino acid sequence of SEQ ID NO:484,

[0052] (xiii) FR1 having the amino acid sequence of SEQ ID NO:394 FR2 having the amino acid sequence of SEQ ID NQ:406 FR3 having the amino acid sequence of SEQ ID NO:432 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0053] (xiv) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:407 FR3 having the amino acid sequence of SEQ ID NO:433 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0054] (xv) FR1 having the amino acid sequence of SEQ ID NO:396

[0055] FR2 having the amino acid sequence of SEQ ID NQ:408

[0056] FR3 having the amino acid sequence of SEQ ID NO:434

[0057] FR4 having the amino acid sequence of SEQ ID NO:471 ; or

[0058] (xvi) FR1 having the amino acid sequence of SEQ ID NO:377

[0059] FR2 having the amino acid sequence of SEQ ID NQ:405

[0060] FR3 having the amino acid sequence of SEQ ID NO:435

[0061] FR4 having the amino acid sequence of SEQ ID NO:471 .

[0062] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of a IL-2Rp-binding antibody disclosed herein. In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of a IL-2Rp-binding antibody presented in Table D. In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of a IL-2Rp-binding antibody presented in Table F.

[0063] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu2MAV96, hu3MAV75, hu2MAV103, hu2MAV248, hu2MAV110, or hu3MAV81.

[0064] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu2MAV96.

[0065] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu3MAV75.

[0066] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu2MAV103.

[0067] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu2MAV248.

[0068] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu2MAV110.

[0069] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the CDR sequences of hu3MAV81 .

[0070] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence (e.g., a VHH sequence) incorporating the following CDRs:

[0071] (i) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NQ:304 CDR3 having the amino acid sequence of SEQ ID NQ:305; (ii) CDR1 having the amino acid sequence of SEQ ID N0:300 CDR2 having the amino acid sequence of SEQ ID NO:301 CDR3 having the amino acid sequence of SEQ ID NO:302;

[0072] (iii) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NO:312 CDR3 having the amino acid sequence of SEQ ID NO:313;

[0073] (iv) CDR1 having the amino acid sequence of SEQ ID NQ:306 CDR2 having the amino acid sequence of SEQ ID NQ:307 CDR3 having the amino acid sequence of SEQ ID NQ:308; (v) CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 ,

[0074] (vi) CDR1 having the amino acid sequence of SEQ ID NO:314 CDR2 having the amino acid sequence of SEQ ID NO:315 CDR3 having the amino acid sequence of SEQ ID NO:316;

[0075] (vii) CDR1 having the amino acid sequence of SEQ ID NO:317 CDR2 having the amino acid sequence of SEQ ID NO:318 CDR3 having the amino acid sequence of SEQ ID NO:319;

[0076] (viii) CDR1 having the amino acid sequence of SEQ ID NQ:320 CDR2 having the amino acid sequence of SEQ ID NO:321 CDR3 having the amino acid sequence of SEQ ID NO:322;

[0077] (ix) CDR1 having the amino acid sequence of SEQ ID NO:323 CDR2 having the amino acid sequence of SEQ ID NO:324 CDR3 having the amino acid sequence of SEQ ID NO:325; (x) CDR1 having the amino acid sequence of SEQ ID NO:326 CDR2 having the amino acid sequence of SEQ ID NO:327 CDR3 having the amino acid sequence of SEQ ID NO:328;

[0078] (xi) CDR1 having the amino acid sequence of SEQ ID NO:329 CDR2 having the amino acid sequence of SEQ ID NQ:330 CDR3 having the amino acid sequence of SEQ ID NO:331 ;

[0079] (xii) CDR1 having the amino acid sequence of SEQ ID NO:332 CDR2 having the amino acid sequence of SEQ ID NO:333 CDR3 having the amino acid sequence of SEQ ID NO:334;

[0080] (xiii) CDR1 having the amino acid sequence of SEQ ID NO:335 CDR2 having the amino acid sequence of SEQ ID NO:336 CDR3 having the amino acid sequence of SEQ ID NO:337;

[0081] (xiv) CDR1 having the amino acid sequence of SEQ ID NO:338 CDR2 having the amino acid sequence of SEQ ID NO:339 CDR3 having the amino acid sequence of SEQ ID NQ:340; (xv) CDR1 having the amino acid sequence of SEQ ID NO:341 CDR2 having the amino acid sequence of SEQ ID NO:342 CDR3 having the amino acid sequence of SEQ ID NO:343; (xvi) CDR1 having the amino acid sequence of SEQ ID NO:344 CDR2 having the amino acid sequence of SEQ ID NO:345 CDR3 having the amino acid sequence of SEQ ID NO:346;

[0082] (xvii) CDR1 having the amino acid sequence of SEQ ID NO:347 CDR2 having the amino acid sequence of SEQ ID NO:348 CDR3 having the amino acid sequence of SEQ ID NO:349;

[0083] (xviii) CDR1 having the amino acid sequence of SEQ ID NQ:350 CDR2 having the amino acid sequence of SEQ ID NO:351 CDR3 having the amino acid sequence of SEQ ID NO:352;

[0084] (xix) CDR1 having the amino acid sequence of SEQ ID NO:353 CDR2 having the amino acid sequence of SEQ ID NO:354 CDR3 having the amino acid sequence of SEQ ID NO:355;

[0085] (xx) CDR1 having the amino acid sequence of SEQ ID NO:356 CDR2 having the amino acid sequence of SEQ ID NO:357 CDR3 having the amino acid sequence of SEQ ID NO:358;

[0086] (xxi) CDR1 having the amino acid sequence of SEQ ID NO:359 CDR2 having the amino acid sequence of SEQ ID NQ:360 CDR3 having the amino acid sequence of SEQ ID NO:361 ;

[0087] (xxii) CDR1 having the amino acid sequence of SEQ ID NO:362 CDR2 having the amino acid sequence of SEQ ID NO:363 CDR3 having the amino acid sequence of SEQ ID NO:364;

[0088] (xxiii) CDR1 having the amino acid sequence of SEQ ID NO:365 CDR2 having the amino acid sequence of SEQ ID NO:366 CDR3 having the amino acid sequence of SEQ ID NO:367;

[0089] (xxiv) CDR1 having the amino acid sequence of SEQ ID NO:368 CDR2 having the amino acid sequence of SEQ ID NO:369 CDR3 having the amino acid sequence of SEQ ID NQ:370;

[0090] (xxv) CDR1 having the amino acid sequence of SEQ ID NO:371 CDR2 having the amino acid sequence of SEQ ID NO:372 CDR3 having the amino acid sequence of SEQ ID NO:373; or

[0091] (xxvi) CDR1 having the amino acid sequence of SEQ ID NO:374 CDR2 having the amino acid sequence of SEQ ID NO:375 CDR3 having the amino acid sequence of SEQ ID NO:376.

[0092] In some embodiments, the IL-2Rp-binding moiety comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:479, SEQ ID NQ:480, SEQ ID NO:481 , SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143,

[0093] SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149,

[0094] SEQ ID NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155,

[0095] SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160, SEQ ID NO:161 ,

[0096] SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ ID NO:166. In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence (e.g., a VHH sequence) incorporating the following FRs:

[0097] (i) FR1 having the amino acid sequence of SEQ ID NO:397

[0098] FR2 having the amino acid sequence of SEQ ID NO:402

[0099] FR3 having the amino acid sequence of SEQ ID NO:468

[0100] FR4 having the amino acid sequence of SEQ ID NO:473;

[0101] (ii) FR1 having the amino acid sequence of SEQ ID NO:397

[0102] FR2 having the amino acid sequence of SEQ ID NQ:402

[0103] FR3 having the amino acid sequence of SEQ ID NO:464

[0104] FR4 having the amino acid sequence of SEQ ID NO:473;

[0105] (iii) FR1 having the amino acid sequence of SEQ ID NO:398

[0106] FR2 having the amino acid sequence of SEQ ID NQ:402

[0107] FR3 having the amino acid sequence of SEQ ID NO:464

[0108] FR4 having the amino acid sequence of SEQ ID NO:473;

[0109] (iv) FR1 having the amino acid sequence of SEQ ID NO:399

[0110] FR2 having the amino acid sequence of SEQ ID NO:467

[0111] FR3 having the amino acid sequence of SEQ ID NO:469

[0112] FR4 having the amino acid sequence of SEQ ID NO:473;

[0113] (v) FR1 having the amino acid sequence of SEQ ID NO:397

[0114] FR2 having the amino acid sequence of SEQ ID NQ:410

[0115] FR3 having the amino acid sequence of SEQ ID NQ:470

[0116] FR4 having the amino acid sequence of SEQ ID NO:473;

[0117] (vi) FR1 having the amino acid sequence of SEQ ID NO:385

[0118] FR2 having the amino acid sequence of SEQ ID NQ:402

[0119] FR3 having the amino acid sequence of SEQ ID NO:437

[0120] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0121] (vii) FR1 having the amino acid sequence of SEQ ID NO:383

[0122] FR2 having the amino acid sequence of SEQ ID NQ:402

[0123] FR3 having the amino acid sequence of SEQ ID NO:436

[0124] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0125] (viii) FR1 having the amino acid sequence of SEQ ID NO:385

[0126] FR2 having the amino acid sequence of SEQ ID NQ:402

[0127] FR3 having the amino acid sequence of SEQ ID NQ:440

[0128] FR4 having the amino acid sequence of SEQ ID NO: 471 ;

[0129] (ix) FR1 having the amino acid sequence of SEQ ID NO:383

[0130] FR2 having the amino acid sequence of SEQ ID NQ:409

[0131] FR3 having the amino acid sequence of SEQ ID NO:438

[0132] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0133] (x) FR1 having the amino acid sequence of SEQ ID NO:381

[0134] FR2 having the amino acid sequence of SEQ ID NQ:410

[0135] FR3 having the amino acid sequence of SEQ ID NO:439

[0136] FR4 having the amino acid sequence of SEQ ID NO: 471 ; (xi) FR1 having the amino acid sequence of SEQ ID NO:380

[0137] FR2 having the amino acid sequence of SEQ ID NO:411

[0138] FR3 having the amino acid sequence of SEQ ID NO:441

[0139] FR4 having the amino acid sequence of: TV;

[0140] (xii) FR1 having the amino acid sequence of SEQ ID NO:377

[0141] FR2 having the amino acid sequence of SEQ ID NO:412

[0142] FR3 having the amino acid sequence of SEQ ID NO:442

[0143] FR4 having the amino acid sequence of SEQ ID NO: 471

[0144] (xiii) FR1 having the amino acid sequence of SEQ ID NO:377

[0145] FR2 having the amino acid sequence of SEQ ID NO:402

[0146] FR3 having the amino acid sequence of SEQ ID NO:443

[0147] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0148] (xiv) FR1 having the amino acid sequence of SEQ ID NO:382

[0149] FR2 having the amino acid sequence of SEQ ID NO:402

[0150] FR3 having the amino acid sequence of SEQ ID NO:444

[0151] FR4 having the amino acid sequence of SEQ ID NO:485;

[0152] (xv) FR1 having the amino acid sequence of SEQ ID NO:377

[0153] FR2 having the amino acid sequence of SEQ ID NO:410

[0154] FR3 having the amino acid sequence of SEQ ID NO:445

[0155] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0156] (xvi) FR1 having the amino acid sequence of SEQ ID NO:377

[0157] FR2 having the amino acid sequence of SEQ ID NO:413

[0158] FR3 having the amino acid sequence of SEQ ID NO:446

[0159] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0160] (xvii) FR1 having the amino acid sequence of SEQ ID NO:384

[0161] FR2 having the amino acid sequence of SEQ ID NQ:402

[0162] FR3 having the amino acid sequence of SEQ ID NO:447

[0163] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0164] (xviii) FR1 having the amino acid sequence of SEQ ID NQ:380

[0165] FR2 having the amino acid sequence of SEQ ID NO:414

[0166] FR3 having the amino acid sequence of SEQ ID NO:448

[0167] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0168] (xix) FR1 having the amino acid sequence of SEQ ID NO:386

[0169] FR2 having the amino acid sequence of SEQ ID NO:415

[0170] FR3 having the amino acid sequence of SEQ ID NO:449

[0171] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0172] (xx) FR1 having the amino acid sequence of SEQ ID NO:387

[0173] FR2 having the amino acid sequence of SEQ ID NO:416

[0174] FR3 having the amino acid sequence of SEQ ID NQ:450

[0175] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0176] (xxi) FR1 having the amino acid sequence of SEQ ID NO:388

[0177] FR2 having the amino acid sequence of SEQ ID NO:417 FR3 having the amino acid sequence of SEQ ID NO:451

[0178] FR4 having the amino acid sequence of SEQ ID NO:471 ; (xxii) FR1 having the amino acid sequence of SEQ ID NO:380

[0179] FR2 having the amino acid sequence of SEQ ID NO:418

[0180] FR3 having the amino acid sequence of SEQ ID NO:452

[0181] FR4 having the amino acid sequence of SEQ ID NO:471 ; (xxiii) FR1 having the amino acid sequence of SEQ ID NO:387

[0182] FR2 having the amino acid sequence of SEQ ID NO:419

[0183] FR3 having the amino acid sequence of SEQ ID NO:453

[0184] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0185] (xxiv) FR1 having the amino acid sequence of SEQ ID NO:377

[0186] FR2 having the amino acid sequence of SEQ ID NQ:420

[0187] FR3 having the amino acid sequence of SEQ ID NO:454

[0188] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0189] (xxv) FR1 having the amino acid sequence of SEQ ID NQ:380

[0190] FR2 having the amino acid sequence of SEQ ID NO:421

[0191] FR3 having the amino acid sequence of SEQ ID NO:455

[0192] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0193] (xxvi) FR1 having the amino acid sequence of SEQ ID NO:389

[0194] FR2 having the amino acid sequence of SEQ ID NQ:402

[0195] FR3 having the amino acid sequence of SEQ ID NO:456

[0196] FR4 having the amino acid sequence of SEQ ID NO:471 ; (xxvii) FR1 having the amino acid sequence of SEQ ID NQ:390

[0197] FR2 having the amino acid sequence of SEQ ID NO:422

[0198] FR3 having the amino acid sequence of SEQ ID NO:457

[0199] FR4 having the amino acid sequence of SEQ ID NO:471 ; (xxviii) FR1 having the amino acid sequence of SEQ ID NO:377

[0200] FR2 having the amino acid sequence of SEQ ID NQ:402

[0201] FR3 having the amino acid sequence of SEQ ID NO:458

[0202] FR4 having the amino acid sequence of SEQ ID NO: 471 ;

[0203] (xxix) FR1 having the amino acid sequence of SEQ ID NO;391

[0204] FR2 having the amino acid sequence of SEQ ID NO:423

[0205] FR3 having the amino acid sequence of SEQ ID NO:459

[0206] FR4 having the amino acid sequence of SEQ ID NO: 471 ;

[0207] (xxx) FR1 having the amino acid sequence of SEQ ID NO:377

[0208] FR2 having the amino acid sequence of SEQ ID NO:424

[0209] FR3 having the amino acid sequence of SEQ ID NO:460

[0210] FR4 having the amino acid sequence of SEQ ID NO: 471 ; or

[0211] (xxxi) FR1 having the amino acid sequence of SEQ ID NO:377

[0212] FR2 having the amino acid sequence of SEQ ID NO:402

[0213] FR3 having the amino acid sequence of SEQ ID NO:461

[0214] FR4 having the amino acid sequence of SEQ ID NO:471. In some embodiments, the antigen-binding molecule comprises a yc-binding moiety disclosed herein, and an IL-2Rp-binding moiety disclosed herein. In some embodiments,

[0215] (i) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0216] CDR1 having the amino acid sequence of SEQ ID NO:267

[0217] CDR2 having the amino acid sequence of SEQ ID NO:268

[0218] CDR3 having the amino acid sequence of SEQ ID NO:269, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0219] CDR1 having the amino acid sequence of SEQ ID NQ:303

[0220] CDR2 having the amino acid sequence of SEQ ID NQ:304

[0221] CDR3 having the amino acid sequence of SEQ ID NQ:305;

[0222] (ii) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0223] CDR1 having the amino acid sequence of SEQ ID NO:267

[0224] CDR2 having the amino acid sequence of SEQ ID NO:268

[0225] CDR3 having the amino acid sequence of SEQ ID NO:269, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0226] CDR1 having the amino acid sequence of SEQ ID NQ:300

[0227] CDR2 having the amino acid sequence of SEQ ID NQ:301

[0228] CDR3 having the amino acid sequence of SEQ ID NQ:302;

[0229] (iii) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0230] CDR1 having the amino acid sequence of SEQ ID NO:267

[0231] CDR2 having the amino acid sequence of SEQ ID NO:268

[0232] CDR3 having the amino acid sequence of SEQ ID NO:269, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0233] CDR1 having the amino acid sequence of SEQ ID NQ:309

[0234] CDR2 having the amino acid sequence of SEQ ID NQ:310

[0235] CDR3 having the amino acid sequence of SEQ ID NO:311 .

[0236] (iv) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0237] CDR1 having the amino acid sequence of SEQ ID NO:276

[0238] CDR2 having the amino acid sequence of SEQ ID NO:277

[0239] CDR3 having the amino acid sequence of SEQ ID NO:278, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0240] CDR1 having the amino acid sequence of SEQ ID NQ:303

[0241] CDR2 having the amino acid sequence of SEQ ID NQ:304

[0242] CDR3 having the amino acid sequence of SEQ ID NQ:305;

[0243] (v) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0244] CDR1 having the amino acid sequence of SEQ ID NO:276

[0245] CDR2 having the amino acid sequence of SEQ ID NO:277

[0246] CDR3 having the amino acid sequence of SEQ ID NO:278, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0247] CDR1 having the amino acid sequence of SEQ ID NQ:300

[0248] CDR2 having the amino acid sequence of SEQ ID NQ:301 CDR3 having the amino acid sequence of SEQ ID NO:302;

[0249] (vi) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0250] CDR1 having the amino acid sequence of SEQ ID NO:276 CDR2 having the amino acid sequence of SEQ ID NO:277 CDR3 having the amino acid sequence of SEQ ID NO:278, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 .

[0251] (vii) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0252] CDR1 having the amino acid sequence of SEQ ID NO:273

[0253] CDR2 having the amino acid sequence of SEQ ID NO:274

[0254] CDR3 having the amino acid sequence of SEQ ID NO:275, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NQ:304 CDR3 having the amino acid sequence of SEQ ID NQ:305;

[0255] (viii) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0256] CDR1 having the amino acid sequence of SEQ ID NO:273

[0257] CDR2 having the amino acid sequence of SEQ ID NO:274

[0258] CDR3 having the amino acid sequence of SEQ ID NO:275, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:300 CDR2 having the amino acid sequence of SEQ ID NQ:301 CDR3 having the amino acid sequence of SEQ ID NQ:302;

[0259] (ix) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0260] CDR1 having the amino acid sequence of SEQ ID NO:273

[0261] CDR2 having the amino acid sequence of SEQ ID NO:274

[0262] CDR3 having the amino acid sequence of SEQ ID NO:275, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 .

[0263] (vii) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0264] CDR1 having the amino acid sequence of SEQ ID NQ:270

[0265] CDR2 having the amino acid sequence of SEQ ID NO:271

[0266] CDR3 having the amino acid sequence of SEQ ID NO:272, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NQ:304 CDR3 having the amino acid sequence of SEQ ID NQ:305;

[0267] (viii) the yc-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:270 CDR2 having the amino acid sequence of SEQ ID NO:271 CDR3 having the amino acid sequence of SEQ ID NO:272, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:300 CDR2 having the amino acid sequence of SEQ ID NQ:301 CDR3 having the amino acid sequence of SEQ ID NQ:302; or

[0268] (ix) the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0269] CDR1 having the amino acid sequence of SEQ ID NQ:270 CDR2 having the amino acid sequence of SEQ ID NO:271 CDR3 having the amino acid sequence of SEQ ID NO:272, and the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0270] CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 .

[0271] In some embodiments, the antigen-binding molecule comprises or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:125, SEQ ID NO:124, SEQ ID NO:127, SEQ ID NO:129, SEQ ID NQ:130, SEQ ID NO:138, SEQ ID NQ:140, SEQ ID NO:113,

[0272] SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:1 16, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119,

[0273] SEQ ID NQ:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:128,

[0274] SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136,

[0275] SEQ ID NO:137, and / or SEQ ID NO:139.

[0276] In some embodiments, the antigen-binding molecule comprises or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:251 , SEQ ID NQ:250, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:256, SEQ ID NO:264, SEQ ID NO:266, SEQ ID NO:239,

[0277] SEQ ID NQ:240, SEQ ID NO:241 , SEQ ID NO:242, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:245,

[0278] SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:252, SEQ ID NO:254,

[0279] SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:259, SEQ ID NQ:260, SEQ ID NO:261 , SEQ ID NO:262,

[0280] SEQ ID NO:263, and / or SEQ ID NO:265.

[0281] In some embodiments, the antigen-binding molecule comprises, from N-terminus to C-terminus:

[0282] (a) a yc-binding moiety,

[0283] (b) a linker, and

[0284] (c) an IL-2Rp-binding moiety.

[0285] In some embodiments, the yc-binding moiety or the IL-2Rp-binding moiety comprises a VHH.

[0286] In some embodiments, the yc-binding moiety and the IL-2Rp-binding moiety comprises a VHH. In some embodiments, the linker connects the yc-binding moiety to the IL-2Rp-binding moiety. In some embodiments, the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL- 2Rp-binding moiety. In some embodiments, the linker connects the C-terminus of the IL-2Rp-binding moiety to the N-terminus of the yc-binding moiety.

[0287] Chimeric antigen receptors (CARs) are provided. In some embodiments, the CAR comprises an antigenbinding molecule disclosed herein.

[0288] Nucleic acids are provided. In some embodiments, the nucleic acid encodes an antigen-binding molecule disclosed herein.

[0289] Expression vectors are provided. In some embodiments, the expression vector comprising a nucleic acid which encodes an antigen-binding molecule disclosed herein.

[0290] Cells are provided. In some embodiments, the cell comprises an antigen-binding molecule, a CAR, a nucleic acid, and / or an expression vector disclosed herein.

[0291] Methods are provided. In some embodiments, the method comprises culturing a cell under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

[0292] In some embodiments, the method is a method for generating or expanding a population of cells expressing a yc-containing cytokine receptor, comprising contacting a cell expressing a yc-containing cytokine receptor in vitro, in vivo or ex vivo with an antigen-binding molecule disclosed herein.

[0293] In some embodiments, the method is a method of promoting heteromultimerization of yc and IL-2Rp, comprising contacting yc and IL-2Rp in vitro, in vivo or ex vivo with an antigen-binding molecule disclosed herein.

[0294] In some embodiments, the method is a method for increasing the proliferation, survival and / or effector activity of a cell expressing IL-2Rp, comprising contacting a cell expressing IL-2Rp in vitro, in vivo or ex vivo with an antigen-binding molecule disclosed herein.

[0295] In some embodiments, the cell is an effector immune cell. In some embodiments, the cell is a T cell or a NK cell.

[0296] A composition is provided. In some embodiments, the composition comprises an antigen-binding molecule disclosed herein, a CAR disclosed herein, a nucleic acid or a plurality of nucleic acids disclosed herein, an expression vector or a plurality of expression vectors disclosed herein, or a cell disclosed herein, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0297] In some embodiments, an antigen-binding molecule disclosed herein, a CAR disclosed herein, a nucleic acid or a plurality of nucleic acids disclosed herein, an expression vector or a plurality of expression vectors disclosed herein, a cell disclosed herein, or a composition disclosed herein, is provided for use in a method of treatment or prophylaxis.

[0298] In some embodiments, an antigen-binding molecule disclosed herein, a CAR disclosed herein, a nucleic acid or a plurality of nucleic acids disclosed herein, an expression vector or a plurality of expression vectors disclosed herein, a cell disclosed herein, or a composition disclosed herein, in the manufacture of a medicament for use in a method of treatment or prophylaxis.

[0299] In some embodiments, the method is a method of treatment or a method of prophylaxis, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of an antigen-binding molecule disclosed herein, a CAR disclosed herein, a nucleic acid or a plurality of nucleic acids disclosed herein, an expression vector or a plurality of expression vectors disclosed herein, a cell disclosed herein, or a composition disclosed herein.

[0300] In some embodiments, the method of treatment or prophylaxis is a method of treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in signalling mediated by IL-2.

[0301] In some embodiments, the method of treatment or prophylaxis is a method of treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in signalling mediated by an IL-2 receptor.

[0302] In some embodiments, the method of treatment or prophylaxis is a method of treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in signalling mediated by a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, and / or a yc:IL-2Rp:IL-15Ra receptor.

[0303] In some embodiments, the method of treatment or prophylaxis is a method of treating or preventing a disease / condition characterised by T cell dysfunction, a cancer, or an infectious disease.

[0304] In some embodiments, the cancer is selected from the group consisting of: colon cancer, colon carcinoma, colorectal cancer, nasopharyngeal carcinoma, cervical carcinoma, oropharyngeal carcinoma, gastric carcinoma, hepatocellular carcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, laryngeal cancer, prostate cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, urothelial carcinoma, melanoma, advanced melanoma, renal cell carcinoma, ovarian cancer or mesothelioma.

[0305] An in vitro complex is provided. In some embodiments, the in vitro complex comprises an antigen-binding molecule disclosed herein, bound to yc. In some embodiments, the in vitro complex comprises an antigen-binding molecule disclosed herein, bound to IL-2R0. In some embodiments, the in vitro complex comprises an antigen-binding molecule disclosed herein, bound to yc and IL-2R0. In some embodiments, the method is a method of promoting heteromultimerization of yc and IL-2R0, comprising contacting yc and IL-2R0 in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure, or a CAR according to the present disclosure.

[0306] The present disclosure provides improved antigen-binding molecules.

[0307] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, a linker, and an IL- 2Rp-binding moiety, the improvement comprising: the format of the antigen binding molecule, wherein the linker connects the yc-binding moiety to the IL-2Rp-binding moiety.

[0308] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, a linker, and an IL- 2Rp-binding moiety, the improvement comprising: the format of the antigen binding molecule, wherein the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL-2Rp-binding moiety.

[0309] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, and an IL-2R0- binding moiety, the improvement comprising: the yc-binding moiety comprises a CDR, FR sequence, and / or VH sequence described herein.

[0310] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, and an IL-2R0- binding moiety, the improvement comprising: the IL-2Rp-binding moiety comprises a CDR, FR sequence, and / or VH sequence described herein.

[0311] The present disclosure provides improved methods of treating a patient by administering an antigenbinding molecule.

[0312] In some embodiments, the improved method is a method of treating a patient by administering an antigen-binding molecule with a yc-binding moiety, a linker, and an IL-2Rp-binding moiety, the improvement comprising: the format of the antigen binding molecule, wherein the linker connects the yc-binding moiety to the IL-2Rp-binding moiety.

[0313] In some embodiments, the improved method is a method of treating a patient by administering an antigen-binding molecule comprising a yc-binding moiety, a linker, and an IL-2Rp-binding moiety, the improvement comprising: the format of the antigen binding molecule, wherein the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL-2Rp-binding moiety.

[0314] In some embodiments, the improved method is a method of treating a patient by administering an antigen-binding molecule comprising a yc-binding moiety, and an IL-2Rp-binding moiety, the improvement comprising: the yc-binding moiety comprises a CDR, FR sequence, and / or VH sequence described herein.

[0315] In some embodiments, the improved method is a method of treating a patient by administering an antigen-binding molecule comprising a yc-binding moiety, and an IL-2Rp-binding moiety, the improvement comprising: the IL-2Rp-binding moiety comprises a CDR, FR sequence, and / or VH sequence described herein.

[0316] The present disclosure provides antigen-binding molecule comprising means for binding yc, and means for binding IL-2Rp.

[0317] In some embodiments, the antigen-binding molecule comprises means for binding yc.

[0318] In some embodiments, the antigen-binding molecule comprises means for binding IL-2Rp.

[0319] In some embodiments, the antigen-binding molecule comprises:

[0320] (a) means for binding yc, and

[0321] (b) means for binding I L-2Rp, wherein the antigen-binding molecule binds to the same epitope on yc as an antibody described herein.

[0322] In some embodiments, the antigen-binding molecule comprises:

[0323] (a) means for binding yc,

[0324] (b) a linker, and

[0325] (c) means for binding I L-2Rp, wherein the antigen-binding molecule binds to the same epitope on yc as an antibody described herein.

[0326] In some embodiments, the antigen-binding molecule comprises:

[0327] (a) means for binding yc, and

[0328] (b) means for binding I L-2Rp, wherein the antigen-binding molecule binds to the same epitope on IL-2Rp as an antibody described herein.

[0329] In some embodiments, the antigen-binding molecule comprises:

[0330] (a) means for binding yc,

[0331] (b) a linker, and

[0332] (c) means for binding I L-2Rp, wherein the antigen-binding molecule binds to the same epitope on IL-2Rp as an antibody described herein.

[0333] In some embodiments, the antigen-binding molecule comprises:

[0334] (a) means for binding yc, and (b) means for binding IL-2R0, wherein the antigen-binding molecule binds to the same on yc and the same epitope on IL-2R0 as an antibody described herein.

[0335] In some embodiments, the antigen-binding molecule comprises:

[0336] (a) means for binding yc,

[0337] (b) a linker, and

[0338] (c) means for binding IL-2R0, wherein the antigen-binding molecule binds to the same on yc and the same epitope on IL-2R0 as an antibody described herein.

[0339] In some embodiments, the antigen-binding molecule comprises:

[0340] (a) means for binding yc,

[0341] (b) a linker, and

[0342] (c) means for binding IL-2R0, wherein the linker connects the yc-binding moiety to the IL-2Rp-binding moiety.

[0343] In some embodiments, the antigen-binding molecule comprises:

[0344] (a) means for binding yc,

[0345] (b) a linker, and

[0346] (c) means for binding IL-2R0, wherein the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL- 2Rp-binding moiety.

[0347] In some embodiments, the method of treating a patient comprises administering an antigen-binding molecule, comprising:

[0348] (a) means for binding yc, and

[0349] (b) means for binding IL-2R0, wherein the antigen-binding molecule binds to the same epitope as an antibody described herein.

[0350] In some embodiments, the method of treating a patient comprises administering an antigen-binding molecule, comprising:

[0351] (a) means for binding yc,

[0352] (b) a linker, and

[0353] (c) means for binding IL-2R0, wherein the antigen-binding molecule binds to the same epitope as an antibody described herein.

[0354] In some embodiments, the method of treating a patient comprises administering an antigen-binding molecule, comprising:

[0355] (a) means for binding yc,

[0356] (b) a linker, and

[0357] (c) means for binding IL-2R0, wherein the linker connects the yc-binding moiety to the IL-2Rp-binding moiety.

[0358] In some embodiments, the method of treating a patient comprises administering an antigen-binding molecule, comprising:

[0359] (a) means for binding yc,

[0360] (b) a linker, and

[0361] (c) means for binding I L-2Rp, wherein the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL- 2Rp-binding moiety.

[0362] Description

[0363] The present disclosure provides antigen-binding molecules that bind to common y chain (yc; CD132), and antigen-binding molecules that bind to IL-2Rp (CD122), having novel biophysical and / or functional properties as compared to antigen-binding molecules disclosed in the prior art.

[0364] The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for both yc and IL-2Rp.

[0365] In one aspect, this disclosure describes cytokine receptor agonists in which receptor activation is achieved through heterodimerization of the receptor components by multispecific antigen binding molecules (e.g. bispecific antibodies or bi-functional proteins) possessing anti-yc specificity and anti-IL- 2Rp specificity.

[0366] The antigen binding molecules of the present disclosure are associated with beneficial properties which overcome deficiencies and problems associated with the therapeutic administration of cytokines or engineered cytokines (e.g. PEGylated cytokines and antibody-coupled-cytokines). Additionally, antigen binding molecules of the present disclosure are associated with beneficial properties which overcome deficiencies and problems associated with known antigen-binding molecules that bind to yc and IL-2Rp.

[0367] Common v chain (yc)

[0368] Sequence, structure and functional information relating to Human common gamma (y) chain (yc; also known as CD132, IL-2RG and CIDX) may be identified on publicly available databases such as UniProt (P31785), Genbank (BAA01857.1), and PDB / Alpha fold (AF-P31785-F1). Human yc is the protein identified by UniProt P31785-1. The structure and function of yc is reviewed e.g. in Waickman et al., Cell Mol Life Sci. (2016) 73(2): 253-269 and Leonard et al., Immunity (2019) 50(4):832-850, both of which are hereby incorporated by reference in their entirety.

[0369] The canonical isoform of human yc (isoform 1) has the amino acid sequence shown in SEQ ID NO:1 . The N-terminal 23 amino acids of SEQ ID NO:1 constitute a signal peptide (SEQ ID NO:2), and so the mature form ( / .e. after processing to remove the signal peptide) of human yc has the amino acid sequence shown in SEQ ID NO:3. Amino acids 23 to 262 of SEQ ID NO:1 constitute the extracellular domain of yc (SEQ ID NO:4), positions 263 to 283 form a single-pass transmembrane domain (SEQ ID NO:5), and positions 284 to 369 form the cytoplasmic domain (SEQ ID NO:6). The extracellular domain comprises a fibronectin type III (FNIII) domain (shown in SEQ ID NO:7) comprising a WSXWS motif shown in SEQ ID NO:8. WSXWS motifs are conserved among type I cytokine receptor polypeptides, and the WSXWS motif of yc is thought to be important for conformational changes of the receptor.

[0370] All receptors of the yc receptor family comprise yc as a constituent polypeptide. Janus kinase 3 (JAK3) associates with yc, and upon activation of a yc-containing cytokine receptor, JAK3 becomes phosphorylated and activated. Phosphorylated JAK3 then phosphorylates and activates downstream signalling proteins such as STAT5, and also triggers signalling through the MAPK / ERK and PI3K / Akt signal transduction pathways. Signalling through yc family receptors promotes immune cell activation, proliferation and survival.

[0371] In this specification ‘common y chain’, ‘common gamma chain’, ‘yc’, or ‘CD132’ refers to common y chain from any species, and includes isoforms, fragments, variants or homologues of yc from any species. In some embodiments yc is yc from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the yc is human Yc.

[0372] As used herein, isoforms, fragments, variants or homologues of a given reference protein (e.g. yc) may be characterised as having at least 70% sequence identity, preferably one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of the reference protein.

[0373] A ‘fragment’ generally refers to a fraction of the reference protein. A ‘variant’ generally refers to a protein having an amino acid sequence comprising one or more amino acid substitutions, insertions, deletions or other modifications relative to the amino acid sequence of the reference protein, but retaining a considerable degree of sequence identity (e.g. at least 60%) to the amino acid sequence of the reference protein. An ‘isoform’ generally refers to a variant of the reference protein expressed by the same species as the species of the reference protein. A ‘homologue’ generally refers to a variant of the reference protein produced by a different species as compared to the species of the reference protein. Homologues include orthologues. For example, homologues of human yc include e.g. mouse yc (UniProt P34902).

[0374] Sequence, structure and functional information relating to cynomolgous yc may be identified on publicly available databases such as UniProt (Q38JL2), Genbank (ABB02662.1), and PDB / Alpha fold (AF- Q38JL2-F1). The amino acid sequence of the cynomolgous yc extracellular domain has 97.5% identity to the amino acid sequence of the Human yc extracellular domain.

[0375] Sequence, structure and functional information relating to rat yc may be identified on publicly available databases such as Genbank (NP_543165.1). The amino acid sequence of the rat yc extracellular domain has 71 .6% identity to the amino acid sequence of the Human yc extracellular domain.

[0376] Sequence, structure and functional information relating to mouse yc may be identified on publicly available databases such as UniProt (P34902), Genbank (BAA02974.1), and PDB / Alpha fold (AF- P34902-F1). The amino acid sequence of the mouse yc extracellular domain has 67.9% identity to the amino acid sequence of the Human yc extracellular domain.

[0377] Isoforms, fragments, variants or homologues of a given reference protein may optionally be characterised as having at least 70%, preferably one of >80%, >85%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature ( / .e. after processing to remove signal peptide) form of a specified isoform of the relevant protein from a given species, e.g. human.

[0378] Isoforms, fragments, variants or homologues of yc according to the present disclosure may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature yc isoform from a given species, e.g. human.

[0379] Isoforms, fragments, variants or homologues may optionally be functional isoforms, fragments, variants or homologues, e.g. having a functional property / activity of the reference yc (e.g. human yc isoform 1), as determined by analysis by a suitable assay for the functional property / activity. For example, an isoform, fragment, variant or homologue of yc may display one or more of: association with one or more of IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra, or IL-7Ra, or binding to one or more of IL-2, IL-15, IL-4, IL-9, IL-21 or IL-7.

[0380] A fragment of yc may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 250, 300 or 350 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 250, 300 or 350 amino acids.

[0381] In some embodiments, the yc has at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:1 or 3.

[0382] In some embodiments, a fragment of yc comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:4.

[0383] Signalling through cytokine receptors comprising yc

[0384] There are a number of cytokines that signal through cytokine receptors comprising yc (also referred to herein as yc -containing receptor complexes), e.g. IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Such cytokines are considered to belong to the yc family of cytokines. The biology of the yc family of cytokines is reviewed e.g. in Lin and Leonard, Cold Spring Harb Perspect Biol (2018) 10(9):a028449, Leonard etal., Immunity (2019) 50(4):832-850 and Pulliam et al., Immunol Lett. (2016) 169: 61-72, both of which are hereby incorporated by reference in their entirety.

[0385] Members of the common cytokine receptor gamma chain family of cytokines signal through receptor complexes that contain yc. Such cytokines may be referred to herein as yc-associated cytokines. The gamma-chain subunit associates with different cytokine-specific receptor subunits to form unique heterodimeric receptors. Common gamma-chain family cytokines generally activate three major signalling pathways that promote cellular survival and proliferation, the PI3K-Akt pathway, the RAS-MAPK pathway, and the JAK-STAT pathway. Differences in the expression patterns of the cytokines or their unique receptor components, along with the activation of different STAT proteins may account for some of the distinct effects mediated by gamma-chain family cytokines.

[0386] Interleukin-2 (IL-2) is a cytokine which mediates its effects through binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells. Treatment with IL-2 is an approved immunotherapy for the treatment of cancer, and works by promoting proliferation and activity of effector immune cells such as T cells and NK cells (see e.g. Skorombolas and Frelinger, Expert Rev Clin Immunol. (2014) 10(2): 207-217). However, the high dose of IL-2 that is required for effective treatment of certain diseases is highly toxic. IL-2 exerts its pleiotropic functions by binding to different combinations of receptor components expressed on different cell types: the alpha chain (IL-2Ra), the beta chain (IL-2R0), and yc. Isolated IL-2Ra has been termed the ‘low affinity’ IL-2 receptor (binding affinity KD ~ 10 nM) and is not involved in signal transduction. A complex of IL-2R0 and yc binds IL-2 with intermediate affinity (KD ~ 1 nM), although IL-2R0 alone has very low affinity (KD ~ 100 nM) and yc alone has virtually no detectable binding affinity for IL-2. A complex with all three subunits, IL-2Ra, IL-2R0, and yc, binds IL-2 with high affinity (KD ~ 10 pM). High-affinity a-p-yc IL- 2Rs are typically found on CD4+ T regulatory cells (Tregs) as well as recently activated T cells. Intermediate-affinity p-yc IL-2Rs are present at a low level on naive CD8+ cells but are prominent on antigen-experienced (memory) and memory-phenotype (MP) CD8+ T cells as well as natural killer (NK) cells. Both MPCD8+ T cells and NK cells express very high levels of IL-2Rp and readily respond to IL-2. Engineered IL-2 molecules have been developed for use in therapy. Rationally designed IL-2 variants (IL- 2 muteins) have been developed to overcome some of the problems of IL-2 therapy (Khoryati et al. Sci Immunol. (2020) 5(50): eaba5264). Additionally, PEGylated IL-2 (PEG-IL-2) molecules have been developed for similar reasons (Zhang etal. Nat Biomed Eng. (2021) 5(11):1288-1305). However, neither IL-2 muteins or PEG-IL-2 are associated with all of the benefits associated with the antigen binding molecules of the present disclosure. For example, neither IL-2 muteins or PEG-IL-2 are designed to specifically bind an optimal subset of IL-2R polypeptides ( / .e. yc and I L-2Rp, but not IL-2Ra), they are not tuneable in the same way as the presently disclosed antigen binding molecules, and they do not have the same levels of low immunogenicity.

[0387] Interleukin-4 (IL-4) has many biological roles, including the stimulation of activated B cell and T cell proliferation, and the differentiation of B cells into plasma cells. It is a key regulator in humoral and adaptive immunity. IL-4 induces B cell class switching to IgE, and up-regulates MHC class II production. IL-4 decreases the production of Th1 cells, macrophages, IFNy, and dendritic cells. IL-4 receptors are over-expressed by many epithelial cancers and could be a promising target for metastatic tumor therapy (Bankaitis et al. Clin Exp Metastasis. (2015) 32(8): 847-856). The cytokine-binding receptor chain for IL-4 is IL-4Ra. This receptor chain is widely expressed, with most cells carrying at least low numbers of this receptor chain. Upon IL-4 binding to IL-4Ra, the IL-4 / IL-4Ra complex will bind a secondary receptor chain, either yc or IL-13Ra1 (Junttila. Front Immunol. (2018) 9:888). The expression of these secondary chains varies among different cell types. In non-hematopoietic cells, yc expression is low or absent, whereas higher amounts of IL-13Ra1 are expressed in these cells. By contrast, lymphocytes express only low levels of IL-13Ra1 and relatively large amounts of yc. Finally, myeloid cells fall in between non- hematopoietic cells and lymphocytes, as they express both IL-13Ra1 and yc. IL-4 activates multiple signalling pathways. IL-4 activates JAK1 and JAK3 via the type I IL-4 receptor; however, IL-4 activates JAK1 and either JAK2 or TYK2 (depending on the cell type) via type II IL-4 receptors (Keegan et al. Fac Rev. (2021) 10:71). Regardless of the receptor type, IL-4 is associated with potent activation of STAT6, which docks on key phosphotyrosines on IL-4Ra. The type I IL-4 receptor (containing IL-4Ra and yc) also activates STAT5 signalling. Additionally, IL-4 (via type I IL-4 receptor) activates IRS2 efficiently, therefore IL-4 subsequently activates various pathways including Sos / Ras, PI3K / Akt, PKB / mTOR, or PKC.

[0388] Interleukin-7 (IL-7), a molecule known for its growth-promoting effects on progenitors of B cells, plays a vital role in health maintenance and disease prevention, and congenital deficiency of IL-7 signaling leads to profound immunodeficiency. Elevated IL-7 levels have been associated with poor prognosis of a number of cancers (Zarogoulidis et al., J Cancer. (2014) 5(9): 765-773). IL-7 binds to its receptor which is composed of the two chains IL-7Ra and yc. Whereas yc is expressed by most hematopoietic cells, IL- 7Ra is nearly exclusively expressed on lymphoid cells. After binding to its receptor, IL-7 signals through two different pathways: JAK-STAT (Janus kinase-Signal transducer and activator of transcription) and PI3K / Akt responsible for differentiation and survival (EIKassar and Gress, J Immunotoxicol. (2010) 7(1): 1-7). When IL-7 binds to IL-7Ra, it recruits yc, bringing together intracellular domains bearing JAK1 and JAK3. IL-7 binding to the IL-7 receptor complex results in downstream STAT1 , STAT3, and STAT5 signalling. Under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in IL-7-dependent STAT1 and STAT5 activation (Le Saout et al. JCI Insight. (2017) 2(22): e96228). Activation by IL-7 results in phosphorylation of the Y449 residue on IL-7Ra (Jiang et al., Cytokine Growth Factor Rev. (2005) 16:513-533). The p85a subunit of PI3K binds directly to phosphorylated Y449 via an SH2 domain. This is followed by the allosteric activation of the catalytic subunit P110. PI3K is recruited to the membrane where it produces the phosphatidyl-inositol PIP3 by phosphorylating PIP2. PIP3 activates downstream genes with a plekstrin homology domain such as PDK1 and Akt (Shiroki et al., J Immunol. (2007) 178:1349-1356). Akt, in turn, phosphorylates genes that regulate cell metabolism, cell cycle progression and survival, such as GSK3p, P27 and the death protein BAD.

[0389] Interleukin-9 (IL-9) is a cytokine which stimulates cell proliferation and prevents apoptosis. IL-9 is a pleiotropic cytokine and was primarily studied in the context of T helper 2 (TH2)-associated immuno- pathological conditions such as asthma and parasitic infections. There was a paradigm shift in the biology of IL-9 after the recent discovery of TH9 cells, a new subtype of TH cells which secrete IL-9 in copious amounts. This has resulted in renewed interest in this cytokine, which was neglected since discovery because it was considered it to be just another TH2 cytokine. Recent studies have shown that it has multiple cellular sources and is critically involved in the immune pathogenesis of inflammatory diseases and in guarding immune tolerance (Chakraborty et al. Int J Mol Sci. (2019) 20(9): 2113). IL-9 functions through the interleukin-9 receptor complex, which comprises IL-9 receptor alpha (IL-9Ra) and yc. When IL-9 binds to the IL-9 receptor complex, it activates different signal transducer and activator (STAT) proteins namely STAT 1 , STAT3 and STAT5 and thus connects this cytokine to various biological processes. IL-9 is a pleiotropic cytokine that has both direct and indirect effects on hematopoietic progenitor cells, lymphocytes, mast cells, as well as airway smooth muscle cells and epithelial cells (Lee at al. Pathology & Oncology Research (2020) 26:2017-2022). IL-9 also activates insulin receptor substrates (IRS) 1 and 2. Following JAK mediated phosphorylation, IRS proteins interact with other SH2- containing signaling proteins, such as the regulatory subunit of Phosphatidylinositol-3 Kinase (PI3K) p85, causing the activation of the PI3K catalytic subunit p110. PI3K then activates downstream signaling molecules like PI3K-dependent kinase (PDK) and Akt. Akt then phosphorylates BAD and protects cells by preventing caspase-mediated apoptosis. IL-9 also activates the MAPK pathway in several cell lines of lymphoid and hematopoietic origin, but the IL-9 mediated MAPK activation is weak compared to other cytokines like IL-3.

[0390] Interleukin-15 (IL-15) has structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through a complex composed of IL-2 / IL-15 receptor beta chain (CD122) and yc (CD132). Interleukin 15 is considered as a powerful pro-inflammatory cytokine and has the ability to destabilize chromosomes and induce tumorigenesis (Zarogoulidis et al., J Cancer. (2014) 5(9): 765-773). IL-15 utilizes three distinct receptor chains in at least two different combinations to signal and exert its effects on the immune system. Despite the lack of homology in the amino acid sequence between IL-15 and IL-2, the mature IL- 15 protein binds to the IL-2Rpy heterodimer, activating the intracellular signal leading to cell activation (Mishra et al., Clin Cancer Res. (2014) 20(8): 2044-2050). The third component of the IL-15R complex is a unique a-chain (IL-15Ra). In contrast to the IL-2Ra chain that binds IL-2 with low affinity and confers high affinity for IL-2 only when non-covalently linked the IL-2Rpy complex, IL-15Ra is by itself a high affinity receptor for IL-15 (Giri et al., EMBO J. (1995) 14:3654-63).

[0391] Binding of IL-15 to the IL-2 / 15Rpy heterodimer induces JAK1 activation that subsequently phosphorylates STAT3 via the p chain and JAK3 / STAT5 activation via its y chain. Phosphorylated STAT3 and STAT5 proteins form heterodimers that then translocate to the nucleus where they activate transcription of the anti-apoptotic protein bcl-2 and proto-oncogenes c-myc, c-fos, and c-jun.

[0392] The Akt signaling mechanism utilizes an adaptor protein, She, which binds to a phosphotyrosine residue on the IL-2 / 15Rp resulting in activation of Grb2 and onto AKT via the Shc^Grb2^Gab2^PI3K^Akt signaling pathway to increase cell proliferation, survival and / or effector activity (Gu et al. Mol Cell Biol. 2000;20:7109-20.). In a third signaling pathway that follows the trans-presentation of IL-15 to IL-2 / 15Rpy and Shc-mediated activation of Grb2, the latter binds to the guanine nucleotide exchange factor SOS to form a Grb2-SOS complex that then activates the Ras-Raf pathway by facilitating the removal of GDP from a member of the Ras subfamily that in turn activates the mitogen-activated protein kinase (MAPK) pathway for cellular proliferation (Adunyah et al. Biochem Biophys Res Commun. 1997;232:754-8). Thus IL-15-mediated Grb2 phosphorylation regulates both the PI3K and MAPK pathways. Collectively, these signaling mechanisms induce expression and activation of downstream effector molecules such as c- myc, c-fos, c-jun, Bcl-2 and NF-KB. Interleukin-21 (IL-21) is a cytokine that has potent regulatory effects on cells of the immune system, including natural killer (NK) cells and cytotoxic T cells that can destroy virally infected or cancerous cells. This cytokine induces cell division / proliferation in its target cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanisms involving the activation of NK and T or B cell responses (Croce at al. J Immunol Res. 2015; 2015: 696578). IL-21 signals via heterodimers of the IL-21 receptor (IL-21 R) and yc, and utilizes the JAK-STAT, MARK and PI3K pathways.

[0393] IL-21 binding stabilizes the complex between IL-21 R and yc, leading to the activation of JAK1 and JAK3, which allows the recruitment and phosphorylation of STAT proteins (predominantly STAT3, but also STAT1 and STAT5). IL-21 binding to IL-21 R can also activate the MARK and PI3K signalling pathways. IL-21 induces the transcription of the suppressor of cytokine signalling 1 (SOCS1) and SOCS3 proteins, which downregulate the JAK-STAT pathway.

[0394] In this specification ‘yc-containing cytokine receptor-mediated signalling’ refers to signalling mediated by multimeric receptor complexes comprising yc (e.g. comprising yc and another member of the yc receptor family other than yc). ‘Signalling’ refers to signal transduction and other cellular processes governing cellular activity. yc-containing cytokine receptor-mediated signalling is signalling mediated by a yc-containing polypeptide complex ( / .e. a polypeptide complex comprising one or more yc polypeptides, and another member of the yc receptor family other than yc). Polypeptide complexes according to the present disclosure may be characterised by non-covalent, proteimprotein interaction between constituent polypeptide(s) / peptide(s). In some embodiments, the association comprises electrostatic interaction (e.g. ionic bonding, hydrogen bonding) and / or Van der Waals forces. yc-containing cytokine receptor-mediated signalling may be mediated by heteromultimeric polypeptide complexes comprising one or more yc polypeptides, and additionally comprising one or more polypeptides of the yc receptor family other than yc (e.g. selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra or IL-7Ra). In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex forming a receptor for a yc family cytokine. For example, yc- containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex forming a receptor for IL-2, IL-4, IL-7, IL-9, IL-15 or IL-21.

[0395] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc and another polypeptide of the yc receptor family (e.g. selected from IL-2RP, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra or IL-7Ra).

[0396] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc and IL-2R0 ( / .e. a yc:IL-2Rp complex). As explained hereinabove, yc and IL-2R0 interact to form the intermediate-affinity IL-2 receptor. Such signalling may be referred to as yc:IL-2Rp-mediated signalling. In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising IL-2, yc and IL-2R0 ( / .e. an IL-2:yc:IL- 2Rp complex). Such signalling may be referred to as IL-2:yc:IL-2Rp-mediated signalling ( / .e. signalling mediated by binding of IL-2 to the intermediate-affinity IL-2 receptor).

[0397] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc, IL-2R0 and IL-2Ra ( / .e. a yc:IL-2Rp:IL-2Ra complex). As explained hereinabove, yc, IL-2R0 and IL-2Ra interact to form the high-affinity IL-2 receptor. Such signalling may be referred to as yc:IL-2Rp:IL-2Ra-mediated signalling. In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising IL-2, yc, IL-2R0 and IL-2Ra ( / .e. an IL-2:yc:IL-2Rp:IL-2Ra complex). Such signalling may be referred to as IL-2:yc:IL-2Rp:IL- 2Ra-mediated signalling ( / .e. signalling mediated by binding of IL-2 to the high-affinity IL-2 receptor).

[0398] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc, IL-2R0 and IL-15Ra ( / .e. a yc:IL-2Rp:IL-15Ra complex). As explained hereinabove, yc, IL-2R0 and IL-15Ra interact to form the IL-15 receptor. Such signalling may be referred to as yc:IL-2Rp:IL-15Ra-mediated signalling. In some embodiments, yc-containing cytokine receptor- mediated signalling may be mediated by a polypeptide complex comprising IL-15, yc, IL-2R0 and IL-15Ra ( / .e. an IL-15:yc:IL-2Rp:IL-15Ra complex). Such signalling may be referred to as IL-15:yc:IL-2Rp:IL-15Ra- mediated signalling ( / .e. signalling mediated by binding of IL-15 to the IL-15 receptor).

[0399] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc and IL-4Ra ( / .e. a yc:IL-4Ra complex). As explained hereinabove, yc and IL-4Ra interact to form the IL-4 receptor. Such signalling may be referred to as yc:IL-4Ra-mediated signalling. In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising IL-4, yc and IL-4Ra ( / .e. an IL-4:yc:IL-4Ra complex). Such signalling may be referred to as IL-4:yc:IL-4Ra-mediated signalling ( / .e. signalling mediated by binding of IL-4 to the IL-4 receptor).

[0400] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc and IL-9Ra ( / .e. a yc:IL-9Ra complex). As explained hereinabove, yc and IL-9Ra interact to form the IL-9 receptor. Such signalling may be referred to as yc:IL-9Ra-mediated signalling. In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising IL-9, yc and IL-9Ra ( / .e. an IL-9:yc:IL-9Ra complex). Such signalling may be referred to as IL-9:yc:IL-9Ra-mediated signalling ( / .e. signalling mediated by binding of IL-9 to the IL-9 receptor).

[0401] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc and IL-21 Ra ( / .e. a yc:IL-21 Ra complex). As explained hereinabove, yc and IL-21 Ra interact to form the IL-21 receptor. Such signalling may be referred to as yc:l L-21 Remediated signalling. In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising IL-21 , yc and IL-21 Ra ( / .e. an IL-21 :yc:IL-21Ra complex). Such signalling may be referred to as IL-21 :yc:IL-21 Ra-mediated signalling ( / .e. signalling mediated by binding of IL-21 to the IL-21 receptor).

[0402] In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising yc and IL-7Ra ( / .e. a yc:IL-7Ra complex). As explained hereinabove, yc and IL-7Ra interact to form the IL-7 receptor. Such signalling may be referred to as yc:IL-7Ra-mediated signalling. In some embodiments, yc-containing cytokine receptor-mediated signalling may be mediated by a polypeptide complex comprising IL-7, yc and IL-7Ra ( / .e. an IL-7:yc:IL-7Ra complex). Such signalling may be referred to as IL-7:yc:IL-7Ra-mediated signalling ( / .e. signalling mediated by binding of IL-7 to the IL-7 receptor).

[0403] The present disclosure relates to antigen-binding molecules that selectively bind to more than one component of yc-containing cytokine receptors. In particular, the antigen-binding molecules of the present disclosure are multispecific antigen-binding molecules comprising (i) a yc-binding moiety, and (ii) a moiety that binds to one or more polypeptides of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra). That is, the antigen binding molecule binds to (i) yc, and (ii) at least one of: IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra or IL-7Ra.

[0404] In this specification ‘IL-2R0’ or ‘CD122’ refers to IL-2R0 from any species and includes isoforms, fragments, variants or homologues of IL-2R0 from any species. In some embodiments IL-2R0 is IL-2R0 from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-2R0 is human IL-2R0. A fragment of I L-2R0 may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 450 or 500 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 amino acids. An isoform, fragment, variant or homologue of IL-2R0 may display association with one or more of yc, IL-2Ra, IL-15Ra, IL-2 or IL-15.

[0405] Human IL-2Ra (also known as CD25, IDDM10, IL2R, TCGFR, p55, and IMD41) is the protein identified by UniProt P01589.

[0406] In this specification ‘IL-2Ra’ refers to IL-2Ra from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments IL-2Ra is IL-2Ra from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-2Ra is human IL-2Ra. An isoform, fragment, variant or homologue of IL-2Ra may display association with one or more of yc, or IL-2R0, or IL-2. A fragment of IL- 2Ra may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150 or 200 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200 or 250 amino acids.

[0407] Human IL-15Ra (also known as CD215) is the protein identified by UniProt Q13261.

[0408] In this specification ‘IL-15Ra’ refers to IL-15Ra from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments IL-15Ra is IL-15Ra from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-15Ra is human IL-15Ra. An isoform, fragment, variant or homologue of IL-15Ra may display association with one or more of yc, or IL-2RJ3, or IL-15. A fragment of IL-15Ra may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150 or 200 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200 or 250 amino acids.

[0409] Human IL-4Ra (also known as CD124, IL-4R) is the protein identified by UniProt P24394.

[0410] In this specification ‘IL-4Ra’ refers to IL-4Ra from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments IL-4Ra is IL-4Ra from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-4Ra is human IL-4Ra. An isoform, fragment, variant or homologue of IL-4R may display association with yc or IL-4. A fragment of IL-4Ra may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700 or 800 amino acids, and may have a maximum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700 or 800 amino acids.

[0411] Human IL-9Ra (also known as IL-9R and CD129) is the protein identified by UniProt Q01113.

[0412] In this specification ‘IL-9Ra’ refers to IL-9Ra from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments IL-9Ra is IL-9Ra from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-9Ra is human IL-9Ra. An isoform, fragment, variant or homologue of IL-9R may display association with yc or IL-9. A fragment of IL-9Ra may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400 or 500 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 300, 400 or 500 amino acids.

[0413] Human IL-21 Ra (also known as CD360) is the protein identified by UniProt Q9HBE5.

[0414] In this specification ‘IL-21 Ra’ refers to IL-21 Ra from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments IL-21 Ra is IL-21 Ra from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-21 Ra is human IL-21 Ra. An isoform, fragment, variant or homologue of IL-21 Ra may display association with yc or IL-21 . A fragment of IL-21 Ra may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400 or 500 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 300, 400 or 500 amino acids.

[0415] Human IL-7Ra (also known as IL-7R, CD127) is the protein identified by UniProt P16871 .

[0416] In this specification ‘IL-7Ra’ refers to IL-7Ra from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments IL-7Ra is IL-7Ra from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human). In some embodiments, the IL-7Ra is human IL-7Ra. An isoform, fragment, variant or homologue of IL-7R may display association with yc or IL-7. A fragment of IL-7Ra may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400 or 450 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 300, 400 or 450 amino acids.

[0417] IL-2 and the IL-2 receptor lnterleukin-2 (IL-2) is a cytokine which mediates its effects through binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells. Treatment with IL-2 is an approved immunotherapy for the treatment of cancer, and works by promoting proliferation and activity of effector immune cells such as T cells and NK cells (see e.g. Skorombolas and Frelinger, Expert Rev Clin Immunol. (2014) 10(2): 207-217). However, the high dose of IL-2 that is required for effective treatment of certain diseases is highly toxic. IL-2 exerts its pleiotropic functions by binding to different combinations of receptor components expressed on different cell types: the alpha chain (IL-2Ra), the beta chain (IL-2R0), and yc.

[0418] Isolated IL-2Ra has been termed the ‘low affinity’ IL-2 receptor (binding affinity KD ~ 10 nM) and is not involved in signal transduction. A complex of IL-2R0 and yc binds IL-2 with intermediate affinity (KD ~ 1 nM), although IL-2R0 alone has very low affinity (KD ~ 100 nM) and yc alone has virtually no detectable binding affinity for IL-2. A complex with all three subunits, IL-2Ra, IL-2R0, and yc, binds IL-2 with high affinity (KD ~ 10 pM). High-affinity a-p-yc IL-2Rs are typically found on CD4+ T regulatory cells (Tregs) as well as recently activated T cells. Intermediate-affinity p-yc IL-2Rs are present at a low level on naive CD8+ cells but are prominent on antigen-experienced (memory) and memory-phenotype (MP) CD8+ T cells as well as natural killer (NK) cells. Both MPCD8+ T cells and NK cells express very high levels of IL- 2Rp and readily respond to IL-2.

[0419] Engineered IL-2 molecules have been developed for use in therapy. Rationally designed IL-2 variants (IL- 2 muteins) have been developed to overcome some of the problems of IL-2 therapy (Khoryati et al. Sci Immunol. (2020) 5(50): eaba5264). Additionally, PEGylated IL-2 (PEG-IL-2) molecules have been developed for similar reasons (Zhang etal. Nat Biomed Eng. (2021) 5(11):1288-1305). However, neither IL-2 muteins or PEG-IL-2 are associated with all of the benefits associated with the antigen binding molecules of the present disclosure. For example, neither IL-2 muteins or PEG-IL-2 are designed to specifically bind an optimal subset of IL-2R polypeptides ( / .e. yc and I L-2Rp, but not IL-2Ra), they are not tuneable in the same way as the presently disclosed antigen binding molecules, and they do not have the same levels of low immunogenicity.

[0420] In some embodiments, signalling may be mediated by a polypeptide complex comprising yc and IL-2R0 ( / .e. a yc:IL-2Rp complex). As explained hereinabove, yc and IL-2R0 interact to form the intermediateaffinity IL-2 receptor. Such signalling may be referred to as yc:IL-2Rp-mediated signalling. In some embodiments, signalling may be mediated by a polypeptide complex comprising IL-2, yc and IL-2R0 ( / .e. an IL-2:yc:IL-2Rp complex). Such signalling may be referred to as IL-2:yc:IL-2Rp-mediated signalling ( / .e. signalling mediated by binding of IL-2 to the intermediate-affinity IL-2 receptor). In some embodiments, signalling may be mediated by a polypeptide complex comprising yc, IL-2R0 and IL-2Ra ( / .e. a yc:IL-2Rp:IL-2Ra complex). As explained hereinabove, yc, IL-2R0 and IL-2Ra interact to form the high-affinity IL-2 receptor. Such signalling may be referred to as yc:IL-2Rp:IL-2Ra-mediated signalling. In some embodiments, signalling may be mediated by a polypeptide complex comprising IL-2, yc, IL-2R0 and IL-2Ra ( / .e. an IL-2:yc:IL-2Rp:IL-2Ra complex). Such signalling may be referred to as IL- 2:yc:IL-2Rp:IL-2Ra-mediated signalling ( / .e. signalling mediated by binding of IL-2 to the high-affinity IL-2 receptor).

[0421] Sequence, structure and functional information relating to Human IL-2R0 may be identified on publicly available databases such as UniProt (P14784), Genbank (AAA59143.1), and PDB / Alpha fold (AF- P14784-F1). Human IL-2R0 (also known as CD122, IL15RB and P70-75) is the protein identified by UniProt P14784. The canonical isoform of human IL-2R0 (isoform 1) has the amino acid sequence shown in SEQ ID NO:9. The N-terminal 26 amino acids of SEQ ID NO:9 constitute a signal peptide (SEQ ID NO:10), and so the mature form ( / .e. after processing to remove the signal peptide) of human IL-2R0 protein has the amino acid sequence shown in SEQ ID NO:11 . Amino acids 27 to 240 of SEQ ID NO:9 constitute the extracellular domain of IL-2R0, shown in SEQ ID NO:12. Amino acids 241 to 265 of SEQ ID NO:9 form a transmembrane domain (SEQ ID NO:13), and positions 266 to 551 form the cytoplasmic domain (SEQ ID NO:14).

[0422] In this specification ‘IL-2R0’ or ‘CD122’ refers to IL-2R0 from any species and includes isoforms, fragments, variants or homologues of IL-2R0 from any species. In some embodiments IL-2R0 is IL-2R0 from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-2R0 is human IL-2R0.

[0423] Sequence, structure and functional information relating to cynomolgous IL-2R0 may be identified on publicly available databases such as UniProt (Q38J85), Genbank (ABB03908.1), and PDB / Alpha fold (AF-Q38J85-F1). The amino acid sequence of the cynomolgous IL-2R0 extracellular domain has 96.7% identity to the amino acid sequence of the Human IL-2R0 extracellular domain.

[0424] Sequence, structure and functional information relating to rat IL-2R0 may be identified on publicly available databases such as UniProt (P26896), Genbank (AAA41429.1), and PDB / Alpha fold (AF- P26896-F1). The amino acid sequence of the rat IL-2R0 extracellular domain has 62.2% identity to the amino acid sequence of the Human IL-2R0 extracellular domain.

[0425] Sequence, structure and functional information relating to mouse IL-2R0 may be identified on publicly available databases such as UniProt (P16297), Genbank (AAA39283.1), and PDB / Alpha fold (AF- P16297-F1). The amino acid sequence of the mouse IL-2R0 extracellular domain has 59.3% identity to the amino acid sequence of the Human IL-2R0 extracellular domain.

[0426] A fragment of IL-2R0 may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 450 or 500 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 amino acids. An isoform, fragment, variant or homologue of IL-2Rp may display association with one or more of yc, IL-2Ra, IL-15Ra, IL-2 or IL-15.

[0427] In some embodiments, the IL-2R0 has at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:9 or 11. In some embodiments, a fragment of IL-2R0 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:12.

[0428] Antigen-binding molecules

[0429] The present disclosure provides antigen-binding molecules capable of binding to yc. An antigen-binding molecule that is capable of binding to yc may also be described as an antigen-binding molecule that binds to yc.

[0430] The present disclosure also provides antigen-binding molecules capable of binding to IL-2R0. An antigenbinding molecule that is capable of binding to IL-2R0 may also be described as an antigen-binding molecule that binds to IL-2R0.

[0431] The present disclosure also provides antigen-binding molecules capable of binding to yc and IL-2R0. An antigen-binding molecule that is capable of binding to yc and IL-2R0 may also be described as an antigen-binding molecule that binds to yc and IL-2R0.

[0432] An ‘antigen-binding molecule’ refers to a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies ( / .e. immunoglobulins (Igs)) and antigen-binding fragments thereof. As used herein, ‘antibodies’ include monoclonal antibodies, polyclonal antibodies, monospecific and multispecific (e.g., bispecific, trispecific, etc.) antibodies, and antigen-binding molecules such as scFv, scFab, diabodies, triabodies, scFv-Fc, minibodies, single domain antibodies (e.g. VHH), etc. Antigen-binding fragments of antibodies include e.g. Fv, Fab, F(ab’)2 and F(ab’) fragments. In some embodiments, an antigen-binding molecule may be an antibody or an antigen-binding fragment thereof.

[0433] Antigen-binding molecules according to the present disclosure also include antibody-derived molecules, e.g. molecules comprising an antigen-binding region / domain derived from an antibody. Antibody-derived antigen-binding molecules may comprise an antigen-binding region / domain that comprises, or consists of, the antigen-binding region of an antibody (e.g. an antigen-binding fragment of an antibody). In some embodiments, the antigen-binding region / domain of an antibody-derived antigen-binding molecule may be or comprise the Fv (e.g. provided as an scFv) or the Fab region of an antibody, or the whole antibody. For example, antigen-binding molecules according to the present disclosure include antibody-drug conjugates (ADCs) comprising a (cytotoxic) drug moiety (e.g. as described hereinbelow). Antigen-binding molecules according to the present disclosure also include multispecific antigen-binding molecules such as immune cell engager molecules comprising a domain for recruiting (effector) immune cells (reviewed e.g. in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17: 418-434 and Ellerman, Methods (2019) 154:102-117, both of which are hereby incorporated by reference in their entirety), including BiTEs, BiKEs and TriKEs. Antigen-binding molecules according to the present disclosure also include chimeric antigen receptors (CARs), which are recombinant receptors providing both antigen-binding and T cell activating functions (CAR structure, function and engineering is reviewed e.g. in Dotti et al., Immunol Rev (2014) 257(1) and Jayaraman et al., EBioMedicine (2020) 58:102931 , both of which are hereby incorporated by reference in their entirety).

[0434] The antigen-binding molecule of the present disclosure comprises a moiety or moieties capable of binding to a target antigen(s). In some embodiments, the moiety capable of binding to a target antigen comprises an antibody heavy chain variable region (VH). In some embodiments, the moiety capable of binding to a target antigen comprises a Variable domain of the Heavy chain of a Heavy-chain antibody (VHH). In some embodiments, the moiety capable of binding to a target antigen comprises an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specific binding to the target antigen. In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an aptamer capable of binding to the target antigen, e.g. a nucleic acid aptamer (reviewed, for example, in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202). In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an antigenbinding peptide / polypeptide, e.g. a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, fynomer, atrimer, DARPin, affibody, nanobody ( / .e. a single-domain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody or fibronectin - reviewed e.g. in Reverdatto et al., Curr Top Med Chem. 2015; 15(12): 1082-1101 , which is hereby incorporated by reference in its entirety (see also e.g. Boersma et al., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).

[0435] As used herein, a ‘peptide’ refers to a chain of two or more amino acid monomers linked by peptide bonds. A peptide typically has a length in the region of about 2 to 50 amino acids. A ‘polypeptide’ is a polymer chain of two or more peptides. Polypeptides typically have a length greater than about 50 amino acids.

[0436] The antigen-binding molecules of the present disclosure comprise an antigen-binding domain. In some embodiments, the antigen-binding domain comprises an antibody heavy chain variable region (VH). In some embodiments, the antigen-binding domain comprises a Variable domain of the Heavy chain of a Heavy-chain antibody (VHH). A VHH may also be referred to herein as a single-domain antibody (sdAb), a nanobody, a single variable domain of a heavy chain antibody, or a heavy chain only antibody (HcAb).

[0437] In some embodiments, the antigen-binding domain comprises a VH and a VL of an antibody capable of specific binding to the target antigen. The antigen-binding domain formed by a VH and a VL may also be referred to herein as an Fv region.

[0438] An antigen-binding molecule may be, or may comprise, an antigen-binding polypeptide, or an antigenbinding polypeptide complex. An antigen-binding molecule may comprise more than one polypeptide which together form an antigen-binding domain. The polypeptides may associate covalently or non- covalently. In some embodiments, the polypeptides form part of a larger polypeptide comprising the polypeptides. An antigen-binding molecule may refer to a non-covalent or covalent complex of more than one polypeptide (e.g. 2, 3, 4, 6, or 8 polypeptides), e.g. an IgG-like antigen-binding molecule comprising two heavy chain polypeptides and two light chain polypeptides, or a multispecific antigen-binding molecule comprising more than one antigen-binding domain.

[0439] The antigen-binding molecules of the present disclosure may be designed and prepared using the sequences of antigen-binding molecules (e.g., antibodies, antibody derived molecules, or fragments or antibodies) capable of binding to yc and / or IL-2Rp. An ‘antigen-binding region’ is any fragment of an antibody that binds to the target for which the given antibody is specific.

[0440] Antibodies often comprise six complementarity-determining regions (CDRs); three in the heavy chain variable (VH) region: HC-CDR1 , HC-CDR2 and HC-CDR3, and three in the light chain variable (VL) region: LC-CDR1 , LC-CDR2, and LC-CDR3. The six CDRs together define the paratope of the antibody, which is the part of the antibody that binds to the target antigen.

[0441] The VH region and VL region comprise framework regions (FRs) either side of each CDR, which provide a scaffold for the CDRs. From N-terminus to C-terminus, VH regions comprise the following structure: N term-[HC-FR1]-[HC-CDR1]-[HC-FR2]-[HC-CDR2]-[HC-FR3]-[HC-CDR3]-[HC-FR4]-C term; and VL regions comprise the following structure: N term-[LC-FR1]-[LC-CDR1]-[LC-FR2]-[LC-CDR2]-[LC-FR3]- [LC-CDR3]-[LC-FR4]-C term.

[0442] Some antigen binding molecules contain less than six CDRs. In some embodiments, the antigen-binding molecule (or antigen-binding moiety) comprises three CDRs. In some embodiments, the antigen-binding molecule (or antigen-binding moiety) has only three CDRs. In some embodiments, the antigen-binding molecule comprises one binding moiety which has only three CDRs, and a second binding moiety which has only three CDRs.

[0443] VHH antibodies are formed of a single antibody variable domain which comprises three CDRs. VHH antibodies further comprise framework regions (FRs) either side of each CDR, which provide a scaffold for the CDRs.

[0444] The designation ‘VHH’ is an acronym for ‘Variable Heavy domain of Heavy chain’. VHH antibodies are also known as ‘VHHs’, ‘single domain antibodies (sdAbs)’, ‘nanobodies’, ‘single variable domain on a heavy chain antibodies’, and ‘heavy chain only antibodies (HcAbs)’, and are described e.g. in Henry and MacKenzie, Front Immunol. (2018) 9:41 , Bever et al., Anal Bioanal Chem. (2016) 408(22): 5985-6002, and Tang et al. Int J Mol Sci. 2023 Feb; 24(4): 4176, all of which are hereby incorporated by reference in their entirety.

[0445] In some embodiments, the antigen-binding molecule comprises a VHH. In some embodiments, the antigen-binding molecule is a VHH. In some embodiments, the antibody is a VHH. In some embodiments, the antigen-binding moiety is a VHH. In some embodiments, the antigen-binding molecule comprises a VHH moiety. In some embodiments, the antigen-binding molecule comprises two VHH moieties.

[0446] The terms ‘VHH antibody’, ‘VHH molecule’, ‘VHH’, ‘nanobody’, ‘HcAb’, ‘single domain antibody’, and ‘sdAb’, as used herein, encompass VHH antibodies, VHH molecules, VHHs, nanobodies, HcAbs, single domain antibodies, and sdAbs derived from animals (e.g., camelids such as a llama), humanized molecules, and synthetic / rationally designed molecules.

[0447] In some embodiments, the VHH is a camelid VHH. In some embodiments, the VHH is a humanised VHH. In some embodiments, the VHH is a synthetic / rationally designed VHH molecule. In some embodiments, the VHH has been modified. In some embodiments, the VHH has been modified to optimise physical properties such as charge and / or hydrophobicity.

[0448] In some embodiments, the single domain antibody is a camelid single domain antibody. In some embodiments, the single domain antibody is a humanized single domain antibody. In some embodiments, the single domain antibody is a synthetic / rationally designed single domain antibody molecule. In some embodiments, the single domain antibody has been modified. In some embodiments, the single domain antibody has been modified to optimise physical properties such as charge and / or hydrophobicity.

[0449] A VHH is formed of a single antibody variable domain which comprises three CDRs: CDR1 , CDR2 and CDR3. The three CDRs together define the paratope of the molecule, which is the portion of the molecule through which it binds to its target antigen. From N-terminus to C-terminus, a VHH generally comprises the following structure: N term-[FR1]-[CDR1]-[FR2]-[CDR2]-[FR3]-[CDR3]-[FR4]-C term.

[0450] There are several different conventions for defining antibody CDRs and FRs, such as those described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et a!., J. Mol. Biol. 196:901-917 (1987), and VBASE2, as described in Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1): D671-D674. The CDRs and FRs of the VH regions and VL regions of the antibody clones described herein were defined according to the international IMGT (ImMunoGeneTics) information system (LeFranc et al., Nucleic Acids Res. (2015) 43 (Database issue):D413-22), which uses the IMGT V-DOMAIN numbering rules as described in Lefranc et al., Dev. Comp. Immunol. (2003) 27:55-77. In preferred embodiments, the CDRs and FRs of antigenbinding molecules referred to herein are defined according to the IMGT information system.

[0451] In some embodiments, the antigen-binding molecule comprises means for binding yc.

[0452] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to yc. In some embodiments, the antigen-binding molecule comprises the FRs of an antigenbinding molecule that binds to yc. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to yc. In some embodiments, the antigenbinding molecule comprises the VH region of an antigen-binding molecule that binds to yc. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigenbinding molecule that binds to yc.

[0453] In some embodiments, the antigen-binding molecule comprises means for binding IL-2Rp.

[0454] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to IL-2Rp. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to IL-2Rp. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to IL-2Rp. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to IL-2Rp. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to IL-2R0.

[0455] In some embodiments, the antigen-binding molecule comprises (i) means for binding yc, and (b) means for binding IL-2R0.

[0456] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to yc and IL-2R0. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to yc and IL-2R0. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to yc and IL-2R0. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to yc and IL-2R0. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to yc and IL-2R0.

[0457] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule described herein. In some embodiments, the antigen-binding molecule comprises the CDRs, FRs and / or the VH and / or VL regions of an antigen-binding molecule described herein, or CDRs, FRs and / or VH and / or VL regions which are derived from those of an antigen-binding molecule described herein.

[0458] In some embodiments, a yc-binding antibody is selected from an antibody described in Table A, B, or C, herein.

[0459] In some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Ab codes: MA003, MA004, MA005, MA006, MA007, MA008, MA009, MA010, MA011 , MA013, MA014, and MA015. In other words, in some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2RGT38, 2RGT238, 2RGT212, 2RGT30, 2RGT123, 3RGT35, 3RGT83, 2RGT12, 2RGT50, 2RGT222, 3RGT31 , and 2RGT156.

[0460] In some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Ab codes: MA003, MA004, MA005, MA006, MA007, MA008, MA009, MA010, MA011 , MA013, MA014, MA015, MA081 , MA085, MA052, MA080, MA103, MA047, MA097, MA095, MA058, MA060, MA063, MA097, MA049, MA093, MA089, huMA089, MA090, or huMA093. In other words, in some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2RGT38, 2RGT238, 2RGT212, 2RGT30, 2RGT123, 3RGT35, 3RGT83, 2RGT12, 2RGT50, 2RGT222, 3RGT31 , 2RGT156, 217P3P1_A8, 217P3P1_H1 , 217P3P1_F11 , 217P2P1G8, 217P3P1_D12, 217P3P1_B3, 217P2P2_F12, 217P2P2_F4, 217P2P1_A2, 217P2P1_A5, 217P2P1_B1 , 217P3P1JH8, 217P3P1_B11 , 217P2P2_E2, 217P2P2_A6, hu217P2P2_A6, 217P2P2_C3, Hu217P2P2_E2.

[0461] In some embodiments, the yc-binding antibody is selected from: MA003, MA004, MA005, and MA009.

[0462] In some embodiments, the yc-binding antibody is MA003. In some embodiments, the yc-binding antibody is MA004. In some embodiments, the yc-binding antibody is MA009. In some embodiments, the yc- binding antibody is MA005.

[0463] In some embodiments, the yc-binding antibody is 2RGT38. In some embodiments, the yc-binding antibody is 2RGT238. In some embodiments, the yc-binding antibody is 2RGT212. In some embodiments, the yc-binding antibody is 2RGT30.

[0464] In some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: hu2RGT238-2, hu2RGT38-1 , hu2RGT238, hu2RGT212.

[0465] In some embodiments, the yc-binding antibody is hu2RGT38-2. In some embodiments, the yc-binding antibody is hu2RGT38-1 . In some embodiments, the yc-binding antibody is hu2RGT238. In some embodiments, the yc-binding antibody is hu2RGT212.

[0466] In some embodiments, an IL-2Rp-binding antibody is selected from an antibody described in Table D, E, or F, herein.

[0467] In some embodiments, the IL-2Rp-binding antibody is selected from: MA016, MA017, MA018, MA019, MA020, MA021 , MA022, MA023, MA024, MA025, MA026, MA027, MA028, MA029, MA030, MA031 , MA032, MA033, MA034, MA035, MA036, MA037, MA038, MA039, MA040, MA041. In other words, in some embodiments, the IL-2Rp-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2MAV110, 2MAV176, 2MAV84, 2MAV216, 2MAV117, 2MAV248, 2MAV73, 2MAV162, 2MAV87, 2MAV18, 2MAV96, 3MAV29, 3MAV52, 3MAV81 , 2MAV268, 2MAV118, 2MAV251 , 3MAV90, 2MAV103, 2MAV182, 2MAV206, 2MAV265, 2MAV151 , 2MAV154, 3MAV75, and 2MAV263.

[0468] In some embodiments, the IL-2Rp-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2MAV110, 2MAV176, 2MAV84, 2MAV216, 2MAV117, 2MAV248, 2MAV73, 2MAV162, 2MAV87, 2MAV18, 2MAV96, 3MAV29, 3MAV52, 3MAV81 , 2MAV268, 2MAV118, 2MAV251 , 3MAV90, 2MAV103, 2MAV182, 2MAV206, 2MAV265, 2MAV151 , 2MAV154, 3MAV75, 2MAV263, or hu3MAV81 . In some embodiments, the IL-2Rp-binding antibody is selected from: MA016, MA021 , MA026, MA034, and MA040.

[0469] In some embodiments, the IL-2Rp-binding antibody is MA016. In some embodiments, the IL-2Rp-binding antibody is MA021 . In some embodiments, the IL-2Rp-binding antibody is MA026. In some embodiments, the IL-2Rp-binding antibody is MA034. In some embodiments, the IL-2Rp-binding antibody is MA040.

[0470] In some embodiments, the IL-2Rp-binding antibody is selected from: hu3MAV75, hu2MAV103, hu2MAV96, hu2MAV248, hu2MAV110, and hu3MAV81.

[0471] In some embodiments, the IL-2Rp-binding antibody is selected from: hu3MAV75, hu2MAV103, hu2MAV96, hu2MAV248, and hu2MAV110.

[0472] In some embodiments, the IL-2Rp-binding antibody is hu3MAV75. In some embodiments, the IL-2R0- binding antibody is hu2MAV103. In some embodiments, the IL-2Rp-binding antibody is hu2MAV96. In some embodiments, the IL-2Rp-binding antibody is hu2MAV248. In some embodiments, the IL-2R0- binding antibody is hu2MAV110. In some embodiments, the IL-2Rp-binding antibody is hu3MAV81.

[0473] In some embodiments, an antibody that binds yc and IL-2R0 is selected from an antibody described in Table G, H, or I, herein.

[0474] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS079, BS078, BS081 , BS083, BS084, BS092, and BS094.

[0475] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS007, BS008, BS009, BS010, BS011 , BS012, BS013, BS014, BS015, BS016, BS017, BS018, BS019, BS020, BS021 , BS022,

[0476] BS023, BS024, BS025, BS026, BS027, BS028, BS029, BS030, BS031 , BS032, BS033, BS034, BS035,

[0477] BS036, BS037, BS038, BS039, BS040, BS041 , BS042, BS043, BS044, BS045, BS046, BS047, BS048,

[0478] BS049, BS050, BS051 , BS052, BS053, BS054, BS055, BS056, BS057, BS058, BS059, BS060, BS061 ,

[0479] BS062, BS063, BS064, BS065, BS066, BS067, BS068, BS069, BS070, BS071 , BS072, BS073, BS074,

[0480] BS075, BS076, BS077, BS078, BS079, BS080, BS081 , BS082, BS083, BS084, BS085, BS086, BS087,

[0481] BS088, BS089, BS090, BS091 , BS092, BS093, and BS094.

[0482] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS007, BS008, BS009, BS010, BS011 , BS012, BS013, BS014, BS015, BS016, BS017, BS018, BS019, BS020, BS021 , BS022,

[0483] BS023, BS024, BS025, BS026, BS027, BS028, BS029, BS030, BS031 , BS032, BS033, BS034, BS035,

[0484] BS036, BS037, BS038, BS039, BS040, BS041 , BS042, BS043, BS044, BS045, BS046, BS047, BS048,

[0485] BS049, BS050, BS051 , BS052, BS053, BS054, BS055, BS056, BS057, BS058, BS059, BS060, BS061 ,

[0486] BS062, BS063, BS064, BS065, and BS066. In some embodiments, the antibody that binds yc and IL-2R0 is selected from: BS007, BS008, BS009, BS010, BS011 , BS012, BS013, BS014, BS015, BS016, BS028, BS029, BS030, BS032, BS033, BS034, BS035, BS036.

[0487] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS051 , BS053, BS054, BS008, BS009, BS010, BS011 , BS014, BS015, BS034, BS007, BS012, BS016, BS033, BS029, BS035, BS036, BS048, BS049, and BS050.

[0488] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS051 , BS053, BS054, BS008, BS009, BS010, BS011 , BS014, BS015, and BS034.

[0489] In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 which is lower than the pSTAT5 ECso of IL-2. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 which is higher than the pSTAT5 ECso of IL-2.

[0490] The concentration of a given agent at which 50% of the maximal level of the relevant activity is attained may be referred to as the ‘half-maximal effective concentration’ of the agent in relation to the relevant activity, which may also be referred to as the ‘EC50’.

[0491] The pSTAT5 EC50 of an agonist (e.g., IL-2 or an antigen-binding molecule) is the concentration of the agonist required to increase pSTAT5 signalling to half ( / .e., 50%) of its maximal value. This can be determined through the use of a cell-based reporter gene assay which enables pSTAT5 signalling to be stimulated and measured (e.g., the assays reported in Example 3 herein).

[0492] The pSTAT5 EC50 ratio of an antigen-binding molecule is determined by comparing the pSTAT5 ECso of human IL-2 with the pSTAT5 ECso of the antigen-binding molecule in question, using the following calculation: (pSTAT5 EC50 of human IL-2 / EC50 of pSTAT5 on the agonist) x 100.

[0493] As a first example, an antigen-binding molecule with a pSTAT5 EC50 ratio of 105 has a lower pSTAT5 EC50 than IL-2, and this indicates that this antigen-binding molecule is a stronger agonist than IL-2 (as a lower concentration of the antigen-binding molecule is required to increase pSTAT5 signalling to half ( / .e., 50%) of its maximal value.

[0494] As a second example, an antigen-binding molecule with a pSTAT5 EC50 ratio of 40 has a higher pSTAT5 EC50 than IL-2, and this indicates that this antigen-binding molecule is a weaker agonist than IL-2 (as a higher concentration of the antigen-binding molecule is required to increase pSTAT5 signalling to half ( / .e., 50%) of its maximal value.

[0495] The pSTAT5 EC50 ratio (and the pSTAT5 EC50 ratio) of a given antigen-binding molecule can be determined through the use of a cell-based reporter gene assay (e.g., an assay reported in Example 3 herein). In some embodiments, the pSTAT5 EC50 of a given antigen-binding molecule is determined using a cellbased reporter gene assay. In some embodiments, the pSTAT5 EC50 of a given antigen-binding molecule is determined using the assay described in Example 3 herein.

[0496] In some embodiments, the pSTAT5 EC50 ratio of a given antigen-binding molecule is determined using a cell-based reporter gene assay. In some embodiments, the pSTAT5 EC50 ratio of a given antigen-binding molecule is determined using the assay described in Example 3 herein.

[0497] It will be understood that the pSTAT5 EC50 of an antigen-binding molecule comprising a yc-binding moiety and an IL-2Rp-binding moiety can be determined through the use of a cell-based reporter gene assay, wherein the cell expresses the relevant IL-2 receptor polypeptides (e.g., (a) cells which express IL-2R0 and yc, (b) cells which express IL-2Ra, IL-2R0, and yc, or (c) or cells which express IL-2R0, IL-15Ra and yc). In some embodiments, the cells utilised in the cell-based reporter gene assay are cells which express 2Rp and yc. In some embodiments, the cells utilised in the cell-based reporter gene assay are cells which express IL-2Ra, IL-2R0, and yc. In some embodiments, the cells utilised in the cell-based reporter gene assay are cells which express IL-2R0, IL-15Ra and yc.

[0498] In some embodiments, pSTAT5 EC50 of an antigen-binding molecule is determined by following an assay such as the below: i. Culture, harvest and wash reporter cells which express IL-2R0 and yc; ii. Stimulate reporter cells with the antigen-binding molecule, and separately stimulate cells with a human IL-2 control (both at a range of concentrations);

[0499] Hi. Collect supernatant from different samples, and analyse these supernatants to quantify the level of STAT5 phosphorylation after stimulation. iv. Determine the concentration of the agonist required to increase pSTAT5 signalling to half (i.e., 50%) its maximal level of pSTAT5 signalling.

[0500] In some embodiments, an antigen-binding molecule is categorised as (i) a strong agonist, (ii) an intermediate agonist, (iii) a weak agonist, or (iv) none of these agonist categorisations, by following an assay such as the below: i. Culture, harvest and wash reporter cells which express IL-2R0 and yc; ii. Stimulate reporter cells with the antigen-binding molecule, and separately stimulate cells with a human IL-2 control (both at a range of concentrations); iii. Collect supernatant from different samples, and analyse these supernatants to quantify the level of STAT5 phosphorylation after stimulation. iv. Determine the pSTAT5 EC50 ratio (pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100).

[0501] In some embodiments, cells are stimulated (e.g., with an antigen binding molecule and / or IL-2) for a duration of at least 12 hours. In some embodiments, cells are stimulated (e.g., with an antigen binding molecule and / or IL-2) for a duration of 24 hours. In some embodiments, cells are stimulated with antigen-binding molecules at a maximum concentration of 5 nM. In some embodiments, cells are stimulated with antigen-binding molecules at a minimum concentration of 0.0016 nM. In some embodiments, cells are separately stimulated with antigen-binding molecules at a range of concentrations between 0.0016 nM and 5 nM.

[0502] In some embodiments, the reporter cell is reporter cell which is used in an assay described in the Examples herein. In some embodiments, the reporter cell is reporter cell which is used in an assay described in Example 4 herein. In some embodiments, the reporter cell is a CD25HEB2 (HEK Blue IL-2) cell. In some embodiments, the reporter cell is a HEK-Blue CD122 / CD132 cell.

[0503] A strong agonist of the IL-2 receptor is defined herein as an antigen-binding molecule which increases signalling mediated by an IL-2 receptor to a level which is comparable to IL-2.

[0504] A strong agonist of a receptor comprising yc and IL-2R0 is defined herein as an antigen-binding molecule which increases signalling mediated by a receptor comprising yc and IL-2R0 to a level which is comparable to IL-2.

[0505] In some embodiments, a strong agonist has a pSTAT5 EC50 which is <200% the pSTAT5 EC50 of human IL-2. In some embodiments, a strong agonist has a pSTAT5 EC50 which is <150% the pSTAT5 EC50 of human IL-2. In some embodiments, a strong agonist has a pSTAT5 EC50 which is <140% the pSTAT5 EC50 of human IL-2. In some embodiments, a strong agonist has a pSTAT5 EC50 which is <130% the pSTAT5 EC50 of human IL-2. In some embodiments, a strong agonist has a pSTAT5 EC50 which is <120% the pSTAT5 EC50 of human IL-2. In some embodiments, a strong agonist has a pSTAT5 EC50 which is <110% the pSTAT5 EC50 of human IL-2.

[0506] In some embodiments, a strong agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), between 50 and 100. In some embodiments, the strong agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 1 agonist pSTAT5 EC50) x 100), between 60 and 100. In some embodiments, the strong agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), between 70 and 100. In some embodiments, the strong agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 1 agonist pSTAT5 EC50) x 100), between 80 and 100. In some embodiments, the strong agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 1 agonist pSTAT5 EC50) x 100), between 90 and 100.

[0507] In some embodiments, the antigen-binding molecule that binds yc and IL-2R0 is a strong agonist. In some embodiments, the strong agonist is an antibody comprising the CDRs of an antibody selected from: BS008, BS009, BS010, BS011 , BS014, BS015, BS034, BS051 , and BS054. In some embodiments, the strong agonist is an antibody selected from: BS008, BS009, BS010, BS011 , BS014, BS015, BS034, BS051 , and BS054. In some embodiments, the antibody that binds yc and IL-2R0 is selected from: BS008, BS009, BS010, BS011 , BS014, BS015, BS034, BS051 , and BS054. An intermediate agonist of the IL-2 receptor is defined herein as an antigen-binding molecule which is a functional agonist of an IL-2 receptor, but increases signalling mediated by an IL-2 receptor to a lower degree than IL-2. In other words, an intermediate agonist of the IL-2 receptor has reduced agonistic effects (compared to IL-2), but is an effective agonist.

[0508] An intermediate agonist of a receptor comprising yc and IL-2R0 is defined herein as an antigen-binding molecule which is a functional agonist of a receptor comprising yc and IL-2R0, but increases signalling mediated by a receptor comprising yc and IL-2R0 to a lower degree than IL-2. In other words, an intermediate agonist of a receptor comprising yc and IL-2R0 has reduced agonistic effects (compared to IL-2), but is an effective agonist.

[0509] In some embodiments, the antigen-binding molecule that binds yc and IL-2R0 is an intermediate agonist. In some embodiments, the intermediate agonist is an antibody comprising the CDRs of an antibody selected from: BS007, BS012, BS016, BS033, BS029, BS035, BS036, BS047, BS048, BS049, BS050 and BS053. In some embodiments, the intermediate agonist is an antibody selected from: BS007, BS012, BS016, BS033, BS029, BS035, BS036, BS047, BS048, BS049, BS050 and BS053. In some embodiments, the antibody that binds yc and IL-2R0 is selected from: BS007, BS012, BS016, BS033, BS029, BS035, BS036, BS047, BS048, BS049, BS050 and BS053.

[0510] In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is <50.

[0511] In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >10. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >11. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >12. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >13. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >14. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >15.

[0512] In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >10 and 50. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >11 and 50. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >12 and 50. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 1 agonist pSTAT5 EC50) x 100), which is >13 and 50. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >14 and 50. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is >15 and 50. A weak agonist of the IL-2 receptor is defined herein as an antigen-binding molecule which is a functional agonist of an IL-2 receptor, but increases signalling mediated by an IL-2 receptor to a lower degree than an intermediate agonist. In other words, a weak agonist of the IL-2 receptor has reduced agonistic effects (compared to an intermediate agonist), but still functions as an agonist.

[0513] A weak agonist of a receptor comprising yc and IL-2R0 is defined herein as an antigen-binding molecule which is a functional agonist of a receptor comprising yc and IL-2R0, but increases signalling mediated by a receptor comprising yc and IL-2R0 to a lower degree than an intermediate agonist. In other words, a weak agonist of a receptor comprising yc and IL-2R0 has reduced agonistic effects (compared to an intermediate agonist), but still functions as an agonist.

[0514] In some embodiments, the weak agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is less than 15. In some embodiments, the weak agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is less than 14. In some embodiments, the weak agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is less than 13. In some embodiments, the weak agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is less than 12. In some embodiments, the weak agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is less than 11 . In some embodiments, the weak agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is less than 10.

[0515] In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table A, B, C, D, E, F, G, H, or I herein.

[0516] By way of example, BS078 is a humanized antibody, and BS008 is the corresponding parental antibody. In other words, BS008 underwent humanization, and this humanization resulted in humanized antibody BS078.

[0517] In some embodiments, the antibody that binds yc is a humanized antibody. In some embodiments, the antibody that binds yc is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody that binds yc is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table A, B, or C herein.

[0518] In some embodiments, the antibody that binds IL-2R0 is a humanized antibody. In some embodiments, the antibody that binds IL-2R0 is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody that binds IL-2R0 is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table D, E, or F herein. In some embodiments, the antibody that binds yc and IL-2R0 is a humanized antibody. In some embodiments, the antibody that binds yc and IL-2R0 is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody that binds yc and IL-2R0 is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table G, H, or I herein.

[0519] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS067, BS068, BS069, BS070, BS071 , BS072, BS073, BS074, BS075, BS076, BS077, BS078, BS079, BS080, BS081 , BS082, BS083, BS084, BS085, BS086, BS087, BS088, BS089, BS090, BS091 , BS092, BS093, and BS094.

[0520] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS078, BS079, BS081 , BS083, BS084, and BS092.

[0521] In some embodiments, the antibody that binds yc and IL-2Rp is BS078. In some embodiments, the antibody that binds yc and IL-2Rp is BS079. In some embodiments, the antibody that binds yc and IL-2R0 is BS081. In some embodiments, the antibody that binds yc and IL-2Rp is BS083. In some embodiments, the antibody that binds yc and IL-2Rp is BS084. In some embodiments, the antibody that binds yc and IL- 2Rp is BS092.

[0522] Exemplary antigen-binding molecules are defined below by reference to their amino acid sequences. It will be appreciated that for antigen-binding molecules and antigen-binding moieties that comprise a heavy chain, but do not comprise a light chain (e.g., a VHH / scAb / nanobody / heavy chain-only antibody), the terms CDR1 , CDR2, and CDR3 are interchangeable with HC-CDR1 , HC-CDR2, and HC-CDR3.

[0523] Additionally, the terms FR1 , FR2, FR3, and FR4 are interchangeable with HC-FR1 , HC-FR2, HC-FR3, and HC-FR4, for antigen-binding molecules and antigen-binding moieties that comprise a heavy chain, but do not comprise a light chain.

[0524] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety.

[0525] In some embodiments, the antigen-binding molecule comprises:

[0526] (1) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0527] HC-CDR1 having the amino acid sequence of SEQ ID NO:267 HC-CDR2 having the amino acid sequence of SEQ ID NO:268 HC-CDR3 having the amino acid sequence of SEQ ID NO:269, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0528] (2) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0529] HC-CDR1 having the amino acid sequence of SEQ ID NQ:270 HC-CDR2 having the amino acid sequence of SEQ ID NO:271 HC-CDR3 having the amino acid sequence of SEQ ID NO:272, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0530] (3) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0531] HC-CDR1 having the amino acid sequence of SEQ ID NO:276

[0532] HC-CDR2 having the amino acid sequence of SEQ ID NO:277

[0533] HC-CDR3 having the amino acid sequence of SEQ ID NO:278, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0534] (4) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0535] HC-CDR1 having the amino acid sequence of SEQ ID NO:273

[0536] HC-CDR2 having the amino acid sequence of SEQ ID NO:274

[0537] HC-CDR3 having the amino acid sequence of SEQ ID NO:275, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0538] (5) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0539] HC-CDR1 having the amino acid sequence of SEQ ID NO:279

[0540] HC-CDR2 having the amino acid sequence of SEQ ID NQ:280

[0541] HC-CDR3 having the amino acid sequence of SEQ ID NO:281 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0542] (6) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0543] HC-CDR1 having the amino acid sequence of SEQ ID NO:279

[0544] HC-CDR2 having the amino acid sequence of SEQ ID NQ:280

[0545] HC-CDR3 having the amino acid sequence of SEQ ID NO:281 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0546] (7) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0547] HC-CDR1 having the amino acid sequence of SEQ ID NO:282 HC-CDR2 having the amino acid sequence of SEQ ID NO:283 HC-CDR3 having the amino acid sequence of SEQ ID NO:284, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0548] (8) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0549] HC-CDR1 having the amino acid sequence of SEQ ID NO:285

[0550] HC-CDR2 having the amino acid sequence of SEQ ID NO:286

[0551] HC-CDR3 having the amino acid sequence of SEQ ID NO:287, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0552] (9) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0553] HC-CDR1 having the amino acid sequence of SEQ ID NO:288

[0554] HC-CDR2 having the amino acid sequence of SEQ ID NO:289

[0555] HC-CDR3 having the amino acid sequence of SEQ ID NQ:290, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0556] (10) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0557] HC-CDR1 having the amino acid sequence of SEQ ID NO:291

[0558] HC-CDR2 having the amino acid sequence of SEQ ID NO:292

[0559] HC-CDR3 having the amino acid sequence of SEQ ID NO:293, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0560] (11) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0561] HC-CDR1 having the amino acid sequence of SEQ ID NO:294

[0562] HC-CDR2 having the amino acid sequence of SEQ ID NO:295

[0563] HC-CDR3 having the amino acid sequence of SEQ ID NO:296, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0564] (12) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0565] HC-CDR1 having the amino acid sequence of SEQ ID NO:297

[0566] HC-CDR2 having the amino acid sequence of SEQ ID NO:298

[0567] HC-CDR3 having the amino acid sequence of SEQ ID NO:299, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0568] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0569] (13) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0570] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0571] HC-FR2 having the amino acid sequence of SEQ ID NQ:400

[0572] HC-FR3 having the amino acid sequence of SEQ ID NO:463

[0573] HC-FR4 having the amino acid sequence of SEQ ID NO:475, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0574] (13.1) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0575] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0576] HC-FR2 having the amino acid sequence of SEQ ID NQ:400

[0577] HC-FR3 having the amino acid sequence of SEQ ID NO:462

[0578] HC-FR4 having the amino acid sequence of SEQ ID NO:475, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0579] (14) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0580] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0581] HC-FR2 having the amino acid sequence of SEQ ID NQ:401

[0582] HC-FR3 having the amino acid sequence of SEQ ID NO:465

[0583] HC-FR4 having the amino acid sequence of SEQ ID NO:473, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0584] (15) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0585] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0586] HC-FR2 having the amino acid sequence of SEQ ID NQ:403

[0587] HC-FR3 having the amino acid sequence of SEQ ID NO:466

[0588] HC-FR4 having the amino acid sequence of SEQ ID NO:474, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid. (16) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0589] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0590] HC-FR2 having the amino acid sequence of SEQ ID NQ:400

[0591] HC-FR3 having the amino acid sequence of SEQ ID NO:425

[0592] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0593] (17) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0594] HC-FR1 having the amino acid sequence of SEQ ID NO:378

[0595] HC-FR2 having the amino acid sequence of SEQ ID NQ:401

[0596] HC-FR3 having the amino acid sequence of SEQ ID NO:426

[0597] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0598] (18) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0599] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[0600] HC-FR2 having the amino acid sequence of SEQ ID NQ:403

[0601] HC-FR3 having the amino acid sequence of SEQ ID NO:428

[0602] HC-FR4 having the amino acid sequence of SEQ ID NO:472, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0603] (19) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0604] HC-FR1 having the amino acid sequence of SEQ ID NO:379

[0605] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0606] HC-FR3 having the amino acid sequence of SEQ ID NO:427

[0607] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0608] (20) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0609] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[0610] HC-FR2 having the amino acid sequence of SEQ ID NO:392

[0611] HC-FR3 having the amino acid sequence of SEQ ID NO:429

[0612] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0613] (21) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0614] HC-FR1 having the amino acid sequence of SEQ ID NO:395

[0615] HC-FR2 having the amino acid sequence of SEQ ID NO:392

[0616] HC-FR3 having the amino acid sequence of SEQ ID NO:429

[0617] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0618] (22) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0619] HC-FR1 having the amino acid sequence of SEQ ID NO:393

[0620] HC-FR2 having the amino acid sequence of SEQ ID NQ:404

[0621] HC-FR3 having the amino acid sequence of SEQ ID NQ:430

[0622] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0623] (23) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0624] HC-FR1 having the amino acid sequence of SEQ ID NO:382

[0625] HC-FR2 having the amino acid sequence of SEQ ID NQ:405

[0626] HC-FR3 having the amino acid sequence of SEQ ID NO:431

[0627] HC-FR4 having the amino acid sequence of SEQ ID NO:484, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0628] (24) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0629] HC-FR1 having the amino acid sequence of SEQ ID NO:394

[0630] HC-FR2 having the amino acid sequence of SEQ ID NQ:406

[0631] HC-FR3 having the amino acid sequence of SEQ ID NO:432

[0632] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0633] (25) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0634] HC-FR1 having the amino acid sequence of SEQ ID NO:377 HC-FR2 having the amino acid sequence of SEQ ID NO:407

[0635] HC-FR3 having the amino acid sequence of SEQ ID NO:433

[0636] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0637] (26) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0638] HC-FR1 having the amino acid sequence of SEQ ID NO:396

[0639] HC-FR2 having the amino acid sequence of SEQ ID NQ:408

[0640] HC-FR3 having the amino acid sequence of SEQ ID NO:434

[0641] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0642] (27) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0643] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0644] HC-FR2 having the amino acid sequence of SEQ ID NQ:405

[0645] HC-FR3 having the amino acid sequence of SEQ ID NO:435

[0646] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0647] (28) In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to (12) above, and the FRs according to any one of (13) to (27) above.

[0648] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region):

[0649] (29) comprising the CDRs according to (1) and the FRs according to (13).

[0650] (30) comprising the CDRs according to (1) and the FRs according to (13.1).

[0651] (31) comprising the CDRs according to (1) and the FRs according to (16).

[0652] (32) comprising the CDRs according to (2) and the FRs according to (14).

[0653] (33) comprising the CDRs according to (2) and the FRs according to (17). (34) comprising the CDRs according to (3) and the FRs according to (18).

[0654] (35) comprising the CDRs according to (3) and the FRs according to (15).

[0655] (36) comprising the CDRs according to (4) and the FRs according to (19).

[0656] (37) comprising the CDRs according to (5) and the FRs according to (20).

[0657] (38) comprising the CDRs according to (6) and the FRs according to (21).

[0658] (39) comprising the CDRs according to (7) and the FRs according to (22).

[0659] (40) comprising the CDRs according to (8) and the FRs according to (23).

[0660] (41) comprising the CDRs according to (9) and the FRs according to (24).

[0661] (42) comprising the CDRs according to (10) and the FRs according to (25).

[0662] (43) comprising the CDRs according to (11) and the FRs according to (26).

[0663] (44) comprising the CDRs according to (12) and the FRs according to (27).

[0664] (45) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:501 , SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178.

[0665] (46) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:501 , SEQ ID NO:476, SEQ ID NO:477, or SEQ ID NO:478.

[0666] (47) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:501. (47.1) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:476.

[0667] (48) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:477.

[0668] (49) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:478.

[0669] In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety.

[0670] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0671] (50) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0672] HC-CDR1 having the amino acid sequence of SEQ ID NQ:303

[0673] HC-CDR2 having the amino acid sequence of SEQ ID NQ:304

[0674] HC-CDR3 having the amino acid sequence of SEQ ID NQ:305, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0675] (51) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0676] HC-CDR1 having the amino acid sequence of SEQ ID NQ:300

[0677] HC-CDR2 having the amino acid sequence of SEQ ID NQ:301

[0678] HC-CDR3 having the amino acid sequence of SEQ ID NQ:302, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0679] (52) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0680] HC-CDR1 having the amino acid sequence of SEQ ID NQ:303

[0681] HC-CDR2 having the amino acid sequence of SEQ ID NO:312

[0682] HC-CDR3 having the amino acid sequence of SEQ ID NO:313, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0683] (53) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0684] HC-CDR1 having the amino acid sequence of SEQ ID NQ:306 HC-CDR2 having the amino acid sequence of SEQ ID NO:307

[0685] HC-CDR3 having the amino acid sequence of SEQ ID NO:308, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0686] (54) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0687] HC-CDR1 having the amino acid sequence of SEQ ID NQ:309

[0688] HC-CDR2 having the amino acid sequence of SEQ ID NQ:310

[0689] HC-CDR3 having the amino acid sequence of SEQ ID NO:311 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0690] (55) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0691] HC-CDR1 having the amino acid sequence of SEQ ID NO:314

[0692] HC-CDR2 having the amino acid sequence of SEQ ID NO:315

[0693] HC-CDR3 having the amino acid sequence of SEQ ID NO:316, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0694] (56) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0695] HC-CDR1 having the amino acid sequence of SEQ ID NO:317

[0696] HC-CDR2 having the amino acid sequence of SEQ ID NO:318

[0697] HC-CDR3 having the amino acid sequence of SEQ ID NO:319, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0698] (57) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0699] HC-CDR1 having the amino acid sequence of SEQ ID NQ:320

[0700] HC-CDR2 having the amino acid sequence of SEQ ID NO:321

[0701] HC-CDR3 having the amino acid sequence of SEQ ID NO:322, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0702] (58) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0703] HC-CDR1 having the amino acid sequence of SEQ ID NO:323 HC-CDR2 having the amino acid sequence of SEQ ID NO:324 HC-CDR3 having the amino acid sequence of SEQ ID NO:325, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0704] (59) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0705] HC-CDR1 having the amino acid sequence of SEQ ID NO:326

[0706] HC-CDR2 having the amino acid sequence of SEQ ID NO:327

[0707] HC-CDR3 having the amino acid sequence of SEQ ID NO:328, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0708] (60) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0709] HC-CDR1 having the amino acid sequence of SEQ ID NO:329

[0710] HC-CDR2 having the amino acid sequence of SEQ ID NQ:330

[0711] HC-CDR3 having the amino acid sequence of SEQ ID NO:331 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0712] (61) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0713] HC-CDR1 having the amino acid sequence of SEQ ID NO:332

[0714] HC-CDR2 having the amino acid sequence of SEQ ID NO:333

[0715] HC-CDR3 having the amino acid sequence of SEQ ID NO:334, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0716] (62) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0717] HC-CDR1 having the amino acid sequence of SEQ ID NO:335

[0718] HC-CDR2 having the amino acid sequence of SEQ ID NO:336

[0719] HC-CDR3 having the amino acid sequence of SEQ ID NO:337, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0720] (63) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0721] HC-CDR1 having the amino acid sequence of SEQ ID NO:338 HC-CDR2 having the amino acid sequence of SEQ ID NO:339 HC-CDR3 having the amino acid sequence of SEQ ID NQ:340, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0722] (64) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0723] HC-CDR1 having the amino acid sequence of SEQ ID NO:341 HC-CDR2 having the amino acid sequence of SEQ ID NO:342 HC-CDR3 having the amino acid sequence of SEQ ID NO:343, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0724] (65) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0725] HC-CDR1 having the amino acid sequence of SEQ ID NO:344

[0726] HC-CDR2 having the amino acid sequence of SEQ ID NO:345

[0727] HC-CDR3 having the amino acid sequence of SEQ ID NO:346, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0728] (66) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0729] HC-CDR1 having the amino acid sequence of SEQ ID NO:347

[0730] HC-CDR2 having the amino acid sequence of SEQ ID NO:348

[0731] HC-CDR3 having the amino acid sequence of SEQ ID NO:349, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0732] (67) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0733] HC-CDR1 having the amino acid sequence of SEQ ID NQ:350

[0734] HC-CDR2 having the amino acid sequence of SEQ ID NO:351

[0735] HC-CDR3 having the amino acid sequence of SEQ ID NO:352, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0736] (68) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0737] HC-CDR1 having the amino acid sequence of SEQ ID NO:353 HC-CDR2 having the amino acid sequence of SEQ ID NO:354 HC-CDR3 having the amino acid sequence of SEQ ID NO:355, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0738] (69) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0739] HC-CDR1 having the amino acid sequence of SEQ ID NO:356

[0740] HC-CDR2 having the amino acid sequence of SEQ ID NO:357

[0741] HC-CDR3 having the amino acid sequence of SEQ ID NO:358, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0742] (70) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0743] HC-CDR1 having the amino acid sequence of SEQ ID NO:359

[0744] HC-CDR2 having the amino acid sequence of SEQ ID NQ:360

[0745] HC-CDR3 having the amino acid sequence of SEQ ID NO:361 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0746] (71) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0747] HC-CDR1 having the amino acid sequence of SEQ ID NO:362

[0748] HC-CDR2 having the amino acid sequence of SEQ ID NO:363

[0749] HC-CDR3 having the amino acid sequence of SEQ ID NO:364, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0750] (72) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0751] HC-CDR1 having the amino acid sequence of SEQ ID NO:365

[0752] HC-CDR2 having the amino acid sequence of SEQ ID NO:366

[0753] HC-CDR3 having the amino acid sequence of SEQ ID NO:367, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0754] (73) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0755] HC-CDR1 having the amino acid sequence of SEQ ID NO:368 HC-CDR2 having the amino acid sequence of SEQ ID NO:369 HC-CDR3 having the amino acid sequence of SEQ ID NQ:370, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0756] (74) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0757] HC-CDR1 having the amino acid sequence of SEQ ID NO:371

[0758] HC-CDR2 having the amino acid sequence of SEQ ID NO:372

[0759] HC-CDR3 having the amino acid sequence of SEQ ID NO:373, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0760] (75) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0761] HC-CDR1 having the amino acid sequence of SEQ ID NO:374

[0762] HC-CDR2 having the amino acid sequence of SEQ ID NO:375

[0763] HC-CDR3 having the amino acid sequence of SEQ ID NO:376, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0764] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0765] (76) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0766] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0767] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0768] HC-FR3 having the amino acid sequence of SEQ ID NO:468

[0769] HC-FR4 having the amino acid sequence of SEQ ID NO:473, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0770] (77) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0771] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0772] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0773] HC-FR3 having the amino acid sequence of SEQ ID NO:464

[0774] HC-FR4 having the amino acid sequence of SEQ ID NO:473, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0775] (78) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0776] HC-FR1 having the amino acid sequence of SEQ ID NO:398 HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0777] HC-FR3 having the amino acid sequence of SEQ ID NO:464

[0778] HC-FR4 having the amino acid sequence of SEQ ID NO:473, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0779] (79) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0780] HC-FR1 having the amino acid sequence of SEQ ID NO:399

[0781] HC-FR2 having the amino acid sequence of SEQ ID NO:467

[0782] HC-FR3 having the amino acid sequence of SEQ ID NO:469

[0783] HC-FR4 having the amino acid sequence of SEQ ID NO:473, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0784] (80) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0785] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0786] HC-FR2 having the amino acid sequence of SEQ ID NQ:410

[0787] HC-FR3 having the amino acid sequence of SEQ ID NQ:470

[0788] HC-FR4 having the amino acid sequence of SEQ ID NO:473, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0789] (81) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0790] HC-FR1 having the amino acid sequence of SEQ ID NO:385

[0791] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0792] HC-FR3 having the amino acid sequence of SEQ ID NO:437

[0793] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0794] (82) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0795] HC-FR1 having the amino acid sequence of SEQ ID NO:383

[0796] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0797] HC-FR3 having the amino acid sequence of SEQ ID NO:436

[0798] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid. (83) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0799] HC-FR1 having the amino acid sequence of SEQ ID NO:385

[0800] HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0801] HC-FR3 having the amino acid sequence of SEQ ID NQ:440

[0802] HC-FR4 having the amino acid sequence of SEQ ID NO: 471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0803] (84) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0804] HC-FR1 having the amino acid sequence of SEQ ID NO:383

[0805] HC-FR2 having the amino acid sequence of SEQ ID NQ:409

[0806] HC-FR3 having the amino acid sequence of SEQ ID NO:438

[0807] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0808] (85) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0809] HC-FR1 having the amino acid sequence of SEQ ID NO:381

[0810] HC-FR2 having the amino acid sequence of SEQ ID NQ:410

[0811] HC-FR3 having the amino acid sequence of SEQ ID NO:439

[0812] HC-FR4 having the amino acid sequence of SEQ ID NO: 471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0813] (86) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0814] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[0815] HC-FR2 having the amino acid sequence of SEQ ID NO:411

[0816] HC-FR3 having the amino acid sequence of SEQ ID NO:441

[0817] HC-FR4 having the amino acid sequence of TV, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0818] (87) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0819] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0820] HC-FR2 having the amino acid sequence of SEQ ID NO:412

[0821] HC-FR3 having the amino acid sequence of SEQ ID NO:442

[0822] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0823] (88) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0824] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0825] HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0826] HC-FR3 having the amino acid sequence of SEQ ID NO:443

[0827] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0828] (89) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0829] HC-FR1 having the amino acid sequence of SEQ ID NO:382

[0830] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0831] HC-FR3 having the amino acid sequence of SEQ ID NO:444

[0832] HC-FR4 having the amino acid sequence of SEQ ID NO:485, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0833] (90) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0834] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0835] HC-FR2 having the amino acid sequence of SEQ ID NQ:410

[0836] HC-FR3 having the amino acid sequence of SEQ ID NO:445

[0837] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0838] (91) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0839] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0840] HC-FR2 having the amino acid sequence of SEQ ID NO:413

[0841] HC-FR3 having the amino acid sequence of SEQ ID NO:446

[0842] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0843] (92) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0844] HC-FR1 having the amino acid sequence of SEQ ID NO:384 HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0845] HC-FR3 having the amino acid sequence of SEQ ID NO:447

[0846] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0847] (93) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0848] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[0849] HC-FR2 having the amino acid sequence of SEQ ID NO:414

[0850] HC-FR3 having the amino acid sequence of SEQ ID NO:448

[0851] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0852] (94) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0853] HC-FR1 having the amino acid sequence of SEQ ID NO:386

[0854] HC-FR2 having the amino acid sequence of SEQ ID NO:415

[0855] HC-FR3 having the amino acid sequence of SEQ ID NO:449

[0856] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0857] (95) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0858] HC-FR1 having the amino acid sequence of SEQ ID NO:387

[0859] HC-FR2 having the amino acid sequence of SEQ ID NO:416

[0860] HC-FR3 having the amino acid sequence of SEQ ID NQ:450

[0861] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0862] (96) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0863] HC-FR1 having the amino acid sequence of SEQ ID NO:388

[0864] HC-FR2 having the amino acid sequence of SEQ ID NO:417

[0865] HC-FR3 having the amino acid sequence of SEQ ID NO:451

[0866] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid. (97) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0867] HC-FR1 having the amino acid sequence of SEQ ID NO:380

[0868] HC-FR2 having the amino acid sequence of SEQ ID NO:418

[0869] HC-FR3 having the amino acid sequence of SEQ ID NO:452

[0870] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0871] (98) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0872] HC-FR1 having the amino acid sequence of SEQ ID NO:387

[0873] HC-FR2 having the amino acid sequence of SEQ ID NO:419

[0874] HC-FR3 having the amino acid sequence of SEQ ID NO:453

[0875] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0876] (99) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0877] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0878] HC-FR2 having the amino acid sequence of SEQ ID NQ:420

[0879] HC-FR3 having the amino acid sequence of SEQ ID NO:454

[0880] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0881] (100) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0882] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[0883] HC-FR2 having the amino acid sequence of SEQ ID NO:421

[0884] HC-FR3 having the amino acid sequence of SEQ ID NO:455

[0885] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0886] (101) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0887] HC-FR1 having the amino acid sequence of SEQ ID NO:389

[0888] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0889] HC-FR3 having the amino acid sequence of SEQ ID NO:456

[0890] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0891] (102) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0892] HC-FR1 having the amino acid sequence of SEQ ID NO:390

[0893] HC-FR2 having the amino acid sequence of SEQ ID NO:422

[0894] HC-FR3 having the amino acid sequence of SEQ ID NO:457

[0895] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0896] (103) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0897] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0898] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0899] HC-FR3 having the amino acid sequence of SEQ ID NO:458

[0900] HC-FR4 having the amino acid sequence of SEQ ID NO: 471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0901] (104) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0902] HC-FR1 having the amino acid sequence of SEQ ID NO:391

[0903] HC-FR2 having the amino acid sequence of SEQ ID NO:423

[0904] HC-FR3 having the amino acid sequence of SEQ ID NO:459

[0905] HC-FR4 having the amino acid sequence of SEQ ID NO: 471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0906] (105) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0907] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0908] HC-FR2 having the amino acid sequence of SEQ ID NO:424

[0909] HC-FR3 having the amino acid sequence of SEQ ID NQ:460

[0910] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0911] (106) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0912] HC-FR1 having the amino acid sequence of SEQ ID NO:377 HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0913] HC-FR3 having the amino acid sequence of SEQ ID NO:461

[0914] HC-FR4 having the amino acid sequence of SEQ ID NO:471 , or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0915] (107) In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (50) to (75) above, and the FRs according to any one of (76) to (106) above.

[0916] In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety (e.g., a VHH, or a VH region):

[0917] (108) comprising the CDRs according to (50) and the FRs according to (76).

[0918] (109) comprising the CDRs according to (50) and the FRs according to (81).

[0919] (110) comprising the CDRs according to (51) and the FRs according to (77).

[0920] (111) comprising the CDRs according to (51) and the FRs according to (82).

[0921] (112) comprising the CDRs according to (52) and the FRs according to (78).

[0922] (113) comprising the CDRs according to (52) and the FRs according to (83).

[0923] (114) comprising the CDRs according to (53) and the FRs according to (79).

[0924] (115) comprising the CDRs according to (53) and the FRs according to (84).

[0925] (116) comprising the CDRs according to (54) and the FRs according to (80).

[0926] (117) comprising the CDRs according to (54) and the FRs according to (85).

[0927] (118) comprising the CDRs according to (55) and the FRs according to (86).

[0928] (119) comprising the CDRs according to (56) and the FRs according to (87).

[0929] (120) comprising the CDRs according to (57) and the FRs according to (88).

[0930] (121) comprising the CDRs according to (58) and the FRs according to (89). (122) comprising the CDRs according to (59) and the FRs according to (90).

[0931] (123) comprising the CDRs according to (60) and the FRs according to (91).

[0932] (124) comprising the CDRs according to (61) and the FRs according to (92).

[0933] (125) comprising the CDRs according to (62) and the FRs according to (93).

[0934] (126) comprising the CDRs according to (63) and the FRs according to (94).

[0935] (127) comprising the CDRs according to (64) and the FRs according to (95).

[0936] (128) comprising the CDRs according to (65) and the FRs according to (96).

[0937] (129) comprising the CDRs according to (66) and the FRs according to (97).

[0938] (130) comprising the CDRs according to (67) and the FRs according to (98).

[0939] (131) comprising the CDRs according to (68) and the FRs according to (99).

[0940] (132) comprising the CDRs according to (69) and the FRs according to (100)

[0941] (133) comprising the CDRs according to (70) and the FRs according to (101)

[0942] (134) comprising the CDRs according to (71) and the FRs according to (102)

[0943] (135) comprising the CDRs according to (72) and the FRs according to (103)

[0944] (136) comprising the CDRs according to (73) and the FRs according to (104)

[0945] (137) comprising the CDRs according to (74) and the FRs according to (105)

[0946] (138) comprising the CDRs according to (75) and the FRs according to (106)

[0947] (139) an IL-2Rp-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID

[0948] NO:479, SEQ ID NO:480, SEQ ID NO:481 , SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:141 , SEQ ID

[0949] NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID

[0950] NO:148, SEQ ID NO:149, SEQ ID NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160, SEQ ID N0:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ ID NO:166.

[0951] (140) an IL-2Rp-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:479, SEQ ID NQ:480, SEQ ID NO:481 , SEQ ID NO:482, or SEQ ID NO:483.

[0952] (141) In some embodiments, the antigen-binding molecule comprises:

[0953] (i) a yc-binding moiety, and

[0954] (ii) an IL-2Rp-binding moiety.

[0955] (142) In some embodiments, the antigen-binding molecule comprises:

[0956] (i) a yc-binding moiety, and

[0957] (ii) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0958] (50) to (75) above.

[0959] (143) In some embodiments, the antigen-binding molecule comprises:

[0960] (i) a yc-binding moiety, and

[0961] (ii) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0962] (50) to (75) above, and the FRs according to any one of (76) to (106) above.

[0963] (144) In some embodiments, the antigen-binding molecule comprises:

[0964] (i) a yc-binding moiety, and

[0965] (ii) an IL-2Rp-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:479, SEQ ID NQ:480, SEQ ID NO:481 , SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID

[0966] NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID

[0967] NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID

[0968] NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID

[0969] NQ:160, SEQ ID NO:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID

[0970] NO:165, or SEQ ID NO:166.

[0971] (145) In some embodiments, the antigen-binding molecule comprises:

[0972] (i) a yc-binding moiety, and

[0973] (ii) an IL-2Rp-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481 , SEQ ID NO:482, or SEQ ID NO:483.

[0974] (146) In some embodiments, the antigen-binding molecule comprises:

[0975] (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[0976] (12) above, and

[0977] (iv) an IL-2Rp-binding moiety.

[0978] (147) In some embodiments, the antigen-binding molecule comprises:

[0979] (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[0980] (12) above, and the FRs according to any one of (13) to (27) above, and

[0981] (iv) an IL-2Rp-binding moiety.

[0982] (148) In some embodiments, the antigen-binding molecule comprises:

[0983] (iii) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:501 , SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178, and

[0984] (iv) an IL-2Rp-binding moiety.

[0985] (149) In some embodiments, the antigen-binding molecule comprises:

[0986] (iii) a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:501 , SEQ ID NO:476, SEQ ID NO:477, or SEQ ID NO:478, and

[0987] (iv) an IL-2Rp-binding moiety.

[0988] (150) In some embodiments, the antigen-binding molecule comprises CDRs according to one of (1) to (12) above, and CDRs according to one of (50) to (75) above.

[0989] (151) In some embodiments, the antigen-binding molecule comprises:

[0990] (v) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[0991] (12) above, and the FRs according to any one of (13) to (27) above, and

[0992] (vi) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0993] (50) to (75) above, and the FRs according to any one of (76) to (106) above.

[0994] In some embodiments, the antigen-binding molecule comprises: a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:501 , SEQ

[0995] ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ

[0996] ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ

[0997] ID NO:176, SEQ ID NO:177, or SEQ ID NO:178, and an IL-2Rp-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:479, SEQ ID NQ:480, SEQ ID NO:481 , SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:141 , SEQ ID NO:142,

[0998] SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148,

[0999] SEQ ID NO:149, SEQ ID NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154,

[1000] SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160,

[1001] SEQ ID NO:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ ID

[1002] NO:166.

[1003] In some embodiments, the antigen-binding molecule comprises: a yc-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:501 , SEQ ID NO:476, SEQ ID NO:477, or SEQ ID NO:478, and an IL-2Rp-binding moiety comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:479, SEQ ID NQ:480, SEQ ID NO:481 , SEQ ID NO:482, or SEQ ID NO:483.

[1004] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:125, SEQ ID NO:124, SEQ ID NO:127, SEQ ID NO:129, SEQ ID NQ:130, SEQ ID NO:138, SEQ ID NQ:140, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ

[1005] ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NQ:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ

[1006] ID NO:123, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ

[1007] ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:139, SEQ ID NO:53, SEQ ID

[1008] NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NOW, SEQ ID NO:61 , SEQ ID NOW, SEQ ID NOW, SEQ ID NO:64, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NO:70, SEQ ID NO:71 , SEQ ID NO:72, SEQ ID NOW, SEQ ID NO:74, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW , SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NO:91 , SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID NOW, SEQ ID N0:100, SEQ ID NO:101 , SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NQ:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NQ:110, SEQ ID N0:111 , and / or SEQ ID NO:112.

[1009] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:125, SEQ ID NO:124, SEQ ID NO:127, SEQ ID NO:129, SEQ ID NQ:130, SEQ ID NO:138, SEQ ID NQ:140, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ

[1010] ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NQ:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ

[1011] ID NO:123, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ

[1012] ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, and / or SEQ ID NO:139.

[1013] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:125, SEQ ID NO:124, SEQ ID NO:127, SEQ ID NO:129, SEQ ID NQ:130, SEQ ID NO:138, and / or SEQ ID NQ:140.

[1014] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:251 , SEQ ID NQ:250, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:256, SEQ ID NO:264, SEQ ID NO:266, SEQ ID NO:239, SEQ ID NQ:240, SEQ ID NO:241 , SEQ ID NO:242, SEQ

[1015] ID NO:243, SEQ ID NO:244, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, SEQ

[1016] ID NO:249, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:259, SEQ

[1017] ID NQ:260, SEQ ID NO:261 , SEQ ID NO:262, SEQ ID NO:263, SEQ ID NO:265, SEQ ID NO:179, SEQ

[1018] ID NQ:180, SEQ ID NO:181 , SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ

[1019] ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NQ:190, SEQ ID NO:191 , SEQ

[1020] ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ

[1021] ID NO:198, SEQ ID NO:199, SEQ ID NQ:200, SEQ ID NQ:201 , SEQ ID NQ:202, SEQ ID NQ:203, SEQ

[1022] ID NQ:204, SEQ ID NQ:205, SEQ ID NQ:206, SEQ ID NQ:207, SEQ ID NQ:208, SEQ ID NQ:209, SEQ

[1023] ID NQ:210, SEQ ID NO:211 , SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ

[1024] ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NQ:220, SEQ ID NO:221 , SEQ

[1025] ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ

[1026] ID NO:228, SEQ ID NO:229, SEQ ID NQ:230, SEQ ID NO:231 , SEQ ID NO:232, SEQ ID NO:233, SEQ

[1027] ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, and / or SEQ ID NO:238.

[1028] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:251 , SEQ ID NQ:250, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:256, SEQ ID NO:264, SEQ ID NO:266, SEQ ID NO:239, SEQ ID NQ:240, SEQ ID NO:241 , SEQ ID NO:242, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, SEQ

[1029] ID NO:249, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:259, SEQ

[1030] ID NO:260, SEQ ID NO:261 , SEQ ID NO:262, SEQ ID NO:263, and / or SEQ ID NO:265.

[1031] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least

[1032] 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:251 , SEQ ID NQ:250, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:256, SEQ ID NO:264, and / or SEQ ID NO:266.

[1033] In embodiments in accordance with the present disclosure, one or more amino acids are substituted with another amino acid. A substitution comprises substitution of an amino acid residue with a non-identical 'replacement' amino acid residue. A replacement amino acid residue of a substitution according to the present disclosure may be a naturally-occurring amino acid residue ( / .e. encoded by the genetic code) which is non-identical to the amino acid residue at the relevant position of the equivalent, unsubstituted amino acid sequence, selected from: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie): leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Vai). In some embodiments, a replacement amino acid may be a non-naturally occurring amino acid residue - i.e. an amino acid residue other than those recited in the preceding sentence. Examples of non-naturally occurring amino acid residues include norleucine, ornithine, norvaline, homoserine, aib, and other amino acid residue analogues such as those described in Ellman, et al., Meth. Enzym. 202 (1991) 301-336.

[1034] In some embodiments, a substitution may be biochemically conservative. In some embodiments, where an amino acid to be substituted is provided in one of rows 1 to 5 of the table below, the replacement amino acid of the substitution is another, non-identical amino acid provided in the same row:

[1035] By way of illustration, in some embodiments wherein substitution is of a Met residue, the replacement amino acid may be selected from Ala, Vai, Leu, lie, Trp, Tyr, Phe and Norleucine.

[1036] In some embodiments, a replacement amino acid in a substitution may have the same side chain polarity as the amino acid residue it replaces. In some embodiments, a replacement amino acid in a substitution may have the same side chain charge (at pH 7.4) as the amino acid residue it replaces:

[1037] That is, in some embodiments, a nonpolar amino acid is substituted with another, non-identical nonpolar amino acid. In some embodiments, a polar amino acid is substituted with another, non-identical polar amino acid. In some embodiments, an acidic polar amino acid is substituted with another, non-identical acidic polar amino acid. In some embodiments, a basic polar amino acid is substituted with another, non- identical basic polar amino acid. In some embodiments, a neutral amino acid is substituted with another, non-identical neutral amino acid. In some embodiments, a positive amino acid is substituted with another, non-identical positive amino acid. In some embodiments, a negative amino acid is substituted with another, non-identical negative amino acid.

[1038] In some embodiments, substitution(s) may be functionally conservative. That is, in some embodiments, the substitution may not affect (or may not substantially affect) one or more functional properties (e.g. target binding) of the antigen-binding molecule comprising the substitution as compared to the equivalent unsubstituted molecule.

[1039] In some embodiments, substitution(s) may prevent / reduce degradation of the antigen-binding molecule.

[1040] Degradation of an antigen-binding molecule may occur during manufacturing, processing, storage, handling and / or administration. The degradation may be physical and / or chemical. Degradation processes, e.g. chemical degradation processes, include oxidation, fragmentation, deamination, isomerisation, hydrolysis, deglycosylation, racemization, disulphide bond breakage and formation, Maillard reaction, and p-elimination.

[1041] Oxidation is one of the most common chemical modifications in monoclonal antibodies and may be induced by reactive oxygen species. Oxidation may occur at cysteine, methionine, tryptophan, tyrosine, lysine and other amino acid residues. Oxidation of amino acid residues may impact protein structure and / or function. In some embodiments, one or more amino acids are substituted with another amino acid to remove an oxidation site. In some embodiments, one or more amino acids susceptible to oxidation are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptible to oxidation). In some embodiments, one or more amino acids identified as being oxidised, or identified as being susceptible to oxidation, are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptible to oxidation).

[1042] Amino acid residues susceptible to oxidation may be identified e.g. by in silica methods (e.g. as reviewed in Vatsa S, Mabs, 2022, 14(1):2023938, which is hereby incorporated by reference in its entirety) or by forced oxidation assays (e.g. as reviewed in Nowak C et al, Mabs, 2017, 9(8):1217-1230, and Dyck YFK et al, Bioengineering (Basel), 2019, 6(3):62, which are hereby incorporated by reference in their entirety).

[1043] The VH and VL region of an antigen-binding region of an antibody together constitute the Fv region. In some embodiments, the antigen-binding molecule according to the present disclosure comprises, or consists of, an Fv region that binds to yc and / or IL-2Rp. In some embodiments, the VH and VL regions of the Fv are provided as single polypeptide joined by a linker sequence, i.e. a single chain Fv (scFv).

[1044] The VL and light chain constant (CL) region, and the VH region and heavy chain constant 1 (CH1) region of an antigen-binding region of an antibody together constitute the Fab region. In some embodiments, the antigen-binding molecule comprises a Fab region comprising a VH, a CH1 , a VL and a CL (e.g. CK or CA). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CH1 (e.g. a VH-CH1 fusion polypeptide), and a polypeptide comprising a VL and a CL (e.g. a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CL (e.g. a VH-CL fusion polypeptide) and a polypeptide comprising a VL and a CH (e.g. a VL-CH1 fusion polypeptide); that is, in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1 , VL and CL regions of the Fab or CrossFab are provided as single polypeptide joined by linker regions, i.e. as a single chain Fab (scFab) or a single chain CrossFab (scCrossFab).

[1045] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, a whole antibody that binds to that binds to yc and / or IL-2R0. As used herein, ‘whole antibody’ refers to an antibody having a structure which is substantially similar to the structure of an immunoglobulin (Ig). Different kinds of immunoglobulins and their structures are described e.g. in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202): S41-S52, which is hereby incorporated by reference in its entirety. Immunoglobulins of type G ( / .e. IgG) are -150 kDa glycoproteins comprising two heavy chains and two light chains. From N- to C-terminus, the heavy chains comprise a VH followed by a heavy chain constant region comprising three constant domains (CH1 , CH2, and CH3), and similarly the light chains comprise a VL followed by a CL. Depending on the heavy chain, immunoglobulins may be classed as IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM. The light chain may be kappa (K) or lambda (A).

[1046] Herein, a ‘CH2 domain’ refers to an amino acid sequence corresponding to the CH2 domain of an immunoglobulin (Ig). The CH2 domain is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant domain, according to the EU numbering system (described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85). A ‘CH3 domain’ refers to an amino acid sequence corresponding to the CH3 domain of an immunoglobulin (Ig). The CH3 domain is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant domain, according to the EU numbering system. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 domains of an immunoglobulin (Ig). The CH2-CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant domain, according to the EU numbering system.

[1047] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, an IgG that binds to that binds to yc and / or

[1048] In some embodiments, the antigen-binding molecule of the present disclosure comprises one or more regions (e.g. CH1 , CH2, CH3, etc.) of an immunoglobulin heavy chain constant sequence. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. Ig A1 , lgA2), IgD, IgE or IgM, e.g. a human IgG (e.g. hlgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlg E or hlgM. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of a human lgG1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17).

[1049] In some embodiments, the antigen-binding molecule is or comprises a monoclonal antibody, or an antigen-binding fragment thereof. In some embodiments, the antigen-binding molecule is or comprises a VHH.

[1050] In some embodiments, the antigen-binding molecule is or comprises a fully human antibody / antibody fragment. A fully human antibody / antibody fragment may be encoded by human nucleic acid sequence(s). A fully human antibody / antibody fragment may be devoid of non-human amino acid sequences. Commonly employed techniques for the production of fully human antibodies include (i) phage display, in which human antibody genes are expressed in phage display libraries, and (ii) production of antibodies in transgenic mice engineered to have human antibody genes (described in Park and Smolen, Advances in Protein Chemistry (2001) 56: 369-421). Briefly, in the human antibody genephage display technique, genes encoding the VH and VL chains are generated by PCR amplification and cloning from ‘naive’ human lymphocytes, and assembled into a library from which they can be expressed either as disulfide-linked Fab fragments or as single-chain Fv (scFv) fragments. The Fab- or scFv- encoding genes are fused to a surface coat protein of filamentous bacteriophage and Fab or scFv capable of binding to the target of interest can then be identified by screening the library with antigen. Molecular evolution or affinity maturation procedures can be employed to enhance the affinity of the Fab / scFv fragment. In the transgenic mouse technique, mice in which the endogenous murine Ig gene loci have been replaced by homologous recombination with their human homologues are immunised with antigen, and monoclonal antibody is prepared by conventional hybridoma technology, to yield a fully human monoclonal antibody.

[1051] In some embodiments, the antigen-binding molecule of the present disclosure comprises, or consists of, a camelid antibody / antibody fragment. In some embodiments, the antigen-binding molecule of the present disclosure comprises, or consists of, a llama antibody / antibody fragment. In some embodiments, the antigen-binding molecule of the present disclosure comprises, or consists of, a mouse antibody / antibody fragment. In some embodiments, the antibody / antibody fragment is obtained from phage display using a human naive antibody gene library.

[1052] In some embodiments, the antigen-binding molecule is a camelid / human chimeric antigen-binding molecule ( / .e. an antigen-binding molecule comprising camelid antibody variable domains and human antibody constant regions). In some embodiments, the antigen-binding molecule is a llama / human chimeric antigen-binding molecule ( / .e. an antigen-binding molecule comprising llama antibody variable domains and human antibody constant regions). In some embodiments, the antigen-binding molecule is a mouse / human chimeric antigen-binding molecule ( / .e. an antigen-binding molecule comprising mouse antibody variable domains and human antibody constant regions).

[1053] In some embodiments, the antigen-binding molecule is a humanised antigen-binding molecule.

[1054] In some embodiments, the antigen-binding molecule is a humanised antigen-binding molecule comprising non-human animal antibody variable domains. In some embodiments, the antigen-binding molecule comprises non-human animal antibody CDRs and human antibody framework regions. In some embodiments, the antigen-binding molecule comprises camelid antibody CDRs and human antibody framework regions. In some embodiments, the antigen-binding molecule comprises llama antibody CDRs and human antibody framework regions. In some embodiments, the antigen-binding molecule comprises mouse antibody CDRs and human antibody framework regions.

[1055] In some embodiments, the antibody is a humanised VHH antibody. In some embodiments, the antibody is a humanized multispecific antibody. In some embodiments, the antibody is a multispecific antibody comprising a humanized VHH.

[1056] In some embodiments, VHH antibodies are humanized according to methods known in the art (e.g., Rossotti et al. FEBS J. 2022 Jul;289(14):4304-4327, and Lin et al PLoS One. 2021 Jul 23;16(7):e0254944). In some embodiments, camelid VHH antibodies are humanized according to methods known in the art Back mutations on four residues in the FR2 region (Kabat numbering: 37, 44, 45, and 47) can improve the stability of VHH molecules (Rossotti et al. FEBS J. 2022 Jul;289(14):4304-4327).

[1057] In some embodiments, a back mutation to a residue in the FR2 region is performed. In some embodiments, back mutations to two residues in the FR2 region is performed. In some embodiments, back mutations to three residues in the FR2 region is performed. In some embodiments, back mutations to four residues in the FR2 region is performed. In some embodiments, the back mutation is performed at position 37, 44, 45, and / or 47 of the FR2 region (Kabat numbering). In some embodiments, back mutations are performed at positions 37, 44, 45, and 47 of the FR2 region (Kabat numbering).

[1058] In some embodiments, the humanized VHH comprises a mutation in the FR2 region, compared to the camelid VHH sequence. In some embodiments, the humanized VHH comprises two mutations in the FR2 region, compared to the camelid VHH sequence. In some embodiments, the humanized VHH comprises three mutations in the FR2 region, compared to the camelid VHH sequence. In some embodiments, the humanized VHH comprises four mutations in the FR2 region, compared to the camelid VHH sequence. In some embodiments, the mutation is at positions 37, 44, 45, and / or 47 of the FR2 region (Kabat numbering). In some embodiments, the humanized VHH comprises four mutations at positions 37, 44, 45, and / or 47 of the FR2 region (Kabat numbering).

[1059] Immunogenicity can be reduced by including an alanine residue as the final residue of a VHH antibody (Lin ef a / PLoS One. 2021 Jul 23;16(7):e0254944).

[1060] In some embodiments, the humanized VHH comprises a mutation to its final amino acid residue. In some embodiments, the humanized VHH comprises an alanine as its final amino acid residue. In some embodiments, the humanized VHH comprises an alanine at the C-terminus.

[1061] Mouse / human chimeric antigen-binding molecules can be prepared from mouse antibodies by the process of chimerization, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 8 thereof, in particular section 3 of Chapter 8.

[1062] Humanised antigen-binding molecules can be prepared from non-human antibodies by the process of humanisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 7 thereof, in particular section 3.1 of Chapter 7 entitled ‘Antibody Humanization’. Techniques for antibody humanisation are also described e.g. in Safdari et al., Biotechnol Genet Eng Rev (2013) 29:175- 86.

[1063] Aspects of the present disclosure relate to multispecific antigen-binding molecules. By ‘multispecific’ it is meant that the antigen-binding molecule displays specific binding to more than one target. In some embodiments, the antigen-binding molecule is a bispecific antigen-binding molecule. In some embodiments, the antigen-binding molecule comprises at least two different antigen-binding domains ( / .e. at least two antigen-binding domains, e.g. comprising two non-identical VHH molecules).

[1064] In some embodiments, the antigen-binding molecule binds to yc and another target (e.g. an antigen other than yc), and so is at least bispecific.

[1065] In some embodiments, the antigen-binding molecule binds to IL-2Rp and another target (e.g. an antigen other than I L-2Rp) , and so is at least bispecific.

[1066] The term ‘bispecific’ means that the antigen-binding molecule is able to bind specifically to at least two distinct antigenic determinants.

[1067] It will be appreciated that an antigen-binding molecule according to the present disclosure (e.g. a multispecific antigen-binding molecule) may comprise antigen-binding molecules capable of binding to the targets for which the antigen-binding molecule is specific. For example, an antigen-binding molecule that binds to yc and an antigen other than yc may comprise: (i) an antigen-binding molecule that binds to yc, and (ii) an antigen-binding molecule that binds to an antigen other than yc. An antigen-binding molecule that binds to IL-2Rp and an antigen other than IL-2Rp may comprise: (i) an antigen-binding molecule that binds to I L-2Rp, and (ii) an antigen-binding molecule that binds to an antigen other than IL-2Rp.

[1068] It will also be appreciated that an antigen-binding molecule according to the present disclosure (e.g. a multispecific antigen-binding molecule) may comprise antigen-binding polypeptides or antigen-binding polypeptide complexes capable of binding to the targets for which the antigen-binding molecule is specific.

[1069] In some embodiments, a component antigen-binding molecule of a larger antigen-binding molecule (e.g. a multispecific antigen-binding molecule) may be referred to e.g. as an ‘antigen-binding moiety, ‘antigenbinding domain’ or ‘antigen-binding region’ of the larger antigen-binding molecule.

[1070] In some embodiments, the antigen-binding molecule is an immune cell engager. Immune cell engagers are reviewed e.g. in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17: 418-434 and Ellerman, Methods (2019) 154:102-117, both of which are hereby incorporated by reference in their entirety.

[1071] Immune cell engager molecules comprise an antigen-binding region for a target antigen of interest, and an antigen-binding region for recruiting / engaging an immune cell of interest. Immune cell engagers recruit / engage immune cells through an antigen-binding region specific for an immune cell surface molecule.

[1072] Multispecific antigen-binding molecules according to the present disclosure may be provided in any suitable format, such as those formats described in described in Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212, which is hereby incorporated by reference in its entirety. Suitable formats include those shown in Figure 2 of Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212: antibody conjugates, e.g. lgG2, F(ab’)2 or CovX-Body; IgG or IgG-like molecules, e.g. IgG, chimeric IgG, KA-body common HC; CH1 / CL fusion proteins, e.g. scFv2-CH1 / CL, VHH2-CH1 / CL; ‘variable domain only’ bispecific antigenbinding molecules, e.g. tandem scFv (taFV), triplebodies, diabodies (Db), dsDb, Db(kih), DART, scDB, dsFv-dsFv, tandAbs, triple heads, tandem VHH-VHH (tandem VHH / tandem nanobody / tandem sdAb), tertravalent dAb.VHH; Non-lg fusion proteins, e.g. scFv2-albumin, scDb-albumin, taFv-albumin, taFv- toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-lgG-cytokine2, ImmTAC (TCR-scFv); modified Fc and CH3 fusion proteins, e.g. scFv-Fc(kih), scFv-Fc(CH3 charge pairs), scFv-Fc (EW-RVT), scFv-fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc(kih), scFv-Fc(kih)-Fv, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab- scFv-Fc(BEAT), Fab-scFv-Fc (SEEDbody), DART-Fc, scFv-CH3(kih), TriFabs; Fc fusions, e.g. Di- diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-lg, scFv2-Fcab; CH3 fusions, e.g. Dia-diabody, scDb-CH3; IgE / IgM CH2 fusions, e.g. scFv-EHD2-scFv, scFvMHD2-scFv; Fab fusion proteins, e.g. Fab-scFv (bibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, orthogonal Fab-Fab; non-lg fusion proteins, e.g. DNL-Fabs, DNL-Fab2-scFv, DNL-Fab2-lgG-cytokine2; asymmetric IgG or IgG- like molecules, e.g. IgG(kih), IgG(kih) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMab, CrossMab(kih), scFab-lgG(kih), Fab-scFab-lgG(kih), orthogonal Fab IgG(kih), DuetMab, CH3 charge pairs + CH1 / CL charge pairs, hinge / CH3 charge pairs, SEED-body, Duobody, four-in-one- CrossMab(kih), LUZ-Y common LC; LUZ-Y scFab-IgG, FcFc*; appended and Fc-modified IgGs, e.g. lgG(kih)-Fv, IgG HA-TF-Fv, lgG(kih)scFab, scFab-Fc(kih)-scFv2, scFab-Fc(kih)-scFv, half DVD-lg, DVI-lg (four-in-one), CrossMab-Fab; modified Fc and CH3 fusion proteins, e.g. Fab-Fc(kih)-scFv, Fab-scFv- Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc-SEEDbody, TriFab; appended IgGs - HC fusions, e.g. IgG-HC, scFv, IgG-dAb, IgG-taFV, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaCp) Fab, scFv-HC-IgG, tandem Fab-IgG (orthogonal Fab), Fab-lgG(CaCp Fab), Fab-lgG(CR3), Fab-hinge-lgG(CR3); appended IgGs - LC fusions, e.g. IgG-scFv(LC), scFv(LC)-lgG, dAb-IgG; appended IgGs - HC and LC fusions, e.g. DVD- lg, TVD-lg, CODV-lg, scFv4-lgG, Zybody; Fc fusions, e.g. Fab-scFv-Fc, scFv4-lg; F(ab’)2 fusions, e.g. F(ab’)2-scFv2; CH1 / CL fusion proteins e.g. scFv2-CH1-hinge / CL; modified IgGs, e.g. DAF (two-in one- IgG), DutaMab, Mab2; and non-lg fusions, e.g. DNL-Fab4-lgG. The skilled person is readily able to design and produce multispecific antigen-binding molecules.

[1073] In some embodiments, the antigen binding molecule comprises a binding moiety that binds to yc, and a binding moiety that binds to IL-2R0.

[1074] In some embodiments, the antigen binding molecule comprises a first binding moiety, and a second binding moiety. In some embodiments, the antigen binding molecule comprises a first binding moiety that binds to yc, and a second binding moiety that binds to IL-2R0.

[1075] In some embodiments, the antigen binding molecule comprises a binding moiety that binds to yc, and a binding moiety that binds to a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R0, IL- 2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra). In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety. In some embodiments, the antigen-binding molecule comprises an IL-2Ra-binding moiety. In some embodiments, the antigen-binding molecule comprises an IL-15Ra- binding moiety. In some embodiments, the antigen-binding molecule comprises an IL-4Ra-binding moiety. In some embodiments, the antigen-binding molecule comprises an IL-9Ra-binding moiety. In some embodiments, the antigen-binding molecule comprises an IL-21 Ra-binding moiety. In some embodiments, the antigen-binding molecule comprises an IL-7Ra-binding moiety.

[1076] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to yc. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to yc. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to yc. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to yc. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to yc. In some embodiments, the antigen-binding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to yc. Antibodies that bind to yc include e.g. REGN7257 (described in e.g. Floch et al., Hemasphere. (2022) 6(Suppl):694-695), TUGh4 (described in e.g. Ishii etal. Int Immunol. (1994) 6(8):1273-1277) and 3E12 (described in e.g. He et al. Proc Natl Acad Sci USA. (1995) 92(12):5689- 5693). The VHH antibody nb6 has also been shown to bind to yc ((Yen et al., Cell. 2022; 185(8): 1414— 1430).

[1077] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-2R0. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-2R0. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-2R0. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-2R0. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-2R0. In some embodiments, the antigenbinding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-2R0. Antibodies that bind to IL-2R0 include e.g. Mikpl (described in e.g. Tsudo et al. Proc Natl Acad Sci USA. (1989) 86(6):1982-1986), TM-p1 (described in e.g. Tanaka et al. J Immunol. (1991) 147(7):2222-2228) and TU27 (described in e.g. Takeshita et al. J Exp Med. (1989) 169(4):1323-1332).

[1078] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-2Ra. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-2Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-2Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-2Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-2Ra. In some embodiments, the antigenbinding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-2Ra. Antibodies that bind to IL-2Ra include e.g. Daclizumab (described in e.g. Vincenti et al. N Engl J Med. (1998) 338(3):161-165; DrugBank Acc. No. DB00111), Basiliximab (described in e.g. Kapic et al. Med Arh. (2004) 58(6):373-376; DrugBank Acc. No. DB00074), and 7G7 / B6 (described in e.g. Rubin et al. Hybridoma (1985) 4(2):91-102).

[1079] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-15Ra. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-15Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-15Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-15Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-15Ra. In some embodiments, the antigen-binding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-15Ra. Antibodies that bind to IL-15Ra include e.g. JM7A4 (described in e.g. Dubois etal. Immunity (2002) 17(5):537-547).

[1080] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-4Ra. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-4Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-4Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-4Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-4Ra. In some embodiments, the antigenbinding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-4Ra. Antibodies that bind to IL-4Ra include e.g. Dupilumab (also known as SAR231893 and REGN668, described in e.g. Wenzel et al. N Engl J Med. (2013) 368(26):2455-2466; DrugBank Acc. No. DB12159) and 4R34.1.1 (described in e.g. Kim et al., Sci Rep. (2019) 9(1):7772).

[1081] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-9Ra. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-9Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-9Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-9Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-9Ra. In some embodiments, the antigenbinding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-9Ra. Antibodies that bind to IL-9Ra include e.g. RZ-66 (described in e.g. Takatsuka et al., Nature Immunology. (2018) 19(9):1025-1034) and AH9R7 (described in e.g. Smedt et al. J Immunol. (2000) 164(4):1761-1767).

[1082] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-21 Rci. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-21 Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-21 Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-21 Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-21 Ra. In some embodiments, the antigen-binding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-21 Ra. Antibodies that bind to IL-21 Ra include e.g. ATR- 107 (described in e.g. Hua et al., J Clin Pharmacol. (2014) 54(1):14-22) and 4A9 (described in e.g. Jin and Malek. J Leukoc Biol. (2006) 80(6):1416-1423). In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-7Ra. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-7Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-7Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-7Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-7Ra. In some embodiments, the antigenbinding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-7Ra. Antibodies that bind to IL-7Ra include e.g. Lusvertikimab (OSE-127; described in e.g. Belarif et al, Nature Communications 9, 4483. 2018), RN168 (PF-06342674; described in e.g. Herold et al., JCI Insight. 2019 Dec 19; 4(24): e126054), 4A10 (described in e.g. Hixon et al, Leukemia. 2020 Jan; 34(1): 35-49), GSK2618960 (described in e.g. Ellis et al., Br J Clin Pharmacol. (2019) 85(2):304-315), B12 (described in e.g. Akkapeddi et al., Leukemia. (2019) 33(9);2155-2168) and A7R34 (described in e.g. Sudo et al., Proc Natl Acad Sci USA. (1993) 90(19):9125-9129).

[1083] In some embodiments, a first binding moiety comprises a VHH. In some embodiments, a second binding moiety comprises a VHH. In some embodiments, the first binding moiety comprises a VHH molecule and the second binding moiety comprises a VHH molecule.

[1084] In some embodiments, the VHH binds to yc. In some embodiments, the VHH binds to IL-2R0. In some embodiments, the antigen binding molecule comprises a VHH that binds to yc and a VHH that binds to IL- 2Rp.

[1085] A used herein, a ‘VHH’ may alternatively be described as a ‘VHH molecule’, ‘VHH antibody’, ‘VHH antibody fragment’, ‘single domain antibody’, ‘sdAb’, ‘nanobody’, or any other alternative pseudonym which is known in the art.

[1086] In some embodiments, the antigen-binding molecule is multispecific. By ‘multispecific’ it is meant that the antigen-binding molecule binds to more than one target. In some embodiments, the antigen-binding molecule binds to (i) yc, and (ii) IL-2R0. In some embodiments, the antigen-binding molecule binds to (i) yc, and (ii) a polypeptide of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R0, IL- 2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra). It will be appreciated that a multispecific antigenbinding molecule is at least bispecific. The term ‘bispecific’ means that the antigen-binding molecule binds to at least two, distinct antigenic determinants. In some embodiments, the antigen-binding molecule is bispecific, trispecific, tetraspecific, pentaspecific, hexaspecific, heptaspecific, octaspecific, nonaspecific or decaspecific.

[1087] In some embodiments, the multispecific antigen-binding molecule displays at least monovalent binding with respect to yc and / or IL-2R0. In some embodiments, the multispecific antigen-binding molecule displays monovalent binding to more than one antigen. Binding valency refers to the number of binding sites in an antigen-binding molecule for a given antigenic determinant. For example, bispecific antigenbinding molecules in are described herein, which display monovalent binding to yc, and monovalent binding to IL-2R0. Multispecific antigen-binding molecules according to the present disclosure may be provided in any suitable format, such as those formats described in Kontermann, MAbs. (2012) 4(2):182-197, which is hereby incorporated by reference in its entirety. For example, an antigen-binding molecule according to the present disclosure may be a bispecific antibody conjugate (e.g. an lgG2, F(ab’)2 or CovX-Body), a bispecific IgG or IgG-like molecule (e.g. an IgG, scFv4-lg, IgG-scFv, scFv-IgG, DVD-lg, IgG-sVD, sVD- IgG, 2 in 1 -IgG , mAb2, or Tandemab common LC), an asymmetric bispecific IgG or IgG-like molecule (e.g. a kih IgG, kih IgG common LC, CrossMab, kih IgG-scFab, mAb-Fv, charge pair or SEED-body), a small bispecific antibody molecule (e.g. a Diabody (Db), dsDb, DART, scDb, tandAbs, tandem VHH-VHH, tandem scFv-scFv (taFv), triple body, triple head, Fab-scFv, or F(ab’)2-scFv2), a bispecific Fc and CH3 fusion protein (e.g. a taFv-Fc, Di-diabody, scDb-CH3, scFv-Fc-scFv, HCAb-VHH, scFv-kih-Fc, or scFv- kih-CH3), or a bispecific fusion protein (e.g. a scFv2-albumin, scDb-albumin, taFv-toxin, DNL-Fab3, DNL- Fab4-lgG, DNL-Fab4-lgG-cytokine2). See in particular Figure 2 of Kontermann, MAbs. (2012) 4(2):182- 19. See also Brinkmann and Kontermann, MAbs. (2017) 9(2):182-212 (hereby incorporated by reference in its entirety), in particular Figure 2.

[1088] In some embodiments, the multispecific antigen-binding molecule is minimalistic bispecific antibody, such as a tandem VHH-VHH, tandem scFV-VHH, a tandem VHH-scFv, or a tandem scFV-scFv antibody.

[1089] In some embodiments, the multispecific antigen-binding molecule is provided in a tandem VHH-VHH format.

[1090] A tandem multispecific antigen-binding molecule (e.g., a tandem scFv) comprises two (or more) binding moieties (e.g., scFv and / or VHH moieties) and a linker. In some embodiments, the multispecific antigenbinding molecule is provided in a tandem format, where binding moieties are joined by a linker. Examples of tandem format antigen binding molecules include tandem VHH-VHH, scFV-scFv, tandem scFv-VHH, and tandem VHH-scFv. In some embodiments, the multispecific antigen-binding molecule is provided in a tandem VHH format, such as tandem VHH-VHH. In some embodiments, the multispecific antigen-binding molecule is provided in a tandem scFv format, such as tandem scFv-scFv. In some embodiments, the multispecific antigen-binding molecule is provided in a tandem VHH-scFV format. In some embodiments, the multispecific antigen-binding molecule is provided in a tandem scFV-VHH format.

[1091] Binding moieties can be joined by a linker, and different binding moieties can be combined in multiple different ways. By way of example, bispecific antibodies in the tandem VHH-VHH format, comprising a IL- 2Rp-binding VHH moiety and a yc-binding VHH moiety, may be provided in the beta-to-gamma forward orientation or the gamma-to-beta reverse orientation.

[1092] The beta-to-gamma (p-y) forward orientation includes an N-terminal IL-2Rp-binding VHH and a C- terminal yc-binding VHH, wherein the IL-2Rp-binding VHH is joined via a linker from its C-terminus to the N-terminus of an yc-binding VHH.

[1093] The following example shows the format of a bispecific antibody in the p-y forward orientation: N-[l L-2Rp-binding VHH]-L / A / KE / ?-[yc-binding VHH]-C

[1094] The gamma-to-beta (y-p) reverse orientation includes an N-terminal yc-binding VHH and a C-terminal IL- 2Rp-binding VHH, wherein the yc-binding VHH is joined via a linker from its C-terminus to the N-terminus of an IL-2Rp-binding VHH.

[1095] The following example shows the format of a bispecific antibody in the y-p reverse orientation:

[1096] N-[yc-binding VHH]- LINKER -[IL-2Rp-binding VHH]-C

[1097] In some embodiments, the multispecific antigen-binding molecule comprises a linker between binding moieties, for example, a linker between a yc-binding moiety and an IL-2Rp-binding moiety. Such linkers are described by Brinkmann and Kontermann (MAbs. (2017) 9(2):182-212), which is hereby incorporated by reference in its entirety. In some embodiments, the linker is a linker described in Brinkmann and Kontermann (MAbs. (2017) 9(2):182-212).

[1098] In some embodiments, the linker is an amino acid linker. In some embodiments, the linker is a flexible linker. In some embodiments, the linker is a rigid linker. In some embodiments, the linker is a short flexible linker. In some embodiments, the linker is a long rigid linker. In some embodiments, the linker is a linker described herein.

[1099] In some embodiments, the linker has a length of at least 2 amino acids.

[1100] In some embodiments, the linker has a maximum length of 50 amino acids. In some embodiments, the linker has a minimum length of one of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, or 49 amino acids.

[1101] In some embodiments, the linker has a maximum length of one of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids.

[1102] In some embodiments, the linker has a length between 2 and 50 amino acids, 3 and 50 amino acids, 4 and 50 amino acids, 5 and 50 amino acids, 6 and 50 amino acids, 7 and 50 amino acids, 8 and 50 amino acids, 9 and 50 amino acids, 10 and 50 amino acids, 1 1 and 50 amino acids, 12 and 50 amino acids, 13 and 50 amino acids, 14 and 50 amino acids, 15 and 50 amino acids, 16 and 50 amino acids, 17 and 50 amino acids, 18 and 50 amino acids, 19 and 50 amino acids, or 20 and 50 amino acids.

[1103] In some embodiments, the linker has a length between 2 and 40 amino acids, 3 and 40 amino acids, 4 and 40 amino acids, 5 and 40 amino acids, 6 and 40 amino acids, 7 and 50 amino acids, 8 and 40 amino acids, 9 and 40 amino acids, 10 and 40 amino acids, 1 1 and 40 amino acids, 12 and 40 amino acids, 13 and 40 amino acids, 14 and 40 amino acids, 15 and 40 amino acids, 16 and 40 amino acids, 17 and 40 amino acids, 18 and 40 amino acids, 19 and 40 amino acids, or 20 and 40 amino acids.

[1104] In some embodiments, the linker has a length between 2 and 30 amino acids, 3 and 30 amino acids, 4 and 30 amino acids, 5 and 30 amino acids, 6 and 30 amino acids, 7 and 30 amino acids, 8 and 30 amino acids, 9 and 30 amino acids, 10 and 30 amino acids, 11 and 30 amino acids, 12 and 30 amino acids, 13 and 30 amino acids, 14 and 30 amino acids, 15 and 30 amino acids, 16 and 30 amino acids, 17 and 30 amino acids, 18 and 30 amino acids, 19 and 30 amino acids, or 20 and 30 amino acids.

[1105] In some embodiments, the linker has a length between 2 and 20 amino acids, 3 and 20 amino acids, 4 and 20 amino acids, 5 and 20 amino acids, 6 and 20 amino acids, 7 and 20 amino acids, 8 and 20 amino acids, 9 and 20 amino acids, 10 and 20 amino acids, 11 and 20 amino acids, 12 and 20 amino acids, 13 and 20 amino acids, 14 and 20 amino acids, 15 and 20 amino acids, 16 and 20 amino acids, 17 and 20 amino acids, 18 and 20 amino acids, or 19 and 20 amino acids.

[1106] In some embodiments, the linker has a length between 2 and 4 amino acids, 3 and 4 amino acids, 3 and 5 amino acids, 3 and 6 amino acids, 3 and 7 amino acids, 3 and 8 amino acids, 3 and 9 amino acids, 3 and 10 amino acids, 3 and 11 amino acids, 3 and 12 amino acids, 3 and 13 amino acids, 3 and 14 amino acids, 3 and 15 amino acids, 3 and 16 amino acids, 3 and 17 amino acids, 3 and 18 amino acids, 3 and 19 amino acids, or 3 and 20 amino acids.

[1107] In some embodiments, a flexible linker has a length between 2 and 12 amino acids. In some embodiments, a short flexible linker has a length between 2 and 10 amino acids. In some embodiments, a short flexible linker has a length between 2 and 8 amino acids. In some embodiments, a short flexible linker has a length between 2 and 6 amino acids.

[1108] In some embodiments, a rigid linker has a length between 10 and 44 amino acids. In some embodiments, a long rigid linker has a length between 12 and 44 amino acids. In some embodiments, a long rigid linker has a length between 17 and 44 amino acids. In some embodiments, a long rigid linker has a length between 22 and 44 amino acids. In some embodiments, a long rigid linker has a length between 27 and 44 amino acids.

[1109] Methods for producing multispecific antigen-binding molecules include chemical crosslinking of antigenbinding molecules or antibody fragments, e.g. with reducible disulphide or non-reducible thioether bonds, for example as described in Segal and Bast, (2001) Current Protocols in Immunology. Chapter 2:2.13.1- 2.13.16, which is hereby incorporated by reference in its entirety. For example, N-succinimidyl-3-(-2- pyridyldithio)-propionate (SPDP) can be used to chemically crosslink e.g. Fab fragments via hinge region SH- groups, to create disu Ifide-linked bispecific F(ab)2 heterodimers.

[1110] Other methods for producing multispecific antigen-binding molecules include fusing antibody-producing hybridomas e.g. with polyethylene glycol, to produce a quadroma cell capable of secreting bispecific antibody, for example as described in Segal and Bast, (2001) Current Protocols in Immunology. Chapter 2:2.13.1-2.13.16.

[1111] Multispecific antigen-binding molecules according to the present disclosure can also be produced recombinantly, by expression from e.g. a nucleic acid construct encoding polypeptides for the antigenbinding molecules, for example as described in Hornig and Farber-Schwarz, Methods Mol Biol. (2012) 907:713-27, or French, Methods Mol Med. (2000) 40:333-339, the entire contents of both of which are hereby incorporated by reference.

[1112] For example, a DNA construct encoding the light and heavy chain variable domains for the two antigenbinding fragments (i.e. the light and heavy chain variable domains for the antigen-binding fragment capable of binding yc, and the light and heavy chain variable domains for the antigen-binding fragment capable of binding to another target protein), and including sequences encoding a suitable linker or dimerization domain between the antigen-binding fragments can be prepared by molecular cloning techniques. Recombinant bispecific antibody can thereafter be produced by expression (e.g. in vitro) of the construct in a suitable host cell (e.g. a mammalian host cell), and expressed recombinant bispecific antibody can then optionally be purified.

[1113] The present disclosure also provides Chimeric Antigen Receptors (CARs). CARs are recombinant receptors that provide both antigen-binding and T cell activating functions. CAR structure and engineering is reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1), hereby incorporated by reference in its entirety. CARs comprise an antigen-binding region linked to a cell membrane anchor region and a signalling region. An optional hinge region may provide separation between the antigen-binding region and cell membrane anchor region, and may act as a flexible linker.

[1114] In some embodiments, the antigen-binding domain of a CAR according to the present disclosure comprises or consists of an antigen-binding molecule that binds to yc as described herein. In some embodiments, the antigen-binding domain of a CAR according to the present disclosure comprises or consists of an antigen-binding molecule that binds to IL-2Rp as described herein. Accordingly, a CAR according to the present disclosure comprises an antigen-binding molecule as described herein.

[1115] It will be appreciated that an antigen-binding molecule according to the present disclosure forms, or is comprised in, the antigen-binding domain of the CAR. Accordingly, in some embodiments, the antigenbinding molecule of the present disclosure is comprised in a CAR.

[1116] It will also be appreciated that an antigen-binding molecule according to the present disclosure may be a CAR. A CAR having an antigen-binding domain comprising or consisting of an antigen-binding molecule of the present disclosure (e.g. a yc-binding VHH and / or an IL-2Rp-binding VHH) is an antigen-binding molecule. The antigen-binding domain of the CAR of the present disclosure may be provided with any suitable format, e.g. VHH, scFv, etc. The cell membrane anchor region is provided between the antigen-binding region and the signalling region of the CAR and provides for anchoring the CAR to the cell membrane of a cell expressing a CAR, with the antigen-binding region in the extracellular space, and signalling region inside the cell. In some embodiments, the CAR comprises a cell membrane anchor region comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the transmembrane region amino acid sequence for one of CD3- , CD4, CD8 or CD28. As used herein, a region which is ‘derived from’ a reference amino acid sequence comprises an amino acid sequence having at least 60%, e.g. one of at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the reference sequence.

[1117] The signalling region of a CAR allows for activation of the T cell. The CAR signalling regions may comprise the amino acid sequence of the intracellular domain of CD3- , which provides immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation and activation of the CAR-ex pressing T cell. Signalling regions comprising sequences of other ITAM-containing proteins such as FcyRI have also been employed in CARs (Haynes et al., 2001 J Immunol 166(1):182-187). Signalling regions of CARs may also comprise co-stimulatory sequences derived from the signalling region of co-stimulatory molecules, to facilitate activation of CAR-ex pressing T cells upon binding to the target protein. Suitable co-stimulatory molecules include CD28, 0X40, 4-1 BB, ICOS and CD27. In some cases, CARs are engineered to provide for co-stimulation of different intracellular signalling pathways. For example, signalling associated with CD28 costimulation preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway, whereas the 4-1 BB-mediated signalling is through TNF receptor associated factor (TRAF) adaptor proteins. Signalling regions of CARs therefore sometimes contain co-stimulatory sequences derived from signalling regions of more than one co-stimulatory molecule. In some embodiments, the CAR of the present disclosure comprises one or more co-stimulatory sequences comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the intracellular domain of one or more of CD28, 0X40, 4-1 BB, ICOS and CD27.

[1118] An optional hinge region may provide separation between the antigen-binding domain and the transmembrane domain, and may act as a flexible linker. Hinge regions may be derived from IgG 1 or lgG4. In some embodiments, the CAR of the present disclosure comprises a hinge region comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the hinge region of IgG 1 or lgG4.

[1119] Also provided is a cell comprising a CAR according to the present disclosure. The CAR according to the present disclosure may be used to generate CAR-ex pressing immune cells, e.g. CAR-T or CAR-NK cells. Engineering of CARs into immune cells may be performed during culture, in vitro.

[1120] The present disclosure provides improved antigen-binding molecules, and the improvements are described throughout the present disclosure. For example, the disclosed antigen-binding molecules comprise both structural and functional features which are improvements over known antibodies.

[1121] In some embodiments, the improvement comprises the structure of the antigen binding molecule. In some embodiments, the improvement comprises the inclusion of a CDR, FR sequence, and / or VH sequence described herein.

[1122] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, the improvement comprising the inclusion of a CDR, FR sequence, and / or VH sequence described herein.

[1123] In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety, the improvement comprising the inclusion of a CDR, FR sequence, and / or VH sequence described herein.

[1124] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, and an IL-2R0- binding moiety, and the improvement comprises the structure of the antigen binding molecule.

[1125] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, a linker, and an IL- 2Rp-binding moiety, and the improvement comprises the format / structure of the antigen binding molecule, wherein the linker connects the yc-binding moiety to the IL-2Rp-binding moiety.

[1126] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety, a linker, and an IL- 2Rp-binding moiety, and the improvement comprises the format / structure of the antigen binding molecule, wherein the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL-2R0- binding moiety.

[1127] Fc regions

[1128] In some embodiments, the antigen-binding molecules of the present disclosure comprise an Fc region.

[1129] In some embodiments, the antigen-binding molecules of the present disclosure do not comprise an Fc region.

[1130] As used herein, an ‘Fc region’ refers to a polypeptide complex formed by interaction between two polypeptides, each polypeptide comprising the CH2-CH3 region of an immunoglobulin (Ig) heavy chain constant sequence.

[1131] Herein, a ‘CH2 region’ refers to an amino acid sequence corresponding to the CH2 region of an immunoglobulin (Ig). The CH2 region is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1):78-85. A ‘CH3 region’ refers to an amino acid sequence corresponding to the CH3 region of an immunoglobulin (Ig). The CH3 region is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1):78-85. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 regions of an immunoglobulin (Ig). The CH2- CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1)78-85.

[1132] In some embodiments, a CH2 region, CH3 region and / or a CH2-CH3 region according to the present disclosure corresponds to the CH2 region / CH3 region / CH2-CH3 region of an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. Ig A1 , lgA2), IgD, IgE or IgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human IgG (e.g. hlgG1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlgE or hlgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human lgG1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17).

[1133] Fc regions provide for interaction with Fc receptors and other molecules of the immune system to bring about functional effects. Fc-mediated effector functions are reviewed e.g. in Jefferis et al., Immunol Rev (1998) 163:59-76 (hereby incorporated by reference in its entirety), and are brought about through Fc- mediated recruitment and activation of immune cells (e.g. macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells and T cells) through interaction between the Fc region and Fc receptors expressed by the immune cells, recruitment of complement pathway components through binding of the Fc region to complement protein C1q, and consequent activation of the complement cascade. Fc-mediated functions include Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), formation of the membrane attack complex (MAC), cell degranulation, cytokine and / or chemokine production, and antigen processing and presentation.

[1134] Modifications to antibody Fc regions that influence Fc-mediated functions are known in the art, such as those described e.g. in Wang et al., Protein Cell (2018) 9(1):63-73, which is hereby incorporated by reference in its entirety. Exemplary Fc region modifications known to influence antibody effector function are summarised in Table 1 of Wang et al., Protein Cell (2018) 9(1):63-73. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification to increase or reduce an Fc-mediated function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[1135] Where an Fc region / CH2 / CH3 is described as comprising modification(s) ‘corresponding to’ reference substitution(s), equivalent substitution(s) in the homologous Fc / CH2 / CH3 are contemplated. By way of illustration, L234A / L235A substitutions in human lgG1 (numbered according to the EU numbering system as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) correspond to L to A substitutions at positions 117 and 118 of the mouse Ig gamma-2A chain C region (UniProtKB: P01863-1 , v1).

[1136] Where an Fc region is described as comprising a modification, the modification may be present in one or both of the polypeptide chains which together form the Fc region. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification in one or more of the CH2 and / or CH3 regions.

[1137] In some embodiments, the Fc region comprises modification to increase an Fc-mediated function. In some embodiments, the Fc region comprises modification to increase ADCC. In some embodiments, the Fc region comprises modification to increase ADCP. In some embodiments, the Fc region comprises modification to increase CDC. An antigen-binding molecule comprising an Fc region comprising modification to increase an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces an increased level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[1138] In some embodiments, the Fc region comprises modification to increase binding to an Fc receptor. In some embodiments, the Fc region comprises modification to increase binding to an Fey receptor. In some embodiments, the Fc region comprises modification to increase binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRI I la and FcyRlllb. In some embodiments, the Fc region comprises modification to increase binding to FcyRllla. In some embodiments, the Fc region comprises modification to increase binding to FcyRlla. In some embodiments, the Fc region comprises modification to increase binding to FcyRllb. In some embodiments, the Fc region comprises modification to increase binding to FcRn. In some embodiments, the Fc region comprises modification to increase binding to a complement protein. In some embodiments, the Fc region comprises modification to increase binding to C1q. In some embodiments, the Fc region comprises modification to promote hexamerisation of the antigen-binding molecule. In some embodiments, the Fc region comprises modification to increase antigen-binding molecule half-life. In some embodiments, the Fc region comprises modification to increase coengagement.

[1139] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions F243L / R292P / Y300L / V305I / P396L as described in Stavenhagen et al. Cancer Res. (2007) 67:8882-8890. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S239D / I332E or S239D / I332E / A330L as described in Lazar et al., Proc Natl Acad Sci USA. (2006) 103:4005-4010. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S298A / E333A / K334A as described in Shields et al., J Biol Chem. (2001) 276:6591-6604. In some embodiments, the Fc region comprises modification to one of heavy chain polypeptides corresponding to the combination of substitutions L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and modification to the other heavy chain polypeptide corresponding to the combination of substitutions D270E / K326D / A330M / K334E, as described in Mimoto et al., MAbs. (2013) 5:229-236. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions G236A / S239D / I332E as described in Richards etal., Mol Cancer Ther. (2008) 7:2517-2527.

[1140] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions K326W / E333S as described in Idusogie et al. J Immunol. (2001) 166(4):2571-5. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / H268F / S324T as described in Moore et al. MAbs. (2010) 2(2):181-9. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Natsume et al., Cancer Res. (2008) 68(10):3863-72. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions E345R / E430G / S440Y as described in Diebolder et al. Science (2014) 343(6176):1260-3.

[1141] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M252Y / S254T / T256E as described in Dall’Acqua et al. J Immunol. (2002) 169:5171-5180. These so called ‘YTE’ modifications located at the CH2-CH3 interface of the Fc region have been shown to increase the binding affinity at pH 6.0 to the MHC Class I neonatal Fc receptor (FcRn), localised within the acidic endosomes of endothelial and haematopoietic cells, which increases efficient recycling of administered mAb and half-life in the plasma.

[1142] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M428L / N434S as described in Zalevsky et al. Nat Biotechnol. (2010) 28:157-159.

[1143] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / L328F as described in Chu et al., Mol Immunol. (2008) 45:3926-3933. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions N325S / L328F as described in Shang etal. Biol Chem. (2014) 289:15309-15318.

[1144] In some embodiments, the Fc region comprises modification to reduce / prevent an Fc-mediated function. In some embodiments, the Fc region comprises modification to reduce / prevent ADCC. In some embodiments, the Fc region comprises modification to reduce / prevent ADCP. In some embodiments, the Fc region comprises modification to reduce / prevent CDC. An antigen-binding molecule comprising an Fc region comprising modification to reduce / prevent an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces a reduced level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[1145] In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fc receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fey receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRllla. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRlla. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRllb. In some embodiments, the Fc region comprises modification to reduce / prevent binding to a complement protein. In some embodiments, the Fc region comprises modification to reduce / prevent binding to C1q. In some embodiments, the Fc region comprises modification to reduce / prevent glycosylation of the amino acid residue corresponding to N297. In some embodiments, the Fc region is not able to induce one or more Fc-mediated functions ( / .e. lacks the ability to elicit the relevant Fc-mediated function(s)). Accordingly, antigen-binding molecules comprising such Fc regions also lack the ability to induce the relevant function(s). Such antigen-binding molecules may be described as being devoid of the relevant function(s).

[1146] In some embodiments, the Fc region is not able to induce ADCC. In some embodiments, the Fc region is not able to induce ADCP. In some embodiments, the Fc region is not able to induce CDC. In some embodiments, the Fc region is not able to induce ADCC and / or is not able to induce ADCP and / or is not able to induce CDC.

[1147] In some embodiments, the Fc region is not able to bind to an Fc receptor. In some embodiments, the Fc region is not able to bind to an Fey receptor. In some embodiments, the Fc region is not able to bind to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region is not able to bind to FcyRllla. In some embodiments, the Fc region is not able to bind to FcyRlla. In some embodiments, the Fc region is not able to bind to FcyRllb. In some embodiments, the Fc region is not able to bind to FcRn. In some embodiments, the Fc region is not able to bind to a complement protein. In some embodiments, the Fc region is not able to bind to C1q. In some embodiments, the Fc region is not glycosylated at the amino acid residue corresponding to N297.

[1148] In some embodiments, the Fc region comprises modification corresponding to N297A or N297Q or N297G as described in Leabman et al., MAbs. (2013) 5:896-903. In some embodiments, the Fc region comprises modification corresponding to L235E as described in Alegre et al., J Immunol. (1992) 148:3461-3468. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A or F234A / L235A as described in Xu et al., Cell Immunol. (2000) 200:16-26. In some embodiments, the Fc region comprises modification corresponding to P329A or P329G as described in Schlothauer etal., Protein Engineering, Design and Selection (2016), 29(10):457-466. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G as described in Lo et al. J. Biol. Chem (2017) 292(9):3900-3908. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Rother et al., Nat Biotechnol. (2007) 25:1256-1264. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S228P / L235E as described in Newman et al., Clin. Immunol. (2001) 98:164-174. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions H268Q / V309L / A330S / P331S as described in An et al., MAbs. (2009) 1 :572-579. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions

[1149] V234A / G237A / P238S / H268A / V309L / A330S / P331S as described in Vafa et al., Methods. (2014) 65:114- 126. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S as described in US 2015 / 0044231 A1.

[1150] The combination of substitutions ‘L234A / L235A’ and corresponding substitutions (such as e.g. F234A / L235A in human lgG4) are known to disrupt binding of Fc to Fey receptors and inhibit ADCC, ADCP, and also to reduce C1q binding and thus CDC (Schlothauer et al., Protein Engineering, Design and Selection (2016) 29(10):457-466, hereby incorporated by reference in entirety). The substitutions ‘P329G’ and ‘P329A’ reduce C1q binding (and thereby CDC). Substitution of ‘N297’ with ‘A’, ‘G’ or ‘Q’ is known to eliminate glycosylation, and thereby reduce Fc binding to C1q and Fey receptors, and thus CDC and ADCC. Lo et al. J. Biol. Chem (2017) 292(9):3900-3908 (hereby incorporated by reference in its entirety) reports that the combination of substitutions L234A / L235A / P329G eliminated complement binding and fixation as well as Fey receptor dependent, antibody-dependent, cell-mediated cytotoxicity in both murine lgG2a and human lgG1.

[1151] The combination of substitutions L234A / L235E / G237A / A330S / P331S in lgG1 Fc is disclosed in US 2015 / 0044231 A1 to abolish induction of phagocytosis, ADCC and CDC.

[1152] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P as described in Silva et al., J Biol Chem. (2015) 290(9):5462-5469. The substitution S228P in lgG4 Fc reduces Fab-arm exchange (Fab-arm exchange can be undesirable).

[1153] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A. In some embodiments, the Fc region comprises modification corresponding to the substitution P329G. In some embodiments, the Fc region comprises modification corresponding to the substitution N297Q.

[1154] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G.

[1155] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G / N297Q.

[1156] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331 S.

[1157] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P, e.g. in lgG4.

[1158] In some embodiments, the Fc region comprises a CH2-CH3 region comprising an amino acid difference at one or more of the following positions, relative to the amino acid sequence of a CH2-CH3 region of a reference Fc region: 234 or 235 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following specified amino acid residues: A234 or A235 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising A234 and A235. In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following amino acid substitutions, relative to the amino acid sequence of a CH2-CH3 region of the reference Fc region: L234A or L235A (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising the following amino acid substitutions, relative to the amino acid sequence of a CH2-CH3 region of the reference Fc region: L234A and L235A (according to the EU numbering system).

[1159] In some embodiments - particularly embodiments in which the antigen-binding molecule is a multispecific (e.g. bispecific) antigen-binding molecule - the antigen-binding molecule comprises an Fc region comprising modification in one or more of the CH2 and CH3 regions promoting association of the Fc region. Recombinant co-expression of constituent polypeptides of an antigen-binding molecule and subsequent association leads to several possible combinations. To improve the yield of the desired combinations of polypeptides in antigen-binding molecules in recombinant production, it is advantageous to introduce in the Fc regions modification(s) promoting association of the desired combination of heavy chain polypeptides. Modifications may promote e.g. hydrophobic and / or electrostatic interaction between CH2 and / or CH3 regions of different polypeptide chains. Suitable modifications are described e.g. in Ha et al., Front Immnol. (2016) 7:394, which is hereby incorporated by reference in its entirety.

[1160] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising paired substitutions in the CH3 regions of the Fc region according to one of the following formats, as shown in Table 1 of Ha et al., Front Immnol. (2016) 7:394: KiH, KiHs-s, HA-TF, ZW1 , 7.8.60, DD-KK, EW-RVT, EW-RVTs-s, SEED or A107.

[1161] In some embodiments, the multispecific (e.g. bispecific) antigen-binding molecule of the present disclosure is provided with an Fc region comprising the ‘knob-into-hole’ or ‘KiH’ modification, e.g. as described e.g. in US 7,695,936 and Carter, J Immunol Meth. (2001) 248:7-15. In such embodiments, one of the CH3 regions of the Fc region comprises a ‘knob’ modification, and the other CH3 region comprises a ‘hole’ modification. The ‘knob’ and ‘hole’ modifications are positioned within the respective CH3 regions so that the ‘knob’ can be positioned in the ‘hole’ in order to promote heterodimerisation (and inhibit homodimerisation) of the polypeptides and / or stabilise heterodimers. Knobs are constructed by substituting amino acids having small chains with those having larger side chains (e.g. tyrosine or tryptophan). Holes are created by substituting amino acids having large side chains with those having smaller side chains (e.g. alanine or threonine).

[1162] In some embodiments, one of the CH3 regions of the Fc region of the antigen-binding molecule of the present disclosure comprises the substitution (numbering of positions / substitutions in the Fc region herein is according to the EU numbering system as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) T366W, and the other CH3 region of the Fc region comprises the substitution Y407V. In some embodiments, one of the CH3 regions of the Fc region of the antigen-binding molecule comprises the substitution T366W, and the other CH3 region of the Fc region comprises the substitutions T366S and L368A. In some embodiments, one of the CH3 regions of the Fc region of the antigen-binding molecule comprises the substitution T366W, and the other CH3 region of the Fc region comprises the substitutions Y407V, T366S and L368A. In some embodiments, one of the CH3 regions comprises the substitution S354C, and the other CH3 region of the Fc region comprises the substitution Y349C. Introduction of these cysteine residues results in formation of a disulfide bridge between the two CH3 regions of the Fc region, further stabilizing the heterodimer (Carter, J Immunol Methods (2001) 248:7-15).

[1163] In some embodiments, one of the CH3 regions comprises the substitutions K392D and K409D, and the other CH3 region of the Fc region comprises the substitutions E356K and D399K. ‘DDKK’ knob-into-hole technology is described e.g. in WO 2014 / 131694 A1 , and promotes assembly of the heavy chains providing the complementary amino acid residues.

[1164] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region modified as described in Labrijn et al., Proc Natl Acad Sci USA. (2013) 110(13):5145-50, referred to as ‘Duobody’ format. In some embodiments one of the CH3 regions comprises the substitution K409R, and the other CH3 region of the Fc region comprises the substitution K405L.

[1165] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region modified as described in Strop et al., J Mol Biol. (2012) 420(3):204-19, so-called ‘EEE-RRR’ format. In some embodiments one of the CH3 regions comprises the substitutions D221 E, P228E and L368E, and the other CH3 region of the Fc region comprises the substitutions D221 R, P228R and K409R.

[1166] In some embodiments, the antigen-binding molecule comprises an Fc region comprising the ‘EW-RVT’ modification described in Choi etal., Mol Cancer Ther. (2013) 12(12):2748-59. In some embodiments one of the CH3 regions comprises the substitutions K360E and K409W, and the other CH3 region of the Fc region comprises the substitutions Q347R, D399V and F405T.

[1167] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising the ‘SEED’ modification as described in Davis etal., Protein Eng Des Sei. (2010) 23(4):195- 202, in which p-strand segments of human lgG1 CH3 and IgA CH3 are exchanged.

[1168] In some embodiments, one of the CH3 regions comprises the substitutions S364H and F405A, and the other CH3 region of the Fc region comprises the substitutions Y349T and T394F (see e.g. Moore et al., MAbs (2011) 3(6):546-57).

[1169] In some embodiments, one of the CH3 regions comprises the substitutions T350V, L351Y, F405A and Y407V, and the other CH3 region of the Fc region comprises the substitutions T350V, T366L, K392L and T394W (see e.g. Von Kreudenstein et al., MAbs (2013) 5(5):646-54).

[1170] In some embodiments, one of the CH3 regions comprises the substitutions K360D, D399M and Y407A, and the other CH3 region of the Fc region comprises the substitutions E345R, Q347R, T366V and K409V (see e.g. Leaver-Fay et al., Structure (2016) 24(4):641-51). In some embodiments, one of the CH3 regions comprises the substitutions K370E and K409W, and the other CH3 region of the Fc region comprises the substitutions E357N, D399V and F405T (see e.g. Choi et al., PLoS One (2015) 10(12):e0145349).

[1171] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification to increase stability (e.g. thermostability and / or freeze-thaw stability). In some embodiments, the antigen-binding molecule comprises modification to one or more of the CH2 and CH3 regions to increase stability (e.g. thermostability and / or freeze-thaw stability).

[1172] In some embodiments, the antigen-binding molecule of the present disclosure comprises CH3 regions (e.g. within an Fc region, e.g. within CH2-CH3 regions forming an Fc region) comprising paired CH3 region 'KiH' or 'KiHs-s' modifications. Such paired CH3 regions may comprise a CH3 region comprising a knob modification, and a CH3 region comprising a hole modification.

[1173] In some embodiments, a CH3 region comprising a knob modification comprises a tryptophan or tyrosine residue at position 366 ( / .e. 366W or 366Y). In some embodiments, the knob modification is or comprises T366W or T366Y. In some embodiments, a CH3 region comprising a knob modification comprises 366W. In some embodiments, the knob modification is or comprises T366W.

[1174] In some embodiments, a CH3 region comprising a hole modification comprises 407V, 407A, 407S or 407T; 366S, 366V or 366A; and 368A, 368V, 368S or 368T. In some embodiments, the hole modification is or comprises Y407V, Y407A, Y407S or Y407T; T366S, T366V or T366A; and L368A, L368V, L368S or L368T. In some embodiments, a CH3 region comprising a hole modification comprises 407V, 366S and 368A. In some embodiments, the hole modification is or comprises Y407V, T366S, and L368A.

[1175] In some embodiments, the antigen-binding molecule of the present disclosure comprise CH3 region(s) (e.g. within an Fc region, e.g. within CH2-CH3 region(s) of an Fc region) comprising modification for the formation of an interchain disulfide bond ( / .e. between polypeptides comprising CH2-CH3 regions forming the Fc region). Such modification may comprise the introduction of one or more cysteine residues into one or both of the CH3 regions of the constituent polypeptides of a polypeptide complex of the present disclosure. More particularly, such modification may have the result that the CH3:CH3 interface formed between the CH3 regions of polypeptides of polypeptide complexes of the present disclosure comprises a disulfide bond, formed between cysteine residues (one from each polypeptide). In some embodiments, one of the CH3 regions comprises 349C, and the other CH3 region comprises 354C. In some embodiments, one of the CH3 regions comprises Y349C, and the other CH3 region comprises S354C.

[1176] In some embodiments, a CH3 region comprising a knob modification comprises 366W and S354C. In some embodiments, a CH3 region comprising a hole modification comprises Y407V, T366S, L368A and Y349C. Functional properties of the antigen-binding molecules

[1177] The antigen-binding molecules described herein may be characterised by reference to certain functional properties. In some embodiments, the antigen-binding molecule described herein may possess one or more of the following properties:

[1178] Antigen-binding molecules described herein may be characterised by reference to certain functional properties. In some embodiments, an antigen-binding molecule described herein may possess one or more of the following properties: binds to yc; binds to IL-2Rp; binds to yc and IL-2Rp; binds to yc-expressing cells; binds to IL-2Rp-expressing cells; binds to cells expressing a yc and IL-2Rp; binds to cells expressing a yc:IL-2Rp receptor; binds to cells expressing a yc:IL-2Rp:IL-2Ra receptor; binds to cells expressing a yc:IL-2Rp:IL-15Ra receptor; increases multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R , IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra); increases multimerization of yc and IL-2R0; increases signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor); increases signalling mediated by a cytokine receptor comprising yc; increases signalling mediated by a cytokine receptor comprising IL-2R0; increases signalling mediated by a yc:IL-2Rp receptor; increases signalling mediated by a yc:IL-2Rp:IL-2Ra receptor; increases signalling mediated by a yc:IL-2Rp:IL-15Ra receptor; increases signalling mediated by IL-2; increases signalling mediated by IL-2 and IL-15; increases proliferation, survival and / or effector activity of cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL- 21 Ra receptor and yc:IL-7Ra receptor); increases proliferation, survival and / or effector activity of cells expressing a yc:IL-2Rp receptor; increases proliferation, survival and / or effector activity of cells expressing a yc:IL-2Rp:IL-2Ra receptor; increases proliferation, survival and / or effector activity of cells expressing a yc:IL-2Rp:IL-15Ra receptor; reduces expression of one or more markers of immune cell exhaustion by cells expressing a yc- containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor); reduces expression of one or more markers of immune cell exhaustion by cells expressing a yc:IL-2Rp receptor; reduces expression of one or more markers of immune cell exhaustion by cells expressing a yc:IL-2Rp:IL-2Ra receptor; reduces expression of one or more markers of immune cell exhaustion by cells expressing a yc:IL-2Rp:IL-15Ra receptor); increased stability and / or half-life compared to IL-2; increased upregulation of signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds compared to a cytokine that binds to the yc-containing cytokine receptor; increased upregulation of proliferation, survival and / or effector activity of cells expressing a yc- containing cytokine receptor to which the antigen-binding molecule binds compared to a cytokine that binds to the yc-containing cytokine receptor; increased downregulation of expression of one or more markers of immune cell exhaustion by cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds compared to a cytokine that binds to the yc-containing cytokine receptor; and / or enhances anticancer activity of cancer antigen-specific immune cells, e.g. in vivo.

[1179] It will be appreciated that a given antigen-binding molecule may display more than one of the properties recited in the preceding paragraph. A given antigen-binding molecule may be evaluated for the properties recited in the preceding paragraph using suitable assays. For example, the assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays. In some embodiments, the assays may be e.g. in vivo assays, i.e. performed in non-human animals. In some embodiments, the assays may be e.g. ex vivo assays, i.e. performed using cells / tissue / an organ obtained from a subject. Such assays may be utilised to screen for antigen-binding molecules with a desired functional property.

[1180] Relevant benchmark control antigen-binding molecules (e.g., benchmark control antibodies) can be used as controls for the assessment of relative increases / decreases in the functional properties mentioned above. Suitable benchmark control antigen-binding molecules are described in the Examples herein. The benchmark control antigen-binding molecule may comprise a yc-binding moiety and an IL-2Rp-binding moiety. The benchmark control antigen-binding molecule may be an anti-IL-2Rp x anti-yc bispecific antibody (e.g., BMK010 or BMK011 described herein). The benchmark control antigen-binding molecule may be BMK010 (described herein and in W02020160242A1). The benchmark control antigen-binding molecule may be BMK011 (described herein and in W02023078113A1).

[1181] Where assays are cell-based assays, they may comprise treating cells with a given antigen-binding molecule in order to determine whether the antigen-binding molecule displays one or more of the recited properties.

[1182] Assays may employ species labelled with detectable entities in order to facilitate their detection. Assays may comprise evaluating the recited properties following treatment of cells separately with a range of quantities / concentrations of a given antigen-binding molecule (e.g. a dilution series). It will be appreciated that the cells preferably express the target antigen for the antigen-binding molecule.

[1183] Analysis of the results of such assays may comprise determining the concentration at which 50% of the maximal level of the relevant activity is attained. The concentration of a given agent at which 50% of the maximal level of the relevant activity is attained may be referred to as the ‘half-maximal effective concentration’ of the agent in relation to the relevant activity, which may also be referred to as the ‘EC50’. By way of illustration, the EC50 of a given antigen-binding molecule for binding to human yc may be the concentration of the antigen-binding molecule at which 50% of the maximal level of binding to human yc is achieved. Additionally, the EC50 of a given antigen-binding molecule for agonising pSTAT5 signalling (pSTAT5 EC50) is the concentration of the antigen-binding molecule at which 50% of the maximal level of pSTAT5 signalling is achieved in a cell-based reporter gene assay which enables pSTAT5 signalling to be stimulated and measured (e.g., the assays reported in Example 3 herein).

[1184] Depending on the property, the EC50 may also be referred to as the ‘half-maximal inhibitory concentration’ or ‘IC50’, this being the concentration of the agent at which 50% of the maximal level of inhibition of a given property is observed.

[1185] Where the functional properties of agents are compared (e.g. where the antigen binding molecule of the present disclosure are compared with other polypeptides), comparisons are performed at equivalent concentrations and / or quantity of the relevant agents.

[1186] The antigen-binding molecules and antigen-binding moieties described herein preferably display specific binding to yc and / or IL-2Rp. As used herein, ‘specific binding’ refers to binding which is selective for the antigen, and which can be discriminated from non-specific binding to non-target antigen. An antigenbinding molecule / moiety that specifically binds to a target molecule preferably binds the target with greater affinity, and / or with greater duration than it binds to other, non-target molecules.

[1187] The ability of a given polypeptide to bind specifically to a given molecule can be determined by analysis according to methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol. (2012) 907:41 1-442), Bio-Layer Interferometry (BLI; see e.g. Lad et al., J Biomol Screen (2015) 20(4):498-507), flow cytometry, or by a radiolabeled antigen-binding assay (RIA) enzyme-linked immunosorbent assay. Through such analysis binding to a given molecule can be measured and quantified. In some embodiments, the binding may be the response detected in a given assay.

[1188] In some embodiments, the extent of binding of the antigen-binding molecule / moiety to a non-target molecule is less than about 10% of the binding of the antigen-binding molecule / moiety to the target molecule as measured, e.g. by ELISA, SPR, BLI or by RIA. Alternatively, binding specificity may be reflected in terms of binding affinity where the antigen-binding molecule / moiety binds with a dissociation constant (KD) that is at least 0.1 order of magnitude ( / .e. 0.1 x 10n, where n is an integer representing the order of magnitude) greater than the KD of the antigen-binding molecule towards a non-target molecule. This may optionally be one of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .5, or 2.0.

[1189] Binding affinity of an antigen-binding molecule / moiety for its target is often described in terms of its dissociation constant (KD). Binding affinity can be measured by methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol (2012) 907:411-442; or Rich et al., Anal Biochem. (2008) 373(1):112-20), Bio-Layer Interferometry (see e.g. Lad et al., J Biomol Screen (2015) 20(4):498-507; or Concepcion et al., Comb Chem High Throughput Screen. (2009) 12(8)791-800), MicroScale Thermophoresis (MST) analysis (see e.g. Jerabek-Willemsen et al., Assay Drug Dev Technol. (2011) 9(4):342-353), or by a radiolabelled antigen-binding assay (RIA).

[1190] In some embodiments, an antigen-binding molecule / moiety described herein binds to yc. In some embodiments, an antigen-binding molecule / moiety described herein binds to IL-2R0. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and IL-2R0.

[1191] In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-2R0 with an affinity in the micromolar range, i.e. KD = 9.9 x 10-4to 1 x 10-6M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-2R0 with sub-micromolar affinity, i.e. KD < 1 x 106M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-2R0 with an affinity in the nanomolar range, i.e. KD = 9.9 x 107to 1 x 109M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-2R0 with sub- nanomolar affinity, i.e. KD < 1 x 109M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-2R0 with an affinity in the picomolar range, i.e. KD = 9.9 x 10-10to 1 x 10-12M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-2R0 with sub-picomolar affinity, i.e. KD < 1 x 10-12M.

[1192] The antigen-binding molecules and antigen-binding moieties of the present disclosure may bind to a particular region of interest of their target antigen(s). For example, they may bind to a linear epitope of yc and / or IL-2RJ3, consisting of a contiguous sequence of amino acids (i.e. an amino acid primary sequence). In some embodiments, they may bind to a conformational epitope of yc and / or IL-2R0, consisting of a discontinuous sequence of amino acids of the amino acid sequence.

[1193] The region of a given target molecule to which an antigen-binding molecule binds can be determined by the skilled person using various methods well known in the art, including X-ray co-crystallography analysis of antibody-antigen complexes, peptide scanning, mutagenesis mapping, hydrogen-deuterium exchange analysis by mass spectrometry, phage display, competition ELISA and proteolysis-based ‘protection’ methods. Such methods are described, for example, in Gershoni et al., BioDrugs (2007) 21 (3):145-156, which is hereby incorporated by reference in its entirety.

[1194] The antigen-binding molecules and antigen-binding moieties preferably bind to their target antigen(s) in a region which is accessible to an antigen-binding molecule (i.e. an extracellular antigen-binding molecule) when the target antigen(s) is / are expressed at the cell surface (i.e. in or at the cell membrane). In some embodiments, the antigen-binding molecules and antigen-binding moieties are capable of binding to their target antigen(s) when they are expressed at the cell surface.

[1195] The antigen-binding molecules and antigen-binding moieties preferably bind to the extracellular domain(s) of target antigen(s). The extracellular domains of yc and IL-2Rp are described hereinabove.

[1196] The antigen-binding molecule may bind to yc and / or IL-2Rp-expressing cells.

[1197] Such cells include immune cells, e.g. effector immune cells. The immune cell may be a cell of hematopoietic origin, e.g. a neutrophil, eosinophil, basophil, dendritic cell, lymphocyte, or monocyte. A lymphocyte may be e.g. a T cell, B cell, NK cell, NKT cell or innate lymphoid cell (ILC), or a precursor thereof (e.g. a thymocyte or pre-B cell). The immune cell may express a CD3 polypeptide (e.g. CD3y CD3e CD3 or CD36), a TCR polypeptide (TCRa or TCRp), CD27, CD28, CD4 or CD8. In some embodiments, the immune cell is a T cell, e.g. a CD3+ T cell. In some embodiments, the T cell is a CD3+, CD4+ T cell. In some embodiments, the T cell is a CD3+, CD8+ T cell. In some embodiments, the T cell is a T helper cell (TH cell). In some embodiments, the T cell is a cytotoxic T cell (e.g. a cytotoxic T lymphocyte (CTL)). In some embodiments, the immune cell is a T cell or an NK cell.

[1198] An ‘effector immune cell’ may be an immune cell displaying an effector function. An effector immune cell may be a CD8+ T cell, CD8+ cytotoxic T lymphocyte (CD8+ CTL), CD4+ T cell, CD4+ T helper cell, NK cell, IFNy-producing cell, memory T cell, central memory T cell, antigen-experienced T cell or CD45RO+ T cell. An effector immune cell may be characterised by one or more of the following properties: granzyme B expression, IFNy expression, CD107a expression, IL-2 expression, TNFa expression, perforin expression, granulysin expression, and / or FAS ligand (FASL) expression. In some embodiments, an effector immune cell according to the present disclosure is a granzyme B-expressing cell.

[1199] The ability of an antigen-binding molecule to bind to a given cell type (e.g. a cell expressing one or more specified molecules, e.g. selected from yc and / or IL-2R0) can be analysed by contacting cells with the antigen-binding molecule, and detecting antigen-binding molecule bound to the cells, e.g. after a washing step to remove unbound antigen-binding molecule. The ability of an antigen-binding molecule to bind to yc and / or IL-2Rp-expressing cells can be analysed by methods such as flow cytometry and immunofluorescence microscopy.

[1200] In some embodiments, the antigen-binding molecule increases multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc (e.g. selected from yc and / or IL-2R0). In some embodiments, the antigen-binding molecule decreases multimerization of yc and a polypeptide of a yc- containing cytokine receptor other than yc (e.g. selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra, and IL-7Ra).

[1201] As used herein, ‘multimerization’ refers to the formation of a multimeric polypeptide complex ( / .e. formed by non-covalent, protein: protein interaction, as described hereinabove). Multimers comprise two or more polypeptides, and may e.g. be dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers or decamers. Accordingly, multimerization may be dimerization, trimerization, tetramerization, et seq.).

[1202] It will be appreciated that the multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc (e.g., IL-2R0) is heteromultimerization, as the constituent polypeptides of the multimer are non-identical. Thus, the multimers formed by multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc in accordance with the present disclosure are heteromultimers, rather than homomultimers.

[1203] The antigen-binding molecules of the present disclosure may promote multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc through binding to the respective polypeptides, through its constituent antigen-binding moieties. Binding to yc and a polypeptide of a yc- containing cytokine receptor other than yc brings the polypeptides into close physical proximity (e.g. within 50 Angstroms, e.g. within 40, 30, 25, 20, 15, 10 or 5 Angstroms), thereby facilitating their association.

[1204] The antigen-binding molecules of the present disclosure may promote multimerization of yc and IL-2Rp through binding to the respective polypeptides, through its constituent antigen-binding moieties. Binding to yc and IL-2Rp brings the polypeptides into close physical proximity (e.g. within 50 Angstroms, e.g. within 40, 30, 25, 20, 15, 10 or 5 Angstroms), thereby facilitating their association.

[1205] Antigen-binding molecules can be analysed for their ability to increase / promote association between two polypeptides using techniques known to the skilled person. For example, cells expressing the relevant polypeptides can be contacted in vitro with a given test antigen-binding molecule, and association of the relevant polypeptides can thereafter be analysed. Suitable techniques to be employed in the analysis include e.g. resonance energy transfer techniques such as fluorescence resonance energy transfer (FRET) and Bioluminescence Resonance Energy Transfer (BRET), using appropriate labelled interaction partners, e.g. as described in Ciruela, Curr Opin Biotechnol. (2008) 19(4):338-43. Other suitable technologies include protein-fragment complementation systems, e.g. NanoLuc and NanoBiT, which are described e.g. in Thirukkumaran et al., Front Chem. (2020) 7:938 and Dixon et al., ACS Chem Biol. (2016) 1 1 (2):400-408.

[1206] An antigen-binding molecule according to the present disclosure may increase or decrease the level of multimerization relative to the level observed in the absence of the antigen-binding molecule, or in the presence of an appropriate control antigen-binding molecule (e.g. an antigen-binding molecule known not to influence multimerization of the relevant polypeptides, or a benchmark control antigen-binding molecule). In some embodiments, an ‘increased’ level of multimerization refers to a level of multimerization which is greater than 1 times, e.g. one of >1 .01 times, >1 .02 times, >1 .03 times, >1 .04 times, >1 .05 times, >1.1 times, >1 .2 times, >1 .3 times, >1 .4 times, >1 .5 times, >1 .6 times, >1 .7 times, >1 .8 times, >1 .9 times, >2 times, >3 times, >4 times, >5 times, >6 times, >7 times, >8 times, >9 times or >10 times the level observed in the absence of the antigen-binding molecule, or in the presence of an appropriate control antigen-binding molecule (e.g. an antigen-binding molecule known not to influence multimerization of the relevant polypeptides, or a benchmark control antigen-binding molecule). In some embodiments, a ‘decreased’ level of multimerization refers to a level of multimerization which is less than 1 times, e.g. one of e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level observed in the absence of the antigen-binding molecule, or in the presence of an appropriate control antigen-binding molecule (e.g. an antigen-binding molecule known not to influence multimerization of the relevant polypeptides, or a benchmark control antigen-binding molecule).

[1207] In some embodiments, the antigen-binding molecule increases signalling mediated by a yc-containing cytokine receptor (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor). It will be appreciated that the antigen-binding molecule increases signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds. That is, the antigen-binding molecule increases signalling mediated by a yc-containing cytokine receptor comprising or consisting of a polypeptide complex comprising the polypeptides for which the antigen-binding molecule comprises binding moieties. By way of illustration, in embodiments wherein the antigen-binding molecule comprises (i) a yc-binding moiety and (ii) an IL-2R0- binding moiety, the antigen-binding molecule may increase signalling through a yc-containing cytokine receptor comprising yc and IL-2R0, e.g. the yc:IL-2Rp receptor.

[1208] Such antigen-binding molecules may variously be described as ‘upregulating’, ‘inducing’, ‘enhancing’ ‘promoting’, ‘stimulating’, ‘triggering’ or ‘potentiating’ signalling mediated by the relevant yc-containing cytokine receptor. They may also be referred to as ‘agonists’ of, or having ‘agonistic’ or ‘activating’ activity with respect to, the relevant yc-containing cytokine receptor.

[1209] Cytokine signalling can be analysed using cells expressing the relevant cytokine receptor, for example the relevant cytokine receptor for assaying IL-7 signalling would be the yc:IL-7Ra receptor.

[1210] Cells expressing yc and IL-2R0 may be used in assays for assaying IL-2 signalling. For example, the following cytokine receptors could be used to assay for IL-2 signalling: a yc:IL-2Rp receptor, a yc:IL- 2Rp:IL-2Ra receptor, and / or a yc:IL-2Rp:IL-15Ra receptor.

[1211] Suitable assays include e.g. assays for detecting the phosphorylation / activity / expression of factors which are phosphorylated / activated / expressed as a consequence of signalling through the yc-containing cytokine receptor. For example, cytokine signalling can be investigated by evaluating phosphorylation of one or more signal transduction molecules of a signal transduction pathway triggered by signalling through the relevant yc-containing cytokine receptor (e.g. the JAK / STAT, MAPK / ERK or PI3K / Akt pathways). For example, the level of yc-containing cytokine receptor-mediated signalling can be analysed by detection and / or quantification of the level of phosphorylation of STAT1 , STAT3, STAT5 and / or ERK (e.g. STAT5 and / or ERK). The level of cytokine signalling can also be evaluated by analysing one or more correlates of signalling through the relevant receptor. For example, signalling may be investigated by detecting and / or quantifying the expression or activity of a factor whose expression / activity is upregulated or downregulated as a consequence of the specific cytokine signalling. In some embodiments, cytokine signalling may be investigated by detecting and / or quantifying the expression of a factor whose expression is upregulated as a consequence of cytokine signalling (e.g. IL-2 signalling).

[1212] The level of signalling can also be analysed using reporter-based methods. For example, cytokine signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by signalling through the relevant receptor-mediated signalling.

[1213] Signalling mediated by a yc-containing cytokine receptor can be analysed using cells expressing the relevant receptor, e.g. using an assay for detecting and / or quantifying receptor-mediated signalling. Suitable assays include e.g. assays for detecting the phosphorylation / activity / expression of factors which are phosphorylated / activated / expressed as a consequence of signalling through the yc-containing cytokine receptor.

[1214] Such assays may comprise contacting cells expressing a given yc-containing cytokine receptor with an antigen-binding molecule according to the present disclosure. By way of illustration, an assay for investigating the ability of an antigen-binding molecule to increase yc:IL-2Rp-mediated signalling may comprise contacting cells expressing the yc:IL-2Rp receptor with an antigen-binding molecule comprising a yc-binding moiety and an IL-2Rp-binding moiety.

[1215] For example, yc-containing cytokine receptor-mediated signalling can be investigated by evaluating phosphorylation of one or more signal transduction molecules of a signal transduction pathway triggered by signalling through the relevant yc-containing cytokine receptor (e.g. the JAK / STAT, MAPK / ERK or PI3K / Akt pathways). For example, the level of yc:IL-2Rp receptor-mediated signalling can be analysed by detection and / or quantification of the level of phosphorylation of STAT1 , STAT3, STAT5 and / or ERK (e.g. STAT5 and / or ERK).

[1216] In some embodiments, the antigen-binding molecule increases JAK / STAT signalling mediated by a yc- containing cytokine receptor (e.g. selected from a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, and / or a yc:IL-2Rp:IL-15Ra receptor). In some embodiments, the antigen-binding molecule increases MAPK / ERK signalling mediated by a yc-containing cytokine receptor (e.g. selected from a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, and / or a yc:IL-2Rp:IL-15Ra receptor). In some embodiments, the antigen-binding molecule increases PI3K / Akt signalling mediated by a yc-containing cytokine receptor (e.g. selected from a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, and / or a yc:IL-2Rp:IL-15Ra receptor).

[1217] In some embodiments, the antigen-binding molecule increases the phosphorylation of STAT1 , STAT3, STAT5 and / or ERK. In some embodiments, the antigen-binding molecule increases the activation of STAT1 , STAT3, STAT5 and / or ERK. In some embodiments, the antigen-binding molecule increases STAT1 , STAT3, STAT5 and / or ERK activity.

[1218] In some embodiments, the antigen-binding molecule increases the phosphorylation of STAT5. In some embodiments, the antigen-binding molecule increases the activation of STAT5. In some embodiments, the antigen-binding molecule increases STAT5 activity.

[1219] The level of signalling mediated by a given yc-containing cytokine receptor can also be evaluated by analysing one or more correlates of signalling through the relevant receptor. For example, yc-containing cytokine receptor-mediated signalling may be investigated by detecting and / or quantifying the expression or activity of a factor whose expression / activity is upregulated or downregulated as a consequence of signalling through the relevant receptor. In some embodiments, yc-containing cytokine receptor-mediated signalling may be investigated by detecting and / or quantifying the expression of a factor whose expression is upregulated as a consequence of yc-containing cytokine receptor-mediated signalling.

[1220] The level of signalling mediated by a given yc-containing cytokine receptor can also be analysed using reporter-based methods. For example, yc-containing cytokine receptor-mediated signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by signalling through the relevant receptor-mediated signalling. Additionally, yc-containing cytokine receptor-mediated signalling can be investigated using a reporter cell line which express a secretable reporter that can be quantitatively detected from the supernatant and can be readily measured (e.g., Cytokine Reporter Cells described and utilised in Example 3).

[1221] The pSTAT5 EC50 of an agonist (e.g., IL-2 or an antigen-binding molecule according to the present disclosure) is the concentration of the agonist required to increase pSTAT5 signalling to half ( / .e., 50%) of its maximal value. This can be determined through the use of a cell-based reporter gene assay (e.g., an assay reported in Example 3 herein).

[1222] In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 which is >50%, >60%, >70%, >80%, >90% of the pSTAT5 ECso of IL-2. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 which is >90% of the pSTAT5 ECso of IL-2.

[1223] In some embodiments, the antigen-binding molecule is a is a strong agonist of a receptor comprising yc and IL-2R0 (e.g., a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, or a yc:IL-2Rp:IL-15Ra receptor).

[1224] In some embodiments, the antigen-binding molecule is a is an intermediate agonist of a receptor comprising yc and IL-2R0 (e.g., a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, or a yc:IL-2Rp:IL- 15Ra receptor).

[1225] In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 ratio ((pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100), which is greater than 50. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 ratio (pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100), which is greater than 60. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 ratio (pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100), which is greater than 70. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 ratio (pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100), which is greater than 80. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 ratio (pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100), which is greater than 90. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 ratio (pSTAT5 EC50 of human IL-2 / pSTAT5 EC50 of on the antigen-binding molecule) x 100), which is greater than 100.

[1226] A strong agonist of a receptor comprising yc and IL-2R0 (e.g., a yc:IL-2Rp receptor, a yc:IL-2Rp:IL-2Ra receptor, or a yc:IL-2Rp:IL-15Ra receptor) is defined herein as an antigen-binding molecule which increases signalling mediated by a receptor comprising yc and IL-2R0 to a level which is comparable to IL-2. In some embodiments, the strong agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is between 50 and 100.

[1227] An intermediate agonist of a receptor comprising yc and IL-2R0 (e.g., a yc:IL-2Rp receptor, a yc:IL- 2Rp:IL-2Ra receptor, or a yc:IL-2Rp:IL-15Ra receptor) is defined herein as an antigen-binding molecule which a functional agonist of a receptor comprising yc and IL-2RJ3, but increases signalling mediated by a receptor comprising yc and IL-2R0 to a lower degree than IL-2. In other words, an intermediate agonist of a receptor comprising yc and IL-2R0 has reduced agonistic effects (compared to IL-2), but is an effective agonist. In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio (EC50 of pSTAT5 on human IL-2 / EC50 of pSTAT5 on the agonist x 100), which is greater than 15 and less than 50.

[1228] The skilled person is readily able to determine whether an antigen binding molecule is either a a strong agonist, an intermediate agonist, a weak agonist, or none of these agonist categorisations. For example, the skilled person may employ a reporter gene assay (e.g., an assay used in Example 3 herein) to determine the pSTAT5 EC50 ratio of the antigen-binding molecule.

[1229] In some embodiments, an antigen binding molecule is categorised as (i) a strong agonist, (ii) an intermediate agonist, (iii) a weak agonist, or (iv) none of these agonist categorisations, through the use of a reporter gene assay.

[1230] In some embodiments, pSTAT5 EC50 of an antigen-binding molecule is determined by following an assay such as the below: i. Culture, harvest and wash reporter cells which express IL-2R0 and yc; ii. Stimulate reporter cells with the antigen-binding molecule, and separately stimulate cells with a human IL-2 control (both at a range of concentrations); ii...

Claims

Claims:

1. An antigen-binding molecule, optionally isolated, comprising:(i) a yc-binding moiety, and(ii) an IL-2Rp-binding moiety.

2. An antigen-binding molecule, optionally isolated, comprising a yc-binding moiety.

3. An antigen-binding molecule, optionally isolated, comprising an IL-2Rp-binding moiety.

4. The antigen binding molecule according to any one of claims 1 to 3, wherein antigen-binding molecule comprises a VHH binding moiety.

5. The antigen-binding molecule according to any one of claims 1 , 2, or 4, wherein the yc-binding moiety comprises a VH sequence incorporating the following CDRs:(i) CDR1 having the amino acid sequence of SEQ ID NO:267 CDR2 having the amino acid sequence of SEQ ID NO:268 CDR3 having the amino acid sequence of SEQ ID NO:269;(ii) CDR1 having the amino acid sequence of SEQ ID NQ:270 CDR2 having the amino acid sequence of SEQ ID NO:271 CDR3 having the amino acid sequence of SEQ ID NO:272;(iii) CDR1 having the amino acid sequence of SEQ ID NO:276 CDR2 having the amino acid sequence of SEQ ID NO:277 CDR3 having the amino acid sequence of SEQ ID NO:278;(iv) CDR1 having the amino acid sequence of SEQ ID NO:273 CDR2 having the amino acid sequence of SEQ ID NO:274 CDR3 having the amino acid sequence of SEQ ID NO:275;(v) CDR1 having the amino acid sequence of SEQ ID NO:279 CDR2 having the amino acid sequence of SEQ ID NQ:280 CDR3 having the amino acid sequence of SEQ ID NO:281 ;(vi) CDR1 having the amino acid sequence of SEQ ID NO:282 CDR2 having the amino acid sequence of SEQ ID NO:283 CDR3 having the amino acid sequence of SEQ ID NO:284;(vii) CDR1 having the amino acid sequence of SEQ ID NO:285 CDR2 having the amino acid sequence of SEQ ID NO:286CDR3 having the amino acid sequence of SEQ ID NO:287;(viii) CDR1 having the amino acid sequence of SEQ ID NO:288 CDR2 having the amino acid sequence of SEQ ID NO:289 CDR3 having the amino acid sequence of SEQ ID NQ:290;(ix) CDR1 having the amino acid sequence of SEQ ID NO:291 CDR2 having the amino acid sequence of SEQ ID NO:292 CDR3 having the amino acid sequence of SEQ ID NO:293;(x) CDR1 having the amino acid sequence of SEQ ID NO:294 CDR2 having the amino acid sequence of SEQ ID NO:295 CDR3 having the amino acid sequence of SEQ ID NO:296; or(xi) CDR1 having the amino acid sequence of SEQ ID NO:297 CDR2 having the amino acid sequence of SEQ ID NO:298 CDR3 having the amino acid sequence of SEQ ID NO:299;6. The antigen-binding molecule according to any one of claims 1 , 2, 4, or 5, wherein the yc-binding moiety comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NQ:501 , SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178.

7. The antigen-binding molecule according to any one of claims 1 , 2, or 4 to 6, wherein the yc- binding moiety comprises a VH sequence incorporating the following FRs:(i) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:400 FR3 having the amino acid sequence of SEQ ID NO:463 FR4 having the amino acid sequence of SEQ ID NO:475;(ii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:400 FR3 having the amino acid sequence of SEQ ID NO:462 FR4 having the amino acid sequence of SEQ ID NO:475;(iii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:401 FR3 having the amino acid sequence of SEQ ID NO:465 FR4 having the amino acid sequence of SEQ ID NO:473;(iv) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:403 FR3 having the amino acid sequence of SEQ ID NO:466 FR4 having the amino acid sequence of SEQ ID NO:474;(v) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:400 FR3 having the amino acid sequence of SEQ ID NO:425 FR4 having the amino acid sequence of SEQ ID NO:471 ;(vi) FR1 having the amino acid sequence of SEQ ID NO:378 FR2 having the amino acid sequence of SEQ ID NQ:401 FR3 having the amino acid sequence of SEQ ID NO:426 FR4 having the amino acid sequence of SEQ ID NO:471 ;(vii) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NQ:403 FR3 having the amino acid sequence of SEQ ID NO:428 FR4 having the amino acid sequence of SEQ ID NO:472;(viii) FR1 having the amino acid sequence of SEQ ID NO:379 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:427 FR4 having the amino acid sequence of SEQ ID NO:471 ;(ix) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NO:392 FR3 having the amino acid sequence of SEQ ID NO:429 FR4 having the amino acid sequence of SEQ ID NO:471 ;(x) FR1 having the amino acid sequence of SEQ ID NO:395 FR2 having the amino acid sequence of SEQ ID NO:392 FR3 having the amino acid sequence of SEQ ID NO:429 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xi) FR1 having the amino acid sequence of SEQ ID NO:393 FR2 having the amino acid sequence of SEQ ID NQ:404 FR3 having the amino acid sequence of SEQ ID NQ:430 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xii) FR1 having the amino acid sequence of SEQ ID NO:382 FR2 having the amino acid sequence of SEQ ID NQ:405FR3 having the amino acid sequence of SEQ ID NO:431 ;FR4 having the amino acid sequence of SEQ ID NO:484,(xiii) FR1 having the amino acid sequence of SEQ ID NO:394 FR2 having the amino acid sequence of SEQ ID NQ:406 FR3 having the amino acid sequence of SEQ ID NO:432 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xiv) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:407 FR3 having the amino acid sequence of SEQ ID NO:433 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xv) FR1 having the amino acid sequence of SEQ ID NO:396 FR2 having the amino acid sequence of SEQ ID NQ:408 FR3 having the amino acid sequence of SEQ ID NO:434 FR4 having the amino acid sequence of SEQ ID NO:471 ; or(xvi) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:405 FR3 having the amino acid sequence of SEQ ID NO:435 FR4 having the amino acid sequence of SEQ ID NO:471 .

8. The antigen-binding molecule according to any one of claims 1 , or 3 to 7, wherein the IL-2R0- binding moiety comprises a VH sequence incorporating the following CDRs:(i) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NQ:304 CDR3 having the amino acid sequence of SEQ ID NQ:305;(ii) CDR1 having the amino acid sequence of SEQ ID NQ:300 CDR2 having the amino acid sequence of SEQ ID NQ:301 CDR3 having the amino acid sequence of SEQ ID NQ:302;(iii) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NO:312 CDR3 having the amino acid sequence of SEQ ID NO:313;(iv) CDR1 having the amino acid sequence of SEQ ID NQ:306 CDR2 having the amino acid sequence of SEQ ID NQ:307 CDR3 having the amino acid sequence of SEQ ID NQ:308;202(v) CDR1 having the amino acid sequence of SEQ ID NO:309 CDR2 having the amino acid sequence of SEQ ID NO:310 CDR3 having the amino acid sequence of SEQ ID NO:311 ,(vi) CDR1 having the amino acid sequence of SEQ ID NO:314 CDR2 having the amino acid sequence of SEQ ID NO:315 CDR3 having the amino acid sequence of SEQ ID NO:316;(vii) CDR1 having the amino acid sequence of SEQ ID NO:317 CDR2 having the amino acid sequence of SEQ ID NO:318 CDR3 having the amino acid sequence of SEQ ID NO:319;(viii) CDR1 having the amino acid sequence of SEQ ID NQ:320 CDR2 having the amino acid sequence of SEQ ID NO:321 CDR3 having the amino acid sequence of SEQ ID NO:322;(ix) CDR1 having the amino acid sequence of SEQ ID NO:323 CDR2 having the amino acid sequence of SEQ ID NO:324 CDR3 having the amino acid sequence of SEQ ID NO:325;(x) CDR1 having the amino acid sequence of SEQ ID NO:326 CDR2 having the amino acid sequence of SEQ ID NO:327 CDR3 having the amino acid sequence of SEQ ID NO:328;(xi) CDR1 having the amino acid sequence of SEQ ID NO:329 CDR2 having the amino acid sequence of SEQ ID NQ:330 CDR3 having the amino acid sequence of SEQ ID NO:331 ;(xii) CDR1 having the amino acid sequence of SEQ ID NO:332 CDR2 having the amino acid sequence of SEQ ID NO:333 CDR3 having the amino acid sequence of SEQ ID NO:334;(xiii) CDR1 having the amino acid sequence of SEQ ID NO:335 CDR2 having the amino acid sequence of SEQ ID NO:336 CDR3 having the amino acid sequence of SEQ ID NO:337;(xiv) CDR1 having the amino acid sequence of SEQ ID NO:338 CDR2 having the amino acid sequence of SEQ ID NO:339 CDR3 having the amino acid sequence of SEQ ID NQ:340;(xv) CDR1 having the amino acid sequence of SEQ ID NO:341 CDR2 having the amino acid sequence of SEQ ID NO:342203CDR3 having the amino acid sequence of SEQ ID NO:343;(xvi) CDR1 having the amino acid sequence of SEQ ID NO:344CDR2 having the amino acid sequence of SEQ ID NO:345CDR3 having the amino acid sequence of SEQ ID NO:346;(xvii) CDR1 having the amino acid sequence of SEQ ID NO:347CDR2 having the amino acid sequence of SEQ ID NO:348CDR3 having the amino acid sequence of SEQ ID NO:349;(xviii) CDR1 having the amino acid sequence of SEQ ID NQ:350CDR2 having the amino acid sequence of SEQ ID NO:351CDR3 having the amino acid sequence of SEQ ID NO:352;(xix) CDR1 having the amino acid sequence of SEQ ID NO:353CDR2 having the amino acid sequence of SEQ ID NO:354CDR3 having the amino acid sequence of SEQ ID NO:355;(xx) CDR1 having the amino acid sequence of SEQ ID NO:356CDR2 having the amino acid sequence of SEQ ID NO:357CDR3 having the amino acid sequence of SEQ ID NO:358;(xxi) CDR1 having the amino acid sequence of SEQ ID NO:359CDR2 having the amino acid sequence of SEQ ID NQ:360CDR3 having the amino acid sequence of SEQ ID NO:361 ;(xxii) CDR1 having the amino acid sequence of SEQ ID NO:362CDR2 having the amino acid sequence of SEQ ID NO:363CDR3 having the amino acid sequence of SEQ ID NO:364;(xxiii) CDR1 having the amino acid sequence of SEQ ID NO:365CDR2 having the amino acid sequence of SEQ ID NO:366CDR3 having the amino acid sequence of SEQ ID NO:367;(xxiv) CDR1 having the amino acid sequence of SEQ ID NO:368CDR2 having the amino acid sequence of SEQ ID NO:369CDR3 having the amino acid sequence of SEQ ID NQ:370;(xxv) CDR1 having the amino acid sequence of SEQ ID NO:371 CDR2 having the amino acid sequence of SEQ ID NO:372 CDR3 having the amino acid sequence of SEQ ID NO:373; or204(xxvi) CDR1 having the amino acid sequence of SEQ ID NO:374CDR2 having the amino acid sequence of SEQ ID NO:375CDR3 having the amino acid sequence of SEQ ID NO:3769. The antigen-binding molecule according to any one of claims 1 , or 3 to 8, wherein the IL-2R0- binding moiety comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:481 , SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:479, SEQ ID NQ:480, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NQ:150, SEQ ID NO:151 , SEQID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQID NO:158, SEQ ID NO:159, SEQ ID NQ:160, SEQ ID NO:161 , SEQ ID NO:162, SEQ ID NO:163, SEQID NO:164, SEQ ID NO:165, or SEQ ID NO:166.

10. The antigen-binding molecule according to any one of claims 1 , or 3 to 9, wherein the IL-2R0- binding moiety comprises a VH sequence incorporating the following FRs:(i) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:468 FR4 having the amino acid sequence of SEQ ID NO:473;(ii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:464 FR4 having the amino acid sequence of SEQ ID NO:473;(iii) FR1 having the amino acid sequence of SEQ ID NO:398 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:464 FR4 having the amino acid sequence of SEQ ID NO:473;(iv) FR1 having the amino acid sequence of SEQ ID NO:399 FR2 having the amino acid sequence of SEQ ID NO:467 FR3 having the amino acid sequence of SEQ ID NO:469 FR4 having the amino acid sequence of SEQ ID NO:473;(v) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NQ:470 FR4 having the amino acid sequence of SEQ ID NO:473;(vi) FR1 having the amino acid sequence of SEQ ID NO:385205FR2 having the amino acid sequence of SEQ ID NO:402 FR3 having the amino acid sequence of SEQ ID NO:437 FR4 having the amino acid sequence of SEQ ID NO:471 ;(vii) FR1 having the amino acid sequence of SEQ ID NO:383 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:436 FR4 having the amino acid sequence of SEQ ID NO:471 ;(viii) FR1 having the amino acid sequence of SEQ ID NO:385 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NQ:440 FR4 having the amino acid sequence of SEQ ID NO: 471 ;(ix) FR1 having the amino acid sequence of SEQ ID NO:383 FR2 having the amino acid sequence of SEQ ID NQ:409 FR3 having the amino acid sequence of SEQ ID NO:438 FR4 having the amino acid sequence of SEQ ID NO:471 ;(x) FR1 having the amino acid sequence of SEQ ID NO:381 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NO:439 FR4 having the amino acid sequence of SEQ ID NO: 471 ;(xi) FR1 having the amino acid sequence of SEQ ID NO:380 FR2 having the amino acid sequence of SEQ ID NO:411 FR3 having the amino acid sequence of SEQ ID NO:441 FR4 having the amino acid sequence of: TV;(xii) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:412 FR3 having the amino acid sequence of SEQ ID NO:442 FR4 having the amino acid sequence of SEQ ID NO: 471 ;(xiii) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:402 FR3 having the amino acid sequence of SEQ ID NO:443 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xiv) FR1 having the amino acid sequence of SEQ ID NO:382 FR2 having the amino acid sequence of SEQ ID NO:402 FR3 having the amino acid sequence of SEQ ID NO:444206FR4 having the amino acid sequence of SEQ ID NO:485;(xv) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NO:445 FR4 having the amino acid sequence of SEQ ID NO:471(xvi) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:413 FR3 having the amino acid sequence of SEQ ID NO:446 FR4 having the amino acid sequence of SEQ ID NO:471(xvii) FR1 having the amino acid sequence of SEQ ID NO:384 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:447 FR4 having the amino acid sequence of SEQ ID NO:471(xviii) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NO:414 FR3 having the amino acid sequence of SEQ ID NO:448 FR4 having the amino acid sequence of SEQ ID NO:471(xix) FR1 having the amino acid sequence of SEQ ID NO:386 FR2 having the amino acid sequence of SEQ ID NO:415 FR3 having the amino acid sequence of SEQ ID NO:449 FR4 having the amino acid sequence of SEQ ID NO:471(xx) FR1 having the amino acid sequence of SEQ ID NO:387 FR2 having the amino acid sequence of SEQ ID NO:416 FR3 having the amino acid sequence of SEQ ID NQ:450 FR4 having the amino acid sequence of SEQ ID NO:471(xxi) FR1 having the amino acid sequence of SEQ ID NO:388 FR2 having the amino acid sequence of SEQ ID NO:417 FR3 having the amino acid sequence of SEQ ID NO:451 FR4 having the amino acid sequence of SEQ ID NO:471(xxii) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NO:418 FR3 having the amino acid sequence of SEQ ID NO:452 FR4 having the amino acid sequence of SEQ ID NO:471207(xxiii) FR1 having the amino acid sequence of SEQ ID NO:387 FR2 having the amino acid sequence of SEQ ID NO:419 FR3 having the amino acid sequence of SEQ ID NO:453 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxiv) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:420 FR3 having the amino acid sequence of SEQ ID NO:454 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxv) FR1 having the amino acid sequence of SEQ ID NQ:380FR2 having the amino acid sequence of SEQ ID NO:421FR3 having the amino acid sequence of SEQ ID NO:455FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxvi) FR1 having the amino acid sequence of SEQ ID NO:389FR2 having the amino acid sequence of SEQ ID NQ:402FR3 having the amino acid sequence of SEQ ID NO:456FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxvii) FR1 having the amino acid sequence of SEQ ID NQ:390 FR2 having the amino acid sequence of SEQ ID NO:422 FR3 having the amino acid sequence of SEQ ID NO:457 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxviii) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:458 FR4 having the amino acid sequence of SEQ ID NO: 471 ;(xxix) FR1 having the amino acid sequence of SEQ ID NO:391 FR2 having the amino acid sequence of SEQ ID NO:423 FR3 having the amino acid sequence of SEQ ID NO:459 FR4 having the amino acid sequence of SEQ ID NO: 471 ;(xxx) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:424 FR3 having the amino acid sequence of SEQ ID NO:460 FR4 having the amino acid sequence of SEQ ID NO: 471 ; or(xxxi) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NQ:402208FR3 having the amino acid sequence of SEQ ID NO:461FR4 having the amino acid sequence of SEQ ID NO:471 .11 . The antigen-binding molecule according to any one of claims 1 to 10, wherein the antigen-binding molecule comprises:(i) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:267CDR2 having the amino acid sequence of SEQ ID NO:268CDR3 having the amino acid sequence of SEQ ID NO:269, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:303CDR2 having the amino acid sequence of SEQ ID NQ:304CDR3 having the amino acid sequence of SEQ ID NQ:305;(ii) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:267CDR2 having the amino acid sequence of SEQ ID NO:268CDR3 having the amino acid sequence of SEQ ID NO:269, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:300CDR2 having the amino acid sequence of SEQ ID NQ:301CDR3 having the amino acid sequence of SEQ ID NQ:302;(iii) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:267CDR2 having the amino acid sequence of SEQ ID NO:268CDR3 having the amino acid sequence of SEQ ID NO:269, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:309CDR2 having the amino acid sequence of SEQ ID NQ:310CDR3 having the amino acid sequence of SEQ ID NO:311 ;(iv) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:276CDR2 having the amino acid sequence of SEQ ID NO:277CDR3 having the amino acid sequence of SEQ ID NO:278, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:303CDR2 having the amino acid sequence of SEQ ID NQ:304CDR3 having the amino acid sequence of SEQ ID NQ:305;(v) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:276CDR2 having the amino acid sequence of SEQ ID NO:277CDR3 having the amino acid sequence of SEQ ID NO:278, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs:209CDR1 having the amino acid sequence of SEQ ID N0:300CDR2 having the amino acid sequence of SEQ ID NO:301 CDR3 having the amino acid sequence of SEQ ID NQ:302;(vi) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:276CDR2 having the amino acid sequence of SEQ ID NO:277CDR3 having the amino acid sequence of SEQ ID NO:278, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 .(vii) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:273CDR2 having the amino acid sequence of SEQ ID NO:274CDR3 having the amino acid sequence of SEQ ID NO:275, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NQ:304 CDR3 having the amino acid sequence of SEQ ID NQ:305;(viii) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:273CDR2 having the amino acid sequence of SEQ ID NO:274CDR3 having the amino acid sequence of SEQ ID NO:275, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:300 CDR2 having the amino acid sequence of SEQ ID NQ:301 CDR3 having the amino acid sequence of SEQ ID NQ:302;(ix) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:273CDR2 having the amino acid sequence of SEQ ID NO:274CDR3 having the amino acid sequence of SEQ ID NO:275, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 .(vii) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:270CDR2 having the amino acid sequence of SEQ ID NO:271CDR3 having the amino acid sequence of SEQ ID NO:272, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NQ:304210CDR3 having the amino acid sequence of SEQ ID NO:305;(viii) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:270 CDR2 having the amino acid sequence of SEQ ID NO:271 CDR3 having the amino acid sequence of SEQ ID NO:272, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:300 CDR2 having the amino acid sequence of SEQ ID NQ:301 CDR3 having the amino acid sequence of SEQ ID NQ:302; or(ix) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NQ:270 CDR2 having the amino acid sequence of SEQ ID NO:271 CDR3 having the amino acid sequence of SEQ ID NO:272, and an IL-2Rp-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310 CDR3 having the amino acid sequence of SEQ ID NO:311 .

12. The antigen-binding molecule according to any one of claims 1 to 11 , wherein the antigen-binding molecule comprises or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:251 , SEQ ID NQ:250, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:256, SEQ ID NO:264, SEQ ID NO:266, SEQ ID NO:239, SEQ ID NQ:240, SEQ ID NO:241 , SEQ IDNO:242, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ IDNO:248, SEQ ID NO:249, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:257, SEQ ID NO:258, SEQ IDNO:259, SEQ ID NQ:260, SEQ ID NO:261 , SEQ ID NO:262, SEQ ID NO:263, and / or SEQ ID NO:265.

13. The antigen-binding molecule according to any one of claims 1 to 12, wherein the antigen-binding molecule comprises, from N-terminus to C-terminus:(d) a yc-binding moiety,(e) a linker, and(f) an IL-2Rp-binding moiety.

14. The antigen-binding molecule according to any one of claim 13, wherein the yc-binding moiety comprises a VHH, and the IL-2Rp-binding moiety comprises a VHH.

15. The antigen-binding molecule according to claim 13 or claim 14, wherein the linker connects the C-terminus of the yc-binding moiety to the N-terminus of the IL-2Rp-binding moiety.

16. A chimeric antigen receptor (CAR), comprising an antigen-binding molecule according to any one of claims 1 to 15.21117. A nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule according to any one of claims 1 to 15, or a CAR according to claim 16.

18. An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 17.

19. A cell comprising an antigen-binding molecule according to any one of claims 1 to 15, a CAR according to claim 16, a nucleic acid or a plurality of nucleic acids according to claim 17, or an expression vector or a plurality of expression vectors according to claim 18.

20. A method comprising culturing a cell according to claim 19 under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

21. A composition comprising an antigen-binding molecule according to any one of claims 1 to 15, a CAR according to claim 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, or a cell according to claim 19, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

22. An antigen-binding molecule according to any one of claims 1 to 15, a CAR according to claim 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, or a cell according to claim 19, or a composition according to claim 21 , for use in a method of treatment or prophylaxis.

23. Use of an antigen-binding molecule according to any one of claims 1 to 15, a CAR according to claim 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, or a cell according to claim 19, or a composition according to claim 21 , in the manufacture of a medicament for use in a method of treatment or prophylaxis.

24. A method of treatment or prophylaxis, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of an antigen-binding molecule according to any one of claims 1 to 15, a CAR according to claim 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, or a cell according to claim 19, or a composition according to claim 21.

25. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to claim 22, the use according to claim 23 or the method according to claim 24, wherein the method of treatment or prophylaxis is a method of treating or preventing a disease or condition that would derive therapeutic or prophylactic benefit from an increase in signalling mediated by IL-2.21226. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to claim 22, the use according to claim 23 or the method according to claim 24, wherein the method of treatment or prophylaxis is a method of treating or preventing a disease / condition characterised by T cell dysfunction, a cancer, or an infectious disease.

27. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use, the use or the method according to claim 26, wherein the cancer is selected from the group consisting of: colon cancer, colon carcinoma, colorectal cancer, nasopharyngeal carcinoma, cervical carcinoma, oropharyngeal carcinoma, gastric carcinoma, hepatocellular carcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, laryngeal cancer, prostate cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, urothelial carcinoma, melanoma, advanced melanoma, renal cell carcinoma, ovarian cancer or mesothelioma.

28. An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 15, a CAR according to claim 16, bound to yc and IL-2Rp.

29. A method for generating or expanding a population of cells expressing a yc-containing cytokine receptor, comprising contacting a cell expressing a yc-containing cytokine receptor in vitro, in vivo or ex vivo with an antigen-binding molecule according to any one of claims 1 to 15.

30. A method for increasing the proliferation, survival and / or effector activity of a cell expressing IL- 2Rp, comprising contacting a cell expressing IL-2Rp in vitro, in vivo or ex vivo with an antigen-binding molecule according to any one of claims 1 to 15.31 . The method according to claim 30, wherein the cell is an effector immune cell.

32. The method according to claim 30, wherein the cell is a T cell or a NK cell.

33. A method of promoting heteromultimerization of yc and IL-2Rp, comprising contacting yc and IL- 2Rp in vitro, in vivo or ex vivo with an antigen-binding molecule according to any one of claims 1 to 15, or a CAR according to claim 16.213

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