Antigen-binding molecules

Abstract

Antigen binding molecules comprising a PD-1-binding moiety, γc-binding moiety, IL-2Rβ-binding moiety and / or a IL-21Rα-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 / 681730 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 for 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] Immune checkpoint proteins are expressed on the surface of immune cells (e.g., activated T-cells), and regulate the activation of the cells that they are expressed on. This regulation is controlled by ligand binding and subsequent signalling.

[0012] Programmed cell death protein 1 (PD-1) is an inhibitor of both adaptive and innate immune responses, and is expressed on activated T cells, natural killer (NK) cells, B cells, macrophages, dendritic cells (DCs) and monocytes. Importantly, PD-1 is highly expressed on tumor-specific T cells such as tumor infiltrating T lymphocytes (TILs) (Ahmadzadeh et al., Blood. 2009 Aug 20; 114(8): 1537-1544). Programmed Cell Death Ligand 1 (PD-L1) is considered to be a co-inhibitory factor of the immune response. Binding of PD-L1 with PD-1 reduces the proliferation of PD-1 positive cells, inhibits their cytokine secretion, and induces apoptosis (Han et al., Am J Cancer Res. 2020; 10(3): 727-742).

[0013] Immune checkpoint protein inhibitors can function by blocking immune checkpoint proteins from binding their ligands. This blocking is capable of preventing the inhibition of activated T-cells (e.g., activated TILs), and can improve anti-cancer responses.

[0014] Summary

[0015] In a first aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to an immune checkpoint protein.

[0016] In a second aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc.

[0017] In a third aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to IL-2R0.

[0018] In a fourth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to an immune checkpoint protein and another antigen.

[0019] In a fifth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc and another antigen.

[0020] In a sixth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to IL-2R0 and another antigen.

[0021] In a seventh aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to PD-1 , yc, and IL-2R0.

[0022] The present disclosure also provides an antigen-binding molecule, optionally isolated, which binds to IL- 21 Ra.

[0023] The present disclosure also provides an antigen-binding molecule, optionally isolated, which binds to IL- 21 Ra and another antigen.

[0024] The present disclosure also provides an antigen-binding molecule, optionally isolated, which binds to PD- 1 , yc, and IL-21 Ra.

[0025] An antigen-binding molecule is also provided, optionally isolated, comprising

[0026] (i) a yc-binding moiety, (ii) a moiety that binds to a polypeptide of a yc-containing cytokine receptor other than yc, and

[0027] (iii) an immune checkpoint protein-binding moiety.

[0028] In some embodiments, the immune checkpoint protein is PD-1 , CTLA4, GITR, or LAG3.

[0029] In some embodiments, the immune checkpoint protein is PD-1 .

[0030] In some embodiments, the polypeptide of a yc-containing cytokine receptor other than yc is IL-2Rp or IL- 21 Ra.

[0031] In some embodiments, the polypeptide of a yc-containing cytokine receptor other than yc is IL-2R0.

[0032] In some embodiments, the polypeptide of a yc-containing cytokine receptor other than yc is IL-21 Ra.

[0033] In some embodiments, the PD-1-binding moiety comprises a VH sequence incorporating the following CDRs:

[0034] (a) CDR1 having the amino acid sequence of SEQ ID NO:669 CDR2 having the amino acid sequence of SEQ ID NO:670 CDR3 having the amino acid sequence of SEQ ID NO:671 ;

[0035] (b) CDR1 having the amino acid sequence of SEQ ID NO:649 CDR2 having the amino acid sequence of SEQ ID NQ:650 CDR3 having the amino acid sequence of SEQ ID NO:651 ;

[0036] (c) CDR1 having the amino acid sequence of SEQ ID NO:643 CDR2 having the amino acid sequence of SEQ ID NO:644 CDR3 having the amino acid sequence of SEQ ID NO:645;

[0037] (d) CDR1 having the amino acid sequence of SEQ ID NO:674 CDR2 having the amino acid sequence of SEQ ID NO:675 CDR3 having the amino acid sequence of SEQ ID NO:676;

[0038] (e) CDR1 having the amino acid sequence of SEQ ID NO:646 CDR2 having the amino acid sequence of SEQ ID NO:647 CDR3 having the amino acid sequence of SEQ ID NO:648;

[0039] (f) CDR1 having the amino acid sequence of SEQ ID NQ:350 CDR2 having the amino acid sequence of SEQ ID NO:636 CDR3 having the amino acid sequence of SEQ ID NO:637; (g) CDR1 having the amino acid sequence of SEQ ID NO:633

[0040] CDR2 having the amino acid sequence of SEQ ID NO:634 CDR3 having the amino acid sequence of SEQ ID NO:635;

[0041] (h) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NO:638 CDR3 having the amino acid sequence of SEQ ID NO:639;

[0042] (i) CDR1 having the amino acid sequence of SEQ ID NQ:640 CDR2 having the amino acid sequence of SEQ ID NO:641 CDR3 having the amino acid sequence of SEQ ID NO:642;

[0043] (j) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NO:652 CDR3 having the amino acid sequence of SEQ ID NO:653;

[0044] (k) CDR1 having the amino acid sequence of SEQ ID NO:654 CDR2 having the amino acid sequence of SEQ ID NO:655 CDR3 having the amino acid sequence of SEQ ID NO:656;

[0045] (l) CDR1 having the amino acid sequence of SEQ ID NO:657 CDR2 having the amino acid sequence of SEQ ID NO:658 CDR3 having the amino acid sequence of SEQ ID NO:659;

[0046] (m) CDR1 having the amino acid sequence of SEQ ID NQ:660 CDR2 having the amino acid sequence of SEQ ID NO:661 CDR3 having the amino acid sequence of SEQ ID NO:662;

[0047] (n) CDR1 having the amino acid sequence of SEQ ID NO:663 CDR2 having the amino acid sequence of SEQ ID NO:664 CDR3 having the amino acid sequence of SEQ ID NO:665;

[0048] (o) CDR1 having the amino acid sequence of SEQ ID NO:666 CDR2 having the amino acid sequence of SEQ ID NO:667 CDR3 having the amino acid sequence of SEQ ID NO:668; or

[0049] (p) CDR1 having the amino acid sequence of SEQ ID NO:663 CDR2 having the amino acid sequence of SEQ ID NQ:360 CDR3 having the amino acid sequence of SEQ ID NO:673.

[0050] In some embodiments, the PD-1-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:743, SEQ ID NO:738, SEQ ID NO:739, SEQ ID NO:740, SEQ ID NO:741 , SEQ ID NO:742, SEQ ID NO:744, SEQ ID NO:745,

[0051] SEQ ID NO:746, SEQ ID NO: 630, SEQ ID NO:617, SEQ ID NO:618, SEQ ID NO:619, SEQ ID NO:620,

[0052] SEQ ID NO:621 , SEQ ID NO:622, SEQ ID NO:623, SEQ ID NO:624, SEQ ID NO:625, SEQ ID NO:626,

[0053] SEQ ID NO:627, SEQ ID NO:628, SEQ ID NO:629, SEQ ID NO:631 , or SEQ ID NO:632.

[0054] In some embodiments, the PD-1-binding moiety comprises a VH sequence incorporating the following FRs:

[0055] (a) FR1 having the amino acid sequence of SEQ ID NO:397

[0056] FR2 having the amino acid sequence of SEQ ID NO:732

[0057] FR3 having the amino acid sequence of SEQ ID NO:727

[0058] FR4 having the amino acid sequence of SEQ ID NO:728;

[0059] (b) FR1 having the amino acid sequence of SEQ ID NO:377

[0060] FR2 having the amino acid sequence of SEQ ID NO:712

[0061] FR3 having the amino acid sequence of SEQ ID NO:713

[0062] FR4 having the amino acid sequence of SEQ ID NO:714;

[0063] (c) FR1 having the amino acid sequence of SEQ ID NO:377

[0064] FR2 having the amino acid sequence of SEQ ID NQ:402

[0065] FR3 having the amino acid sequence of SEQ ID NO:699

[0066] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0067] (d) FR1 having the amino acid sequence of SEQ ID NO:694

[0068] FR2 having the amino acid sequence of SEQ ID NO:695

[0069] FR3 having the amino acid sequence of SEQ ID NO:696

[0070] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0071] (e) FR1 having the amino acid sequence of SEQ ID NO:715

[0072] FR2 having the amino acid sequence of SEQ ID NO:716 FR3 having the amino acid sequence of SEQ ID NO:717 FR4 having the amino acid sequence of SEQ ID NO:484;

[0073] (f) FR1 having the amino acid sequence of SEQ ID NO:697

[0074] FR2 having the amino acid sequence of SEQ ID NQ:402

[0075] FR3 having the amino acid sequence of SEQ ID NO:698

[0076] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0077] (g) FR1 having the amino acid sequence of SEQ ID NO:687

[0078] FR2 having the amino acid sequence of SEQ ID NO:688

[0079] FR3 having the amino acid sequence of SEQ ID NO:689

[0080] FR4 having the amino acid sequence of SEQ ID NQ:690; (h) FR1 having the amino acid sequence of SEQ ID NO:683 FR2 having the amino acid sequence of SEQ ID NO:402 FR3 having the amino acid sequence of SEQ ID NO:685 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0081] (i) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:422 FR3 having the amino acid sequence of SEQ ID NO:691 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0082] (j) FR1 having the amino acid sequence of SEQ ID NO:692 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NO:693 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0083] (k) FR1 having the amino acid sequence of SEQ ID NO:385 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NQ:700 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0084] (l) FR1 having the amino acid sequence of SEQ ID NQ:701 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NQ:702 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0085] (m) 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 NQ:703 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0086] (n) FR1 having the amino acid sequence of SEQ ID NQ:704 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NQ:705 FR4 having the amino acid sequence of SEQ ID NQ:706;

[0087] (o) FR1 having the amino acid sequence of SEQ ID NQ:707 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NQ:708 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0088] (p) FR1 having the amino acid sequence of SEQ ID NQ:709 FR2 having the amino acid sequence of SEQ ID NO:710 FR3 having the amino acid sequence of SEQ ID NO:711 FR4 having the amino acid sequence of SEQ ID NO:471

[0089] (q) 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 NQ:440 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0090] (r) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:712 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;

[0091] (s) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:726 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;

[0092] (t) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:729 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;

[0093] (u) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:730 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;

[0094] (v) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO.731 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;

[0095] (w) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:733 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;

[0096] (x) 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:734 FR4 having the amino acid sequence of SEQ ID NO:735; or

[0097] (y) FR1 having the amino acid sequence of SEQ ID NO:694

[0098] FR2 having the amino acid sequence of SEQ ID NO:695 FR3 having the amino acid sequence of SEQ ID NO:737

[0099] FR4 having the amino acid sequence of SEQ ID NO:735.

[0100] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0101] (i) CDR1 having the amino acid sequence of SEQ ID NQ:760 CDR2 having the amino acid sequence of SEQ ID NO:776 CDR3 having the amino acid sequence of SEQ ID NO:792,

[0102] (ii) CDR1 having the amino acid sequence of SEQ ID NO:761 CDR2 having the amino acid sequence of SEQ ID NO:777 CDR3 having the amino acid sequence of SEQ ID NO:793,

[0103] (iii) CDR1 having the amino acid sequence of SEQ ID NO:762 CDR2 having the amino acid sequence of SEQ ID NO:778 CDR3 having the amino acid sequence of SEQ ID NO:794,

[0104] (iv) CDR1 having the amino acid sequence of SEQ ID NO:763 CDR2 having the amino acid sequence of SEQ ID NO:779 CDR3 having the amino acid sequence of SEQ ID NO:795,

[0105] (v) CDR1 having the amino acid sequence of SEQ ID NO:764 CDR2 having the amino acid sequence of SEQ ID NQ:780 CDR3 having the amino acid sequence of SEQ ID NO:796,

[0106] (vi) CDR1 having the amino acid sequence of SEQ ID NO:765 CDR2 having the amino acid sequence of SEQ ID NO:781 CDR3 having the amino acid sequence of SEQ ID NO:797,

[0107] (vii) CDR1 having the amino acid sequence of SEQ ID NO:766 CDR2 having the amino acid sequence of SEQ ID NO:782 CDR3 having the amino acid sequence of SEQ ID NO:798,

[0108] (viii) CDR1 having the amino acid sequence of SEQ ID NO:767 CDR2 having the amino acid sequence of SEQ ID NO:783 CDR3 having the amino acid sequence of SEQ ID NO:799,

[0109] (ix) CDR1 having the amino acid sequence of SEQ ID NO:768 CDR2 having the amino acid sequence of SEQ ID NO:784

[0110] CDR3 having the amino acid sequence of SEQ ID NQ:800,

[0111] (X) CDR1 having the amino acid sequence of SEQ ID NO:769

[0112] CDR2 having the amino acid sequence of SEQ ID NO:785

[0113] CDR3 having the amino acid sequence of SEQ ID NQ:801 ,

[0114] (xi) CDR1 having the amino acid sequence of SEQ ID NQ:770

[0115] CDR2 having the amino acid sequence of SEQ ID NO:786

[0116] CDR3 having the amino acid sequence of SEQ ID NQ:802,

[0117] (xii) CDR1 having the amino acid sequence of SEQ ID NO:771

[0118] CDR2 having the amino acid sequence of SEQ ID NO:787

[0119] CDR3 having the amino acid sequence of SEQ ID NQ:803,

[0120] (xiii) CDR1 having the amino acid sequence of SEQ ID NO:772

[0121] CDR2 having the amino acid sequence of SEQ ID NO:788

[0122] CDR3 having the amino acid sequence of SEQ ID NQ:804,

[0123] (xiv) CDR1 having the amino acid sequence of SEQ ID NO:773

[0124] CDR2 having the amino acid sequence of SEQ ID NO:789

[0125] CDR3 having the amino acid sequence of SEQ ID NQ:805,

[0126] (xv) CDR1 having the amino acid sequence of SEQ ID NO:774

[0127] CDR2 having the amino acid sequence of SEQ ID NQ:790

[0128] CDR3 having the amino acid sequence of SEQ ID NQ:806,

[0129] (xvi) CDR1 having the amino acid sequence of SEQ ID NO:775

[0130] CDR2 having the amino acid sequence of SEQ ID NO:791

[0131] CDR3 having the amino acid sequence of SEQ ID NQ:807,

[0132] CDR1 having the amino acid sequence of SEQ ID NO:267

[0133] CDR2 having the amino acid sequence of SEQ ID NO:268

[0134] CDR3 having the amino acid sequence of SEQ ID NO:269;

[0135] (xvii) CDR1 having the amino acid sequence of SEQ ID NQ:270

[0136] CDR2 having the amino acid sequence of SEQ ID NO:271

[0137] CDR3 having the amino acid sequence of SEQ ID NO:272;

[0138] (xviii) CDR1 having the amino acid sequence of SEQ ID NO:276

[0139] CDR2 having the amino acid sequence of SEQ ID NO:277

[0140] CDR3 having the amino acid sequence of SEQ ID NO:278; (xix) CDR1 having the amino acid sequence of SEQ ID NO:273

[0141] CDR2 having the amino acid sequence of SEQ ID NO:274 CDR3 having the amino acid sequence of SEQ ID NO:275;

[0142] (xx) 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 ;

[0143] (xxi) 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;

[0144] (xxii) 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;

[0145] (xxiii) 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;

[0146] (xxiv) 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;

[0147] (xxv) 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

[0148] (xxvi) 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.

[0149] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs:

[0150] (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;

[0151] (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

[0152] CDR2 having the amino acid sequence of SEQ ID NO:277

[0153] CDR3 having the amino acid sequence of SEQ ID NO:278;

[0154] (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;

[0155] (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 ;

[0156] (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;

[0157] (vii) 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;

[0158] (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;

[0159] (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;

[0160] (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

[0161] (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;

[0162] 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 NO:851 , SEQ ID NO:852, SEQ ID NO:853, SEQ ID NO:854, SEQ ID NO:855, SEQ ID NO:856, SEQ ID NO:857, SEQ ID NO:858, SEQ ID

[0163] NO:859, SEQ ID NQ:860, SEQ ID NO:861 , SEQ ID NO:862, SEQ ID NO:863, SEQ ID NO:864, SEQ ID

[0164] NO:865, SEQ ID NO:866, SEQ ID NO:867, SEQ ID NO:868, SEQ ID NQ:501 , SEQ ID NO:476, SEQ ID

[0165] NO:477, SEQ ID NO:478, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID N0:171 , 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.

[0166] 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.

[0167] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following FRs:

[0168] (i) FR1 having the amino acid sequence of SEQ ID NQ:808 FR2 having the amino acid sequence of SEQ ID NO:816 FR3 having the amino acid sequence of SEQ ID NO:831 FR4 having the amino acid sequence of SEQ ID NO:848,

[0169] (ii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:817 FR3 having the amino acid sequence of SEQ ID NO:832 FR4 having the amino acid sequence of SEQ ID NO:849,

[0170] (iii) FR1 having the amino acid sequence of SEQ ID NQ:810 FR2 having the amino acid sequence of SEQ ID NO:818 FR3 having the amino acid sequence of SEQ ID NO:833 FR4 having the amino acid sequence of SEQ ID NO:848,

[0171] (iv) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:819 FR3 having the amino acid sequence of SEQ ID NO:834 FR4 having the amino acid sequence of SEQ ID NO:848,

[0172] (v) FR1 having the amino acid sequence of SEQ ID NO:811 FR2 having the amino acid sequence of SEQ ID NQ:820 FR3 having the amino acid sequence of SEQ ID NO:835 FR4 having the amino acid sequence of SEQ ID NO:848,

[0173] (vi) FR1 having the amino acid sequence of SEQ ID NO:812 FR2 having the amino acid sequence of SEQ ID NO:821 FR3 having the amino acid sequence of SEQ ID NO:836 FR4 having the amino acid sequence of SEQ ID NO:848,

[0174] (vii) FR1 having the amino acid sequence of SEQ ID NQ:809

[0175] FR2 having the amino acid sequence of SEQ ID NO:817 FR3 having the amino acid sequence of SEQ ID NO:837 FR4 having the amino acid sequence of SEQ ID NO:848,

[0176] (viii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:822 FR3 having the amino acid sequence of SEQ ID NO:838 FR4 having the amino acid sequence of SEQ ID NO:848,

[0177] (ix) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:823 FR3 having the amino acid sequence of SEQ ID NO:839 FR4 having the amino acid sequence of SEQ ID NO:848,

[0178] (x) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:817 FR3 having the amino acid sequence of SEQ ID NQ:840 FR4 having the amino acid sequence of SEQ ID NO:848,

[0179] (xi) FR1 having the amino acid sequence of SEQ ID NO:813 FR2 having the amino acid sequence of SEQ ID NO:824 FR3 having the amino acid sequence of SEQ ID NO:841 FR4 having the amino acid sequence of SEQ ID NO:848,

[0180] (xii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:825 FR3 having the amino acid sequence of SEQ ID NO:842 FR4 having the amino acid sequence of SEQ ID NO:848,

[0181] (xiii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:826 FR3 having the amino acid sequence of SEQ ID NO:843 FR4 having the amino acid sequence of SEQ ID NO:848,

[0182] (xiv) FR1 having the amino acid sequence of SEQ ID NO:814 FR2 having the amino acid sequence of SEQ ID NO:827 FR3 having the amino acid sequence of SEQ ID NO:844 FR4 having the amino acid sequence of SEQ ID NO:848,

[0183] (xv) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:828 FR3 having the amino acid sequence of SEQ ID NO:845 FR4 having the amino acid sequence of SEQ ID NO:848, (xvi) FR1 having the amino acid sequence of SEQ ID NO:815 FR2 having the amino acid sequence of SEQ ID NO:828 FR3 having the amino acid sequence of SEQ ID NO:846 FR4 having the amino acid sequence of SEQ ID NQ:850,

[0184] (xvii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:829 FR3 having the amino acid sequence of SEQ ID NO:845 FR4 having the amino acid sequence of SEQ ID NO:848,

[0185] (xviii) FR1 having the amino acid sequence of SEQ ID NO:815 FR2 having the amino acid sequence of SEQ ID NQ:830 FR3 having the amino acid sequence of SEQ ID NO:847 FR4 having the amino acid sequence of SEQ ID NO:848,

[0186] (xix) 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.

[0187] (xx) 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;

[0188] (xxi) 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;

[0189] (xxii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:403 FR3 having the amino acid sequence of SEQ ID NO:466 FR4 having the amino acid sequence of SEQ ID NO:474;

[0190] (xxiii) 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 ;

[0191] (xxiv) FR1 having the amino acid sequence of SEQ ID NO:378 FR2 having the amino acid sequence of SEQ ID NO:401 FR3 having the amino acid sequence of SEQ ID NO:426 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0192] (xxv) 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;

[0193] (xxvi) 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 ;

[0194] (xxvii) 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 ;

[0195] (xxviii) 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 ;

[0196] (xxix) 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 ;

[0197] (xxx) 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,

[0198] (xxxi) 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 ;

[0199] (xxxii) 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 ;

[0200] (xxxiii) FR1 having the amino acid sequence of SEQ ID NO:396

[0201] FR2 having the amino acid sequence of SEQ ID NQ:408

[0202] FR3 having the amino acid sequence of SEQ ID NO:434

[0203] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0204] (xxxiv) FR1 having the amino acid sequence of SEQ ID NO:377

[0205] FR2 having the amino acid sequence of SEQ ID NQ:405

[0206] FR3 having the amino acid sequence of SEQ ID NO:435

[0207] FR4 having the amino acid sequence of SEQ ID NO:471 .

[0208] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following FRs:

[0209] (i) FR1 having the amino acid sequence of SEQ ID NO:397

[0210] FR2 having the amino acid sequence of SEQ ID NQ:400

[0211] FR3 having the amino acid sequence of SEQ ID NO:462

[0212] FR4 having the amino acid sequence of SEQ ID NO:475;

[0213] (ii) FR1 having the amino acid sequence of SEQ ID NO:397

[0214] FR2 having the amino acid sequence of SEQ ID NQ:401

[0215] FR3 having the amino acid sequence of SEQ ID NO:465

[0216] FR4 having the amino acid sequence of SEQ ID NO:473;

[0217] (iii) FR1 having the amino acid sequence of SEQ ID NO:397

[0218] FR2 having the amino acid sequence of SEQ ID NQ:403

[0219] FR3 having the amino acid sequence of SEQ ID NO:466

[0220] FR4 having the amino acid sequence of SEQ ID NO:474;

[0221] (iv) FR1 having the amino acid sequence of SEQ ID NO:377

[0222] FR2 having the amino acid sequence of SEQ ID NQ:400

[0223] FR3 having the amino acid sequence of SEQ ID NO:425

[0224] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0225] (v) FR1 having the amino acid sequence of SEQ ID NO:378

[0226] FR2 having the amino acid sequence of SEQ ID NQ:401

[0227] FR3 having the amino acid sequence of SEQ ID NO:426

[0228] FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0229] (vi) FR1 having the amino acid sequence of SEQ ID NQ:380

[0230] FR2 having the amino acid sequence of SEQ ID NQ:403

[0231] FR3 having the amino acid sequence of SEQ ID NO:428 FR4 having the amino acid sequence of SEQ ID NO:472;

[0232] (vii) 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 ;

[0233] (viii) 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 ;

[0234] (ix) 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 ;

[0235] (x) 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 ;

[0236] (xi) 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,

[0237] (xii) 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 ;

[0238] (xiii) 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 ;

[0239] (xiv) 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 ; (xv) FR1 having the amino acid sequence of SEQ ID NO:377

[0240] FR2 having the amino acid sequence of SEQ ID NO:405 FR3 having the amino acid sequence of SEQ ID NO:435

[0241] FR4 having the amino acid sequence of SEQ ID NO:471 ; or

[0242] (xvi) 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.

[0243] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:

[0244] (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;

[0245] (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;

[0246] (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;

[0247] (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;

[0248] (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 ,

[0249] (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;

[0250] (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;

[0251] (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;

[0252] (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;

[0253] (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;

[0254] (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 ;

[0255] (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;

[0256] (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;

[0257] (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;

[0258] (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;

[0259] (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;

[0260] (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;

[0261] (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; (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;

[0262] (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;

[0263] (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 ;

[0264] (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;

[0265] (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;

[0266] (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;

[0267] (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

[0268] (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.

[0269] 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:875, 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,

[0270] SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148,

[0271] SEQ ID NO:149, SEQ ID NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154,

[0272] SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160,

[0273] SEQ ID NO:161 , 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, 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 NO: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,

[0274] SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149,

[0275] SEQ ID NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155,

[0276] SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160, SEQ ID NO:161 ,

[0277] SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ ID NO:166.

[0278] In some embodiments, the IL-2Rp-binding moiety comprises a VH sequence incorporating the following FRs:

[0279] (i) FR1 having the amino acid sequence of SEQ ID NO:872 FR2 having the amino acid sequence of SEQ ID NO:873 FR3 having the amino acid sequence of SEQ ID NO:874 FR4 having the amino acid sequence of SEQ ID NQ:850;

[0280] (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:468 FR4 having the amino acid sequence of SEQ ID NO:473;

[0281] (iii) 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;

[0282] (iv) 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;

[0283] (v) 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;

[0284] (vi) 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;

[0285] (vii) FR1 having the amino acid sequence of SEQ ID NO:385 FR2 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 ;

[0286] (viii) 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 ;

[0287] (ix) 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 ;

[0288] (x) FR1 having the amino acid sequence of SEQ ID NO:383 FR2 having the amino acid sequence of SEQ ID NO:409 FR3 having the amino acid sequence of SEQ ID NO:438 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0289] (xi) 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 ;

[0290] (xii) 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;

[0291] (xiii) 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 ;

[0292] (xiv) 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 ;

[0293] (xv) 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:444 FR4 having the amino acid sequence of SEQ ID NO:485;

[0294] (xvi) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:410 FR3 having the amino acid sequence of SEQ ID NO:445 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0295] (xvii) 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 ;

[0296] (xviii) 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 ;

[0297] (xix) 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 ;

[0298] (xx) 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 ;

[0299] (xxi) 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 ;

[0300] (xxii) 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 ;

[0301] (xxiii) 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:471 ; (xxiv) 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 ;

[0302] (xxv) 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 ;

[0303] (xxvi) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NO:421 FR3 having the amino acid sequence of SEQ ID NO:455 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0304] (xxvii) FR1 having the amino acid sequence of SEQ ID NO:389 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:456 FR4 having the amino acid sequence of SEQ ID NO:471 ;

[0305] (xxviii) 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 ;

[0306] (xxix) 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 ;

[0307] (xxx) 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 ;

[0308] (xxxi) 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

[0309] (xxxii) FR1 having the amino acid sequence of SEQ ID NO:377

[0310] FR2 having the amino acid sequence of SEQ ID NO:402 FR3 having the amino acid sequence of SEQ ID NO:461 FR4 having the amino acid sequence of SEQ ID NO:471 .

[0311] In some embodiments, the IL-21 Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0312] (i) CDR1 having the amino acid sequence of SEQ ID NO:877 CDR2 having the amino acid sequence of SEQ ID NO:882 CDR3 having the amino acid sequence of SEQ ID NO:887,

[0313] (ii) CDR1 having the amino acid sequence of SEQ ID NO:876 CDR2 having the amino acid sequence of SEQ ID NO:881 CDR3 having the amino acid sequence of SEQ ID NO:886,

[0314] (iii) CDR1 having the amino acid sequence of SEQ ID NO:878 CDR2 having the amino acid sequence of SEQ ID NO:883 CDR3 having the amino acid sequence of SEQ ID NO:888,

[0315] (iv) CDR1 having the amino acid sequence of SEQ ID NO:879 CDR2 having the amino acid sequence of SEQ ID NO:884 CDR3 having the amino acid sequence of SEQ ID NO:889, or

[0316] (v) CDR1 having the amino acid sequence of SEQ ID NQ:880 CDR2 having the amino acid sequence of SEQ ID NO:885 CDR3 having the amino acid sequence of SEQ ID NQ:890.

[0317] In some embodiments, the IL-21 Ra-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:906, SEQ ID NQ:905, SEQ ID NQ:907, SEQ ID NQ:908, or SEQ ID NQ:909.

[0318] In some embodiments, the IL-21 Ra-binding moiety comprises a VH sequence incorporating the following FRs:

[0319] (i) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:895 FR3 having the amino acid sequence of SEQ ID NQ:900 FR4 having the amino acid sequence of SEQ ID NO:848,

[0320] (ii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:894 FR3 having the amino acid sequence of SEQ ID NO:899 FR4 having the amino acid sequence of SEQ ID NO:848, (iii) FR1 having the amino acid sequence of SEQ ID NO:891

[0321] FR2 having the amino acid sequence of SEQ ID NO:896 FR3 having the amino acid sequence of SEQ ID NQ:901 FR4 having the amino acid sequence of SEQ ID NO:848,

[0322] (iv) FR1 having the amino acid sequence of SEQ ID NO:892 FR2 having the amino acid sequence of SEQ ID NO:897 FR3 having the amino acid sequence of SEQ ID NQ:902 FR4 having the amino acid sequence of SEQ ID NQ:904, or

[0323] (v) FR1 having the amino acid sequence of SEQ ID NO:893 FR2 having the amino acid sequence of SEQ ID NO:898 FR3 having the amino acid sequence of SEQ ID NQ:903 FR4 having the amino acid sequence of SEQ ID NO:848.

[0324] 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 NQ:910, SEQ ID NO:911 , SEQ ID NO:912, SEQ ID NO:913, SEQ ID NO:914, SEQ ID NO:915, SEQ ID NO:916, SEQ ID NO:917,

[0325] SEQ ID NO:918, SEQ ID NO:919, SEQ ID NQ:920, SEQ ID NO:921 , SEQ ID NO:922, SEQ ID NO:923,

[0326] SEQ ID NO:924, SEQ ID NO:925, SEQ ID NO:926, SEQ ID NO:927, SEQ ID NO:928, SEQ ID NO:929,

[0327] SEQ ID NQ:930, SEQ ID NO:931 , SEQ ID NO:594, SEQ ID NO:524:, SEQ ID NO:526, SEQ ID NO:528, SEQ ID NQ:530, SEQ ID NO:532, SEQ ID NO:534, SEQ ID NO:536, SEQ ID NO:538, SEQ ID NQ:540,

[0328] SEQ ID NO:542, SEQ ID NO:544, SEQ ID NO:546, SEQ ID NO:548, SEQ ID NQ:550, SEQ ID NO:552,

[0329] SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:558, SEQ ID NQ:560, SEQ ID NO:562, SEQ ID NO:564,

[0330] SEQ ID NO:566, SEQ ID NO:568, SEQ ID NQ:570, SEQ ID NO:572, SEQ ID NO:574, SEQ ID NO:576,

[0331] SEQ ID NO:578, SEQ ID NQ:580, SEQ ID NO:582, SEQ ID NO:584, SEQ ID NO:586, SEQ ID NO:588,

[0332] SEQ ID NQ:590, SEQ ID NO:592, SEQ ID NO:596, SEQ ID NO:598, or SEQ ID NQ:600.

[0333] 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:932, SEQ ID NO:595, SEQ ID NO:525, SEQ ID NO:527, SEQ ID NO:529, SEQ ID NO:531 , SEQ ID NO:533, SEQ ID NO:535,

[0334] SEQ ID NO:537, SEQ ID NO:539, SEQ ID NO:541 , SEQ ID NO:543, SEQ ID NO:545, SEQ ID NO:547,

[0335] SEQ ID NO:549, SEQ ID NO:551 , SEQ ID NO:553, SEQ ID NO:555, SEQ ID NO:557, SEQ ID NO:559,

[0336] SEQ ID NO:561 , SEQ ID NO:563, SEQ ID NO:565, SEQ ID NO:567, SEQ ID NO:569, SEQ ID NO:571 ,

[0337] SEQ ID NO:573, SEQ ID NO:575, SEQ ID NO:577, SEQ ID NO:579, SEQ ID NO:581 , SEQ ID NO:583,

[0338] SEQ ID NO:585, SEQ ID NO:587, SEQ ID NO:589, SEQ ID NO:591 , SEQ ID NO:593, SEQ ID NO:597,

[0339] SEQ ID NO:599, or SEQ ID NQ:601 .

[0340] 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 NQ:910, SEQ ID NO:911 , SEQ ID NO:912, SEQ ID NO:913, SEQ ID NO:914, SEQ ID NO:915, SEQ ID NO:916, SEQ ID NO:917, SEQ ID NO:918, SEQ ID NO:919, SEQ ID NO:920, SEQ ID NO:921 , SEQ ID NO:922, SEQ ID NO:923,

[0341] SEQ ID NO:924, SEQ ID NO:925, SEQ ID NO:926, SEQ ID NO:927, SEQ ID NO:928, SEQ ID NO:929,

[0342] SEQ ID NQ:930, SEQ ID NO:931 , SEQ ID NO:594, SEQ ID NO:524:, SEQ ID NO:526, SEQ ID NO:528,

[0343] SEQ ID NQ:530, SEQ ID NO:532, SEQ ID NO:534, SEQ ID NO:536, SEQ ID NO:538, SEQ ID NQ:540,

[0344] SEQ ID NO:542, SEQ ID NO:544, SEQ ID NO:546, SEQ ID NO:548, SEQ ID NQ:550, SEQ ID NO:552,

[0345] SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:558, SEQ ID NQ:560, SEQ ID NO:562, SEQ ID NO:564,

[0346] SEQ ID NO:566, SEQ ID NO:568, SEQ ID NQ:570, SEQ ID NO:572, SEQ ID NO:574, SEQ ID NO:576,

[0347] SEQ ID NO:578, SEQ ID NQ:580, SEQ ID NO:582, SEQ ID NO:584, SEQ ID NO:586, SEQ ID NO:588,

[0348] SEQ ID NQ:590, SEQ ID NO:592, SEQ ID NO:596, SEQ ID NO:598, or SEQ ID NQ:600, and / or an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:932, SEQ ID NO:595, SEQ ID NO:525, SEQ ID NO:527, SEQ ID NO:529, SEQ ID NO:531 , SEQ ID

[0349] NO:533, SEQ ID NO:535, SEQ ID NO:537, SEQ ID NO:539, SEQ ID NO:541 , SEQ ID NO:543, SEQ ID

[0350] NO:545, SEQ ID NO:547, SEQ ID NO:549, SEQ ID NO:551 , SEQ ID NO:553, SEQ ID NO:555, SEQ ID

[0351] NO:557, SEQ ID NO:559, SEQ ID NO:561 , SEQ ID NO:563, SEQ ID NO:565, SEQ ID NO:567, SEQ ID

[0352] NO:569, SEQ ID NO:571 , SEQ ID NO:573, SEQ ID NO:575, SEQ ID NO:577, SEQ ID NO:579, SEQ ID

[0353] NO:581 , SEQ ID NO:583, SEQ ID NO:585, SEQ ID NO:587, SEQ ID NO:589, SEQ ID NO:591 , SEQ ID

[0354] NO:593, SEQ ID NO:597, SEQ ID NO:599, or SEQ ID NQ:601 .

[0355] 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:594, SEQ ID NO:524:, SEQ ID NO:526, SEQ ID NO:528, SEQ ID NQ:530, SEQ ID NO:532, SEQ ID NO:534, SEQ ID NO:536,

[0356] SEQ ID NO:538, SEQ ID NQ:540, SEQ ID NO:542, SEQ ID NO:544, SEQ ID NO:546, SEQ ID NO:548,

[0357] SEQ ID NQ:550, SEQ ID NO:552, SEQ ID NO:554, SEQ ID NO:556, SEQ ID NO:558, SEQ ID NQ:560,

[0358] SEQ ID NO:562, SEQ ID NO:564, SEQ ID NO:566, SEQ ID NO:568, SEQ ID NQ:570, SEQ ID NO:572,

[0359] SEQ ID NO:574, SEQ ID NO:576, SEQ ID NO:578, SEQ ID NQ:580, SEQ ID NO:582, SEQ ID NO:584,

[0360] SEQ ID NO:586, SEQ ID NO:588, SEQ ID NQ:590, SEQ ID NO:592, SEQ ID NO:596, SEQ ID NO:598, or SEQ ID NQ:600.

[0361] 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:595, SEQ ID NO:525, SEQ ID NO:527, SEQ ID NO:529, SEQ ID NO:531 , SEQ ID NO:533, SEQ ID NO:535, SEQ ID NO:537,

[0362] SEQ ID NO:539, SEQ ID NO:541 , SEQ ID NO:543, SEQ ID NO:545, SEQ ID NO:547, SEQ ID NO:549,

[0363] SEQ ID NO:551 , SEQ ID NO:553, SEQ ID NO:555, SEQ ID NO:557, SEQ ID NO:559, SEQ ID NO:561 ,

[0364] SEQ ID NO:563, SEQ ID NO:565, SEQ ID NO:567, SEQ ID NO:569, SEQ ID NO:571 , SEQ ID NO:573,

[0365] SEQ ID NO:575, SEQ ID NO:577, SEQ ID NO:579, SEQ ID NO:581 , SEQ ID NO:583, SEQ ID NO:585,

[0366] SEQ ID NO:587, SEQ ID NO:589, SEQ ID NO:591 , SEQ ID NO:593, SEQ ID NO:597, SEQ ID NO:599, or SEQ ID NQ:601.

[0367] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0368] (i) a binding-moiety comprising an immune checkpoint protein-binding VHH,

[0369] (ii) a CH2-CH3 polypeptide, (iii) a binding moiety comprising a yc-binding VHH or an VHH that binds to a polypeptide of a yc- containing cytokine receptor other than yc, and

[0370] (iv) a binding moiety comprising a VHH that binds to a polypeptide of a yc-containing cytokine receptor other than yc or a yc-binding VHH.

[0371] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0372] (i) a binding-moiety comprising an immune checkpoint protein-binding VHH,

[0373] (ii) a CH2-CH3 polypeptide,

[0374] (iii) a binding moiety comprising a yc-binding VHH, and

[0375] (iv) a binding moiety comprising an IL-2Rp-binding VHH or an IL-21 Ra-binding VHH.

[0376] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0377] (i) a binding-moiety comprising an immune checkpoint protein-binding VHH,

[0378] (ii) a CH2-CH3 polypeptide,

[0379] (iii) a binding moiety comprising a yc-binding VHH,

[0380] (iv) a linker, and

[0381] (iv) a binding moiety comprising an IL-2Rp-binding VHH or an IL-21 Ra-binding VHH.

[0382] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0383] (i) a binding-moiety comprising an immune checkpoint protein-binding VHH,

[0384] (ii) a CH2-CH3 polypeptide,

[0385] (iii) a binding moiety comprising a yc-binding VHH or an IL-2Rp-binding VHH, and

[0386] (iv) a binding moiety comprising an IL-2Rp-binding VHH or a yc-binding VHH.

[0387] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0388] (i) a binding-moiety comprising an immune checkpoint protein-binding VHH,

[0389] (ii) a CH2-CH3 polypeptide,

[0390] (iii) a binding moiety comprising a yc-binding VHH, and

[0391] (iv) a binding moiety comprising an IL-2Rp-binding VHH.

[0392] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0393] (i) a binding-moiety comprising an immune checkpoint protein-binding VHH,

[0394] (ii) a CH2-CH3 polypeptide,

[0395] (iii) a binding moiety comprising a yc-binding VHH,

[0396] (iv) a linker, and

[0397] (iv) a binding moiety comprising an IL-2Rp-binding VHH. In some embodiments, the antigen-binding molecule comprises a second CH2-CH3 polypeptide, wherein the second CH2-CH3 polypeptide forms an Fc region with the CH2-CH3 region polypeptide specified above.

[0398] In some embodiments, the second CH2-CH3 polypeptide is connected to an antigen-binding moiety.

[0399] In some embodiments, the antigen binding moiety comprises an immune checkpoint protein-binding VHH.

[0400] In some embodiments, the immune checkpoint protein-binding VHH is a PD-1-binding VHH.

[0401] A chimeric antigen receptor (CAR) is provided, comprising an antigen-binding molecule according to the present disclosure.

[0402] A nucleic acid, or a plurality of nucleic acids, is provided, optionally isolated, encoding an antigen-binding molecule according to the present disclosure, or a CAR according to the present disclosure.

[0403] An expression vector, or a plurality of expression vectors, is provided comprising a nucleic acid or a plurality of nucleic acids according to the present disclosure.

[0404] A cell is provided, comprising an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, or an expression vector or a plurality of expression vectors according to the present disclosure.

[0405] A method is provided, comprising culturing a cell according to the present disclosure under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

[0406] A composition is provided, comprising an antigen-binding molecule according to the present disclosure, a CAR according to the present disclosure, a nucleic acid or a plurality of nucleic acids according to the present disclosure, an expression vector or a plurality of expression vectors according to the present disclosure, or a cell according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0407] An antigen-binding molecule according to the present disclosure, a CAR according to the present disclosure, a nucleic acid or a plurality of nucleic acids according to the present disclosure, an expression vector or a plurality of expression vectors according to the present disclosure, a cell according to the present disclosure, or a composition according to the present disclosure, for use in a method of treatment or prophylaxis.

[0408] Use of an antigen-binding molecule according to the present disclosure, a CAR according to the present disclosure, a nucleic acid or a plurality of nucleic acids according to the present disclosure, an expression vector or a plurality of expression vectors according to the present disclosure, a cell according to the present disclosure, or a composition according to the present disclosure, in the manufacture of a medicament for use in a method of treatment or prophylaxis. A method of treatment or prophylaxis is provided, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of an antigen-binding molecule according to the present disclosure, a CAR according to the present disclosure, a nucleic acid or a plurality of nucleic acids according to the present disclosure, an expression vector or a plurality of expression vectors according to the present disclosure, a cell according to the present disclosure, or a composition according to the present disclosure.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] An in vitro complex is provided, optionally isolated, comprising an antigen-binding molecule according to the present disclosure, or a CAR according to the present disclosure, bound to PD-1 , yc, and / or IL-2R0.

[0413] A method for generating or expanding a population of cells is provided, comprising contacting a cell expressing a yc-containing cytokine receptor in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure.

[0414] A method for increasing the proliferation, survival and / or effector activity of a cell expressing IL-2R0 and / or PD-1 is provided, comprising contacting a cell expressing IL-2R0 and / or PD-1 in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure.

[0415] A method for increasing the proliferation, survival and / or effector activity of a cell expressing IL-2R0 and / or PD-1 is provided, comprising contacting a cell expressing yc, IL-2R0, and / or PD-1 in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure.

[0416] A method for increasing the proliferation, survival and / or effector activity of a cell expressing IL-21 Ra and / or PD-1 is provided, comprising contacting a cell expressing IL-21 Ra and / or PD-1 in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure. A method for increasing the proliferation, survival and / or effector activity of a cell expressing IL-21 Ra and / or PD-1 is provided, comprising contacting a cell expressing yc, IL-21 Ra, and / or PD-1 in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure.

[0417] In some embodiments, the cell is an effector immune cell.

[0418] In some embodiments, the cell is a T cell or a NK cell.

[0419] A method of promoting heteromultimerization of yc and IL-2R0 is provided, 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.

[0420] A method of promoting heteromultimerization of yc and IL-21 Ra is provided, comprising contacting yc and IL-21 Ra 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.

[0421] The present disclosure provides improved antigen-binding molecules.

[0422] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety and an IL-2R0- binding moiety, and the improvement is described herein.

[0423] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety and an IL-21 Ra- binding moiety, and the improvement is described herein.

[0424] In some embodiments, the antigen-binding molecule comprises means for binding yc.

[0425] In some embodiments, the antigen-binding molecule comprises means for binding a polypeptide of a yc- containing cytokine receptor other than yc.

[0426] In some embodiments, the antigen-binding molecule comprises means for binding IL-2R0.

[0427] In some embodiments, the antigen-binding molecule comprises means for binding IL-21 Ra.

[0428] In some embodiments, the antigen-binding molecule comprises means for binding an immune checkpoint protein.

[0429] In some embodiments, the antigen-binding molecule comprises means for binding PD-1 .

[0430] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0431] (i) a binding-moiety comprising a means for binding an immune checkpoint protein,

[0432] (ii) a CH2-CH3 polypeptide, (iii) a binding moiety comprising a means for binding yc or a means for binding a polypeptide of a yc-containing cytokine receptor other than yc, and

[0433] (iv) a binding moiety comprising a means for binding a polypeptide of a yc-containing cytokine receptor other than yc or a means for binding yc.

[0434] In some embodiments, the antigen-binding molecule comprises a polypeptide comprising (from N- terminal to C-terminal):

[0435] (i) a binding-moiety comprising a means for binding an immune checkpoint protein,

[0436] (ii) a CH2-CH3 polypeptide,

[0437] (iii) a binding moiety comprising a means for binding yc, and

[0438] (iv) a binding moiety comprising a means for binding a polypeptide of a yc-containing cytokine receptor other than yc.

[0439] In some embodiments, the means for binding an immune checkpoint protein is a means for binding PD-1 .

[0440] In some embodiments, the means for binding a polypeptide of a yc-containing cytokine receptor other than yc is a means for binding IL-2Rp.

[0441] In some embodiments, the means for binding a polypeptide of a yc-containing cytokine receptor other than yc is a means for binding IL-21 Ra.

[0442] Description

[0443] The present disclosure provides antigen-binding molecules that bind to (i) yc, (ii) IL-2R0, and / or (iii) PD-1 , having novel biophysical and / or functional properties as compared to antigen-binding molecules disclosed in the prior art.

[0444] The present disclosure also provides antigen-binding molecules that bind to (i) yc, (ii) IL-21 Ra, and / or (iii) PD-1 , having novel biophysical and / or functional properties as compared to antigen-binding molecules disclosed in the prior art.

[0445] The present disclosure provides antigen-binding molecules that bind to common y chain (yc; CD132), antigen-binding molecules that bind to IL-2R0 (CD122), and antigen-binding molecules that bind to PD-1 (CD279), having novel biophysical and / or functional properties as compared to antigen-binding molecules disclosed in the prior art.

[0446] The present disclosure also provides antigen-binding molecules that bind to common y chain (yc; CD132), antigen-binding molecules that bind to IL-21 Ra (CD360), and antigen-binding molecules that bind to PD-1 (CD279), having novel biophysical and / or functional properties as compared to antigenbinding molecules disclosed in the prior art.

[0447] The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for both yc and IL-2R0. The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for (i) yc, (ii) IL-2R0, and (iii) another target antigen. The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for (i) yc, (ii) IL-2R0, and (iii) PD-1.

[0448] The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for both yc and IL-21 Ra. The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for (i) yc, (ii) IL-21 Ra, and (iii) another target antigen. The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for (i) yc, (ii) IL-21 Ra, and (iii) PD-1.

[0449] In some aspects, 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.

[0450] In some aspects, 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- 21 Ra specificity.

[0451] In some aspects, this disclosure describes antigen binding molecules which are capable of (i) agonising cytokine receptors and (ii) targeting activated immune cells. In some embodiments, cytokine receptor agonists are targeted to cells expressing an immune cell surface molecule. In some embodiments, cytokine receptor agonists are targeted to cells expressing immune checkpoint proteins. Antigen binding molecules comprising: (i) a yc-binding moiety, (ii) an IL-2Rp-binding moiety, and (iii) a PD-1- binding moiety are disclosed, wherein the yc-binding moiety and the IL-2Rp-binding moiety function as IL-2 receptor agonists, and the PD-1 -binding moiety binds to immune cells which express PD-1 . Antigen binding molecules comprising: (i) a yc-binding moiety, (ii) an IL-21 Ra-binding moiety, and (iii) a PD-1- binding moiety are disclosed, wherein the yc-binding moiety and the IL-21 Ra-binding moiety function as IL-21 receptor agonists, and the PD-1-binding moiety binds to immune cells which express PD-1 . Consequently, the antigen binding molecule can increase the local concentration of activated immune cells (e.g., activated tumor infiltrating lymphocytes (TILs)) in the proximity of cells which express yc and IL-2R0. This means that the effects of IL-2 agonism can be further enhanced by the activity of immune cells which express PD-1 (e.g., activated T cells, such as activated TILs).

[0452] In some aspects, this disclosure describes antigen binding molecules which are capable of agonising cytokine receptors and inhibiting immune checkpoints. For example, antigen binding molecules comprising: (i) a yc-binding moiety, (ii) an IL-2Rp-binding moiety, and (iii) a PD-1-binding moiety are disclosed, wherein the yc-binding moiety and the IL-2Rp-binding moiety function as an IL-2 receptor agonist, and the PD-1-binding moiety blocks PD-1 from binding PD-L1. This means that the effects of IL-2 agonism can be further enhanced by the anti-cancer effects of immune checkpoint inhibition (e.g., enhanced antitumor T cell cytotoxicity, enhanced proinflammatory cytokine production, and enhanced immune cell proliferation). In some embodiments, the antigen binding molecule targets activated immune cells (e.g., activated TILs) and also inhibits an immune checkpoint protein (e.g., PD-1). In some embodiments, the antigen binding molecule targets activated immune cells (e.g., activated TILs) but does not inhibit an immune checkpoint protein (e.g., PD-1). These different embodiments have been developed by the inventors to ensure that different treatment options are available for different subjects / indications. In some cases, the disease to be treated may benefit from activated immune cell targeting and immune checkpoint inhibition, but in other cases the disease to be treated may benefit from activated immune cell targeting without immune checkpoint inhibition.

[0453] 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-2R0 or yc and IL-21 Ra.

[0454] Common v chain (yc)

[0455] 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.

[0456] 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.

[0457] 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. 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.

[0458] 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.

[0459] 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).

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] 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.

[0468] 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.

[0469] Signalling through cytokine receptors comprising yc

[0470] 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 et al., 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.

[0471] 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.

[0472] 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-2RJ3, 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 et al. Nat Biomed Eng. (2021) 5(11):1288-1305). However, neither IL-2 muteins nor 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 nor 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 low levels immunogenicity.

[0473] 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. IL4 receptors are over-expressed by many epithelial cancers and could be a promising target for metastatic tumor therapy (Bankaitis etal. 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, selected from 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, but higher amounts of IL-13Ra1 are expressed. 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. 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, with congenital deficiency of IL-7 signaling leading 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 transducer and activator 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.

[0474] Interleukin-9 (IL-9) is a cytokine which stimulates cell proliferation and prevents apoptosis. IL-9 is a pleiotropic cytokine which 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 STAT1 , 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, and 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 IL-9-mediated MAPK activation is weak compared to other cytokines like IL-3.

[0475] 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 which leads 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).

[0476] 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 -apo pt otic protein bcl-2 and proto-oncogenes c-myc, c-fos, and c-jun.

[0477] 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 AKT via the Shc^Grb2^Gab2^PI3K^Akt signaling pathway. This increases 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.

[0478] 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, MAPK and PI3K pathways.

[0479] 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.

[0480] 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 interactions 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.

[0481] 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).

[0482] 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 I L-2: yc:l L- 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).

[0483] 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 I L-2:yc:IL-2Rp:l L- 2Ra-mediated signalling ( / .e. signalling mediated by binding of IL-2 to the high-affinity IL-2 receptor).

[0484] 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).

[0485] 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).

[0486] 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).

[0487] 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-21 Ra 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).

[0488] 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). 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-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra or IL-7Ra.

[0489] In this specification ‘I L-2Rp’ 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 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-2R0 may display association with one or more of yc, IL-2Ra, IL-15Ra, IL-2 or IL-15.

[0490] Human IL-2Ra (also known as CD25, IDDM10, IL2R, TCGFR, p55, and IMD41) is the protein identified by UniProt P01589.

[0491] 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.

[0492] Human IL-15Ra (also known as CD215) is the protein identified by UniProt Q13261 .

[0493] 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-2R0, 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.

[0494] Human IL-4Ra (also known as CD124, IL-4R) is the protein identified by UniProt P24394.

[0495] 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.

[0496] Human IL-9Ra (also known as IL-9R and CD129) is the protein identified by UniProt Q01113.

[0497] 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.

[0498] Human IL-21 Ra (also known as CD360) is the protein identified by UniProt Q9HBE5.

[0499] 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.

[0500] Human IL-7Ra (also known as IL-7R, CD127) is the protein identified by UniProt P16871.

[0501] 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.

[0502] Interleukin-2 (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.

[0503] 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.

[0504] 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.

[0505] 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 et al. Nat Biomed Eng. (2021) 5(11):1288-1305). However, neither IL-2 muteins nor 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 nor 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 low levels of immunogenicity.

[0506] 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).

[0507] 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).

[0508] Sequence, structure and functional information relating to Human IL-2R0 may be identified on publically 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). The mature form ( / .e. after processing to remove the signal peptide) of human IL-2Rp 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-2Rp, 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).

[0509] In this specification ‘I L-2Rp’ or ‘CD122’ refers to IL-2Rp from any species and includes isoforms, fragments, variants or homologues of IL-2Rp from any species. In some embodiments IL-2Rp is IL-2Rp from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the IL-2Rp is human IL-2Rp.

[0510] Sequence, structure and functional information relating to cynomolgous IL-2Rp may be identified on publically available databases such as UniProt (Q38J85), Genbank (ABB03908.1), and PDB / Alpha fold (AF-Q38J85-F1). The amino acid sequence of the cynomolgous IL-2Rp extracellular domain has 96.7% identity to the amino acid sequence of the Human IL-2Rp extracellular domain.

[0511] Sequence, structure and functional information relating to rat IL-2Rp may be identified on publically available databases such as UniProt (P26896), Genbank (AAA41429.1), and PDB / Alpha fold (AF- P26896-F1). The amino acid sequence of the rat IL-2Rp extracellular domain has 62.2% identity to the amino acid sequence of the Human IL-2Rp extracellular domain.

[0512] Sequence, structure and functional information relating to mouse IL-2Rp may be identified on publically available databases such as UniProt (P16297), Genbank (AAA39283.1), and PDB / Alpha fold (AF- P16297-F1). The amino acid sequence of the mouse IL-2Rp extracellular domain has 59.3% identity to the amino acid sequence of the Human IL-2Rp extracellular domain.

[0513] A fragment of IL-2Rp 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.

[0514] 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.

[0515] Interleukin-21 (IL-21) and the IL-21 receptor 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 mechanism 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.

[0516] IL-21 binding stabilizes the complex between IL-21 Ra and the 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 Ra 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.

[0517] Human IL-21 Ra (also known as CD360) is the protein identified by UniProt Q9HBE5. The canonical isoform of human IL-21 Ra has the amino acid sequence of SEQ ID NO:754. The N-terminal 19 amino acids of SEQ ID NO:754 constitute a signal peptide (SEQ ID NO:758), and so the mature form ( / .e. after processing to remove the signal peptide) of human IL-21 Ra has the amino acid sequence shown in SEQ ID NO:759. Human IL-21 Ra comprises an extracellular domain (SEQ ID NO:755), a transmembrane domain (SEQ ID NO:756), and a cytoplasmic domain (SEQ ID NO:757).

[0518] 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.

[0519] 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.

[0520] In some embodiments, the IL-21 Ra 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:754 or 759. In some embodiments, a fragment of IL-21 Ra 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:755.

[0521] Further antigen-binding moiety

[0522] In some embodiments, the antigen-binding molecule comprises a further antigen-binding moiety. In some embodiments, the further antigen-binding moiety binds to a target antigen other than a yc-containing cytokine receptor polypeptide (e.g. a target antigen which is not yc or IL-2R0). In some embodiments, the antigen-binding molecule of the present disclosure comprises (i) a yc-binding moiety, (ii) a moiety that binds to a yc-containing cytokine receptor polypeptide (e.g. a target antigen which is not yc or I L-2Rp), and (iii) a moiety that binds to a target antigen (e.g. an antigen that is not a yc- containing cytokine receptor polypeptide).

[0523] It will be appreciated that an effect of the further binding moiety ( / .e., moiety (iii)) may be to localise the antigen-binding molecule to cells expressing its target. This can be useful to direct the effect of moieties (i) and (ii) of the antigen-binding molecule to cells expressing the target for moiety (iii), and can also lead to the recruitment of cells expressing the target for moiety (iii). By way of illustration, in embodiments wherein moiety (ii) is an IL-2Rp -binding moiety and wherein moiety (iii) is a PD-1 -binding moiety, the effect of moiety (iii) is to target the activity conferred by moieties (i) and (ii) to PD-1+ T cells.

[0524] Furthermore, it will be appreciated that an additional effect of the further binding moiety (i.e., moiety (iii)) may be to modulate an activity of the target of the further binding moiety (i.e., an activity of a polypeptide to which the further binding moiety binds). By way of example, in embodiments wherein moiety (iii) is a PD-1 -binding moiety, an effect of the further binding moiety may be to block PD-1 from binding to a ligand (e.g., PD-L1).

[0525] In some embodiments, the effect of the further binding moiety is to:

[0526] (1) localise the antigen-binding molecule to cells expressing the target antigen of the further binding moiety, and

[0527] (2) modulate an activity of the target antigen of the further binding moiety.

[0528] In some embodiments, the effect of the further binding moiety is to:

[0529] (1) recruit cells (e.g., activated immune cells) which express the target antigen of the further binding moiety, and

[0530] (2) modulate an activity of the target of the further binding moiety.

[0531] Moiety (iii) can also be employed to target the antigen-binding molecule to an anatomical site / tissue / organ of interest. This can be useful to direct the effect of moieties (i) and (ii) of the antigen-binding molecule to such regions. By way of illustration, in embodiments wherein moiety (ii) is an IL-2Rp-binding moiety and wherein moiety (iii) is a cancer cell antigen-binding moiety, an effect of moiety (iii) is to target the yc:IL- 2Rp receptor agonist activity conferred by moieties (i) and (ii) to yc:IL-2Rp receptor-expressing cells in the proximity of the cells expressing the cancer cell antigen.

[0532] Thus, it will be appreciated that moiety (iii) is employed to target / localise the antigen-binding molecule to, and / or increase the local concentration of the antigen-binding molecule in the proximity of, a cell comprising / expressing the target antigen for moiety (iii). The target for moiety (iii) may be any target antigen. In some embodiments, the target antigen may be a peptide / polypeptide, glycoprotein, lipoprotein, glycan, glycolipid, lipid, or fragment thereof. The antigen is preferably expressed at the cell surface of a cell expressing the antigen.

[0533] In some embodiments, the target antigen is a disease-associated antigen, or an antigen expressed by an immune cell.

[0534] A ‘disease-associated antigen’ refers to an antigen whose presence is indicative of a given disease / disease state, or an antigen for which an elevated level of the antigen is positively-correlated with a given disease / disease state. The disease-associated antigen may be an antigen whose expression is associated with the development, progression or severity of symptoms of a given disease. The disease- associated antigen may be associated with the cause or pathology of the disease, or may be expressed abnormally as a consequence of the disease. A disease-associated antigen may be an antigen of an infectious agent or pathogen, a cancer-associated antigen or an autoimmune disease-associated antigen.

[0535] In some embodiments, the disease-associated antigen is an antigen of a pathogen. The pathogen may be prokaryotic (bacteria), eukaryotic (e.g. protozoan, helminth, fungus), virus or prion. In some embodiments, the pathogen is an intracellular pathogen. In some embodiments the pathogen is a virus, e.g. a virus as described hereinabove. In some embodiments the pathogen is a bacterium.

[0536] In some embodiments, the target antigen is a cancer-associated antigen. A cancer-associated antigen is an antigen whose expression or overexpression is associated with cancer. In some embodiments, the cancer-associated antigen is a receptor molecule, e.g. a cell surface receptor. In some embodiments, the cancer-associated antigen is a cell signalling molecule, e.g. a cytokine, chemokine, interferon, interleukin or lymphokine. In some embodiments, the cancer-associated antigen is a growth factor or a hormone. In some embodiments, the cancer-associated antigen is a viral antigen. A cancer cell antigen may be abnormally expressed by a cancer cell (e.g. the cancer cell antigen may be expressed with abnormal localisation), or may be expressed with an abnormal structure by a cancer cell. A cancer cell antigen may be capable of eliciting an immune response. In some embodiments, the antigen is expressed at the cell surface of the cancer cell ( / .e. the cancer cell antigen is a cancer cell surface antigen). In some embodiments, the part of the antigen which is bound by the antigen-binding molecule described herein is displayed on the external surface of the cancer cell ( / .e. is extracellular). The cancer cell antigen may be a cancer-associated antigen. In some embodiments the cancer cell antigen is an antigen whose expression is associated with the development, progression or severity of symptoms of a cancer. The cancer- associated antigen may be associated with the cause or pathology of the cancer, or may be expressed abnormally as a consequence of the cancer. In some embodiments, the cancer cell antigen is an antigen whose expression is upregulated (e.g. at the RNA and / or protein level) by cells of a cancer, e.g. as compared to the level of expression by comparable non-cancerous cells (e.g. non-cancerous cells derived from the same tissue / cell type). In some embodiments, the cancer-associated antigen may be preferentially expressed by cancerous cells, and not expressed by comparable non-cancerous cells (e.g. non-cancerous cells derived from the same tissue / cell type). In some embodiments, the cancer- associated antigen may be the product of a mutated oncogene or mutated tumor suppressor gene. In some embodiments, the cancer-associated antigen may be the product of an overexpressed cellular protein, a cancer antigen produced by an oncogenic virus, an oncofetal antigen, or a cell surface glycolipid or glycoprotein.

[0537] Cancer-associated antigens are reviewed by Zarour HM, DeLeo A, Finn OJ, et al. Categories of Tumor Antigens. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Cancer-associated antigens include oncofetal antigens: CEA, Immature laminin receptor, TAG-72; oncoviral antigens such as HPV E6 and E7; overexpressed proteins: BING-4, calcium-activated chloride channel 2, cyclin-B1 , 9D7, Ep-CAM, EphA3, HER2 / neu, telomerase, mesothelin, SAP-1 , survivin; cancer-testis antigens: BAGE, CAGE, GAGE, MAGE, SAGE, XAGE, CT9, CT10, NY-ESO-1 , PRAME, SSX-2; lineage restricted antigens: MARTI , Gp100, tyrosinase, TRP-1 / 2, MC1R, prostate specific antigen; mutated antigens: p-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, MART-2, p53, Ras, TGF-pRII; post-translationally altered antigens: MUC1 , idiotypic antigens: Ig, TCR. Other cancer cell antigens include heat-shock protein 70 (HSP70), heat-shock protein 90 (HSP90), glucose-regulated protein 78 (GRP78), vimentin, nucleolin, feto-acinar pancreatic protein (FAPP), alkaline phosphatase placental-like 2 (ALPPL-2), siglec-5, stress-induced phosphoprotein 1 (STIP1), protein tyrosine kinase 7 (PTK7), and cyclophilin B. In some embodiments the cancer cell antigen is a cancer cell antigen described in Zhao and Cao, Front Immunol. (2019) 10:2250, which is hereby incorporated by reference in its entirety.

[0538] In some embodiments, the target antigen is an immune cell surface molecule. An immune cell surface molecule is any molecule which is expressed in or at the cell membrane of an immune cell. In some embodiments, the part of the immune cell surface molecule which is bound by the antigen-binding moiety is on the external surface of the immune cell ( / .e. is extracellular). The immune cell surface molecule may be expressed at the cell surface of any immune cell. In some embodiments, the immune cell may be a cell of hematopoietic origin, e.g. a neutrophil, eosinophil, basophil, dendritic cell, lymphocyte, or monocyte. The lymphocyte may be e.g. a T cell, B cell, natural killer (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.

[0539] In some embodiments, the immune cell surface molecule may be a CD3-TCR complex polypeptide, e.g. TCRa, TCRp, TCRy, TCR6, TRAC, TRBC1 , TRBC2, TRGC1 , TRGC2, TRDC, CD3e, CD36, CD3y, CD3 or CD3r|. In some embodiments, the immune cell surface molecule is CD3, CD8, CD4 or CD28.

[0540] In some embodiments, the immune cell surface molecule is a checkpoint molecule. In some embodiments, the immune cell surface molecule is an immune checkpoint protein (e.g. PD-1 , CTLA-4, GITR, LAG-3, TIM-3, VISTA, TIGIT or BTLA), or a ligand thereof. In some embodiments, the target antigen is an immune checkpoint protein. In some embodiments, the immune checkpoint protein is expressed on the surface of a T-cell. In some embodiments the immune cell surface molecule is a costimulatory molecule (e.g. CD28, 0X40, 4-1 BB, ICOS or CD27), or a ligand thereof.

[0541] In some embodiments, when the target antigen of the further binding moiety (e.g., moiety (Hi)) is an immune checkpoint protein (e.g., PD-1), the antigen binding molecule increases the local concentration of the antigen-binding molecule in the proximity of activated immune cells (e.g., activated TILs).

[0542] In some embodiments, when the target antigen of moiety (iii) is an immune checkpoint protein (e.g., PD- 1), the antigen binding molecule increases the local concentration of activated immune cells (e.g., activated TILs) in the proximity of cells which express the target antigen of moieties (1) and (ii).

[0543] In some embodiments, when the target antigen of moiety (iii) is an immune checkpoint protein (e.g., PD- 1), the antigen binding molecule increases the local concentration of activated immune cells (e.g., activated TILs) in the proximity of cells which express yc and a polypeptide of a yc-containing cytokine receptor other than yc.

[0544] In some embodiments, when the target antigen of moiety (iii) is an immune checkpoint protein (e.g., PD- 1), the antigen binding molecule increases the local concentration of activated immune cells (e.g., activated TILs) in the proximity of cells which express yc and IL-2R0.

[0545] In some embodiments, when the target antigen of moiety (iii) is PD-1 , the antigen binding molecule increases the local concentration of activated immune cells (e.g., activated TILs) in the proximity of cells which express yc and a polypeptide of a yc-containing cytokine receptor other than yc.

[0546] In some embodiments, when the target antigen of moiety (iii) is PD-1 , the antigen binding molecule increases the local concentration of activated immune cells (e.g., activated TILs) in the proximity of cells which express yc and IL-2R0.

[0547] In some embodiments, when the target antigen of moiety (iii) is PD-1 , the antigen binding molecule increases the local concentration of activated immune cells (e.g., activated TILs) in the proximity of cells which express yc and IL-21 Ra.

[0548] In some embodiments, the activated immune cell is an activated T cell, an activated NK cell, or an activated B cell. In some embodiments, the activated T cell is an activated CD4+ T cell or an activated CD8+ T cell. In some embodiments, the activated immune cell is an activated tumor infiltrating T lymphocyte (TIL).

[0549] In some embodiments, the target antigen is selected from PD-1 , 4-1 BB and CD8. In some embodiments, the target antigen is selected from PD-1 and CD8. In some embodiments, the target antigen is selected from PD-1 and 4-1 BB. In some embodiments, the target antigen is PD-1 . In some embodiments, the target antigen is 4-1 BB. In some embodiments, the target antigen is CD8. In some embodiments, the target antigen is selected from PD-1 , CTLA-4, GITR, and LAG-3.

[0550] In some embodiments, the target antigen is PD-1 . In some embodiments, the target antigen is CTLA-4. In some embodiments, the target antigen is GITR. In some embodiments, the target antigen is LAG-3.

[0551] In some embodiments, the target antigen is Human PD-1. In some embodiments, the target antigen is Human CTLA-4. In some embodiments, the target antigen is Human GITR. In some embodiments, the target antigen is Human LAG-3.

[0552] Sequence, structure and functional information relating to Human PD-1 may be identified on publically available databases such as UniProt (Q15116). PD-1 is discussed in Ghosh et al. (J Cancer. 2021 ; 12(9): 2735-2746), which is hereby incorporated by reference.

[0553] Sequence, structure and functional information relating to Human CTLA-4 may be identified on publically available databases such as UniProt (P16410). CTLA-4 is discussed in Rowshanravan et al., (Blood. 2018 Jan 4;131 (1):58-67), which is hereby incorporated by reference.

[0554] Sequence, structure and functional information relating to Human GITR may be identified on publically available databases such as UniProt (Q9Y5U5). GITR is discussed in Buzzatti et al., (ESMO Open. 2020 Aug;4(Suppl 3):e000738), which is hereby incorporated by reference.

[0555] Sequence, structure and functional information relating to Human LAG-3 may be identified on publically available databases such as UniProt (P18627). LAG-3 is discussed in Chocarro etal., (Int J Mol Sci. 2021 May 17;22(10):5282), which is hereby incorporated by reference.

[0556] In some embodiments, the PD-1-binding moiety localises the antigen-binding molecule to cells expressing PD-1. In some embodiments, the PD-1-binding moiety: (1) localises the antigen-binding molecule to cells expressing PD-1 , and (2) blocks PD-1 binding a ligand (e.g., PD-L1).

[0557] Programmed cell death protein 1 (PD-1)

[0558] Programmed cell death protein 1 (PD-1) is a cell surface receptor that has a role in regulating the immune response by down-regulating the immune system and promoting self-tolerance by suppressing T cell activity. This down-regulation of the immune system can prevent autoimmune diseases, but it can also prevent the immune system from targeting cancer cells. PD-1 is known to the skilled person, and PD-1 biology and the role of PD-1 in cancer is discussed in Ghosh et al., J Cancer. 2021 ; 12(9): 2735-2746, and Patsoukis et al., Sci Adv. 2020 Sep; 6(38): eabd2712, both of which are hereby incorporated by reference in their entirety.

[0559] In some embodiments, the antigen-binding molecule is capable of binding to PD-1 . In some embodiments, the antigen-binding molecule is capable of binding to yc and PD-1 . In some embodiments, the antigen-binding molecule is capable of binding to yc, a polypeptide of a yc-containing cytokine receptor other than yc, and PD-1. In some embodiments, the antigen-binding molecule is capable of binding to yc, IL-2R0, and PD-1. In some embodiments, the antigen-binding molecule is capable of binding to yc, IL-21 Ra, and PD-1 .

[0560] PD-1 is an immune-inhibitory receptor that is primarily expressed on activated T and B cells. Interaction with its ligands has been shown to down-regulate T-cell responses. PD-1 has two ligands, programmed death-ligand (PD-L)1 (also called B7-H1 ; CD274) and PD-L2 (also called B7-DC; CD273). PD-L2 has higher affinity for PD-1 , but has more restricted expression than PD-L1. Blockade of the interaction between PD-1 and one of its ligands, PD-L1 , has been shown to enhance tumor-specific CD8+ T-cell immunity and may therefore be helpful in clearance of tumor cells by the immune system.

[0561] Sequence, structure and functional information relating to Human PD-1 may be identified on publically available databases such as UniProt (Q15116), Genbank (AAC41700.1), and PDB / Alpha fold (AF- Q15116-F1). Human PD-1 (also known as PD1 , and CD279) is the protein identified by UniProt Q15116. The canonical isoform of human PD-1 has the amino acid sequence shown in SEQ ID NO:502. The N- terminal 23 amino acids of SEQ ID NO:502 constitute a signal peptide (SEQ ID NQ:503). The mature form ( / .e. after processing to remove the signal peptide) of human PD-1 protein has the amino acid sequence shown in SEQ ID NQ:504. Amino acids 24 to 170 of SEQ ID NQ:502 constitute the extracellular domain of PD-1 , shown in SEQ ID NQ:505. Amino acids 171 to 191 of SEQ ID NQ:502 form a transmembrane domain (SEQ ID NQ:506), and positions 192 to 288 form the cytoplasmic domain (SEQ ID NQ:507).

[0562] In this specification ‘PD-1 ’, ‘PD1 ’ or ‘CD279’ refers to PD-1 from any species and includes isoforms, fragments, variants or homologues of PD-1 from any species. In some embodiments PD-1 is PD-1 from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, PD-1 is human PD-1.

[0563] Sequence, structure and functional information relating to cynomolgous PD-1 may be identified on publically available databases such as UniProt (B0LAJ3), Genbank (NP_001271065.1), and PDB / Alpha fold (AF-B0LAJ3-F1). The amino acid sequence of the cynomolgous PD-1 extracellular domain has 95.9% identity to the amino acid sequence of the Human PD-1 extracellular domain.

[0564] Sequence, structure and functional information relating to rat PD-1 may be identified on publically available databases such as UniProt (A6JR44), and Genbank (EDL91893.1). The amino acid sequence of the rat PD-1 extracellular domain has 66.9% identity to the amino acid sequence of the Human PD-1 extracellular domain.

[0565] Sequence, structure and functional information relating to mouse PD-1 may be identified on publically available databases such as UniProt (Q02242), Genbank (CAA48113.1), and PDB / Alpha fold (AF- Q02242-F1). The amino acid sequence of the mouse PD-1 extracellular domain has 62.9% identity to the amino acid sequence of the Human PD-1 extracellular domain. A fragment of PD-1 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, 260, 270, 280, 281 , 282, 283, 284, 285, 286, or 287 amino acids. An isoform, fragment, variant or homologue of PD-1 may display association with one or more of PD-L1 (CD274), PD-L2 (CD273), or another known ligand or binding partner of PD-1 .

[0566] In some embodiments, the PD-1 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:502 or 504. In some embodiments, a fragment of PD-1 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:505.

[0567] The main biological function of PD-1 is to inhibit / down-regulate the activity of immune cells (e.g., T-cells) to limit autoimmunity. PD-1 expression is induced when T-cells are activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. This can cause immune suppression in the tumour microenvironment, because many tumours contain activated tumor-infiltrating lymphocytes (TILs) which can be inhibited by this PD-1 activity.

[0568] Immune checkpoint inhibitors, such as PD-1 inhibitors, have shown promising results for the treatment of diseases such as cancer. Although PD-1 inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. The role of PD-1 and application of immune-checkpoint inhibitors in human cancers is discussed by Tang et al., Front Immunol. 2022; 13: 964442, which is hereby incorporated by reference in its entirety.

[0569] PD-1 inhibitors work by blocking the interactions of PD-1 with its ligands (e.g., PD-L1). Inhibition of PD- 1 / PD-L1 binding has been shown to enhance antitumor T cell cytotoxicity, proinflammatory cytokine production, and immune cell proliferation. A number of anti-PD-1 and anti-PD-L1 Abs have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment. The first approval was for pembrolizumab in 2014, followed closely by nivolumab (LaFleur et al., J Immunol. 2018 Jan 15; 200(2): 375-383). Additional anti-PD-1 antibodies have been generated and investigated in clinical trials. Based on the immense success in clinical trials, ten anti-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) antibodies have been approved for the treatment of various types of cancers (Yi et al. (Mol Cancer. 2022; 21 : 28).

[0570] Anti-PD-1 antibodies known to the skilled person include: nivolumab (DrugBank Accession Number: DB09035), pembrolizumab (DrugBank Accession Number: DB09037), cemiplimab (DrugBank Accession Number: DB14707), sintilimab (DrugBank Accession Number: DB15765), camrelizumab (DrugBank Accession Number: DB14776), toripalimab (DrugBank Accession Number: DB15043), tislelizumab (DrugBank Accession Number: DB14922), zimberelimab (DrugBank Accession Number: DB17505), prolgolimab (DrugBank Accession Number: DB16740), dostarlimab (DrugBank Accession Number: DB15627), MEDI0680 (DrugBank Accession Number: DB15768), and pidilizumab (DrugBank Accession Number: DB15383).

[0571] Nivolumab (DrugBank Accession Number: DB09035) is a monoclonal antibody that binds to PD-1. This antibody was produced in mice and grafted onto human kappa and lgG4 Fc region with the mutation S228P for additional stability and reduced variability. Nivolumab is well known to the skilled person, and is reviewed in the literature. For example, nivolumab is discussed by Brahmer et al. (Future Oncol. (2015) 11 (9), 1307-1326), and Mashima et al. (Onco Targets Ther. 2015 Aug 6:8:2045-51), which are hereby incorporated by reference in their entirety.

[0572] Pembrolizumab (DrugBank Accession Number: DB09037) is a humanized lgG4 antibody directed against PD-1 . It was generated by grafting the variable sequences of a very high-affinity mouse antihuman PD-1 antibody onto a human lgG4-kappa isotype containing a stabilizing S228P Fc mutation. Pembrolizumab is well known to the skilled person, and is reviewed in the literature. For example, Jazirehi et al. (Am J Cancer Res. 2016 Oct 1 ;6(10):2117-2128), and Khoja et al. (J Immunother Cancer. 2015 Aug 18:3:36), which are hereby incorporated by reference in their entirety.

[0573] Cemiplimab (DrugBank Accession Number: DB14707) is a fully human monoclonal antibody against PD- 1 . Cemiplimab was first approved by the FDA on September 28, 2018, as the first FDA-approved treatment for advanced cutaneous squamous cell carcinoma (CSCC). Cemiplimab is well known to the skilled person, and is reviewed in the literature. For example, Migden et al. (N Engl J Med. 2018 Jul 26;379(4):341-351), and Mager et al. (Clin Cosmet Investig Dermatol. 2023; 16: 2135-2142), which are hereby incorporated by reference in their entirety.

[0574] Antigen-binding molecules

[0575] The present disclosure provides antigen-binding molecules capable of binding to PD-1.

[0576] The present disclosure also provides antigen-binding molecules capable of binding to yc.

[0577] The present disclosure also provides antigen-binding molecules capable of binding to 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 or IL-7Ra). In some embodiments, the polypeptide of a yc-containing cytokine receptor other than yc is IL-2R , IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra or IL-7Ra.

[0578] The present disclosure also provides antigen-binding molecules capable of binding to IL-2R0.

[0579] The present disclosure also provides antigen-binding molecules capable of binding to IL-21 Ra.

[0580] The present disclosure provides antigen-binding molecules capable of binding to yc and a polypeptide of a yc-containing cytokine receptor other than yc.

[0581] The present disclosure provides antigen-binding molecules capable of binding to yc and IL-2R0. The present disclosure provides antigen-binding molecules capable of binding to yc and IL-21 Ra.

[0582] The present disclosure also provides antigen-binding molecules capable of binding to yc and an immune checkpoint protein.

[0583] The present disclosure provides antigen-binding molecules capable of binding to yc, a polypeptide of a yc-containing cytokine receptor, and another target antigen.

[0584] The present disclosure also provides antigen-binding molecules capable of binding to yc, IL-2R0, and another target antigen.

[0585] The present disclosure also provides antigen-binding molecules capable of binding to yc, IL-21 Ra, and another target antigen.

[0586] The present disclosure also provides antigen-binding molecules capable of binding to yc, a polypeptide of a yc-containing cytokine receptor other than yc, and an immune checkpoint protein.

[0587] The present disclosure also provides antigen-binding molecules capable of binding to yc, IL-2R0, and an immune checkpoint protein.

[0588] The present disclosure also provides antigen-binding molecules capable of binding to yc, IL-21 Ra, and an immune checkpoint protein.

[0589] The present disclosure also provides antigen-binding molecules capable of binding to yc, IL-2R0, and PD- 1.

[0590] An antigen-binding molecule that is capable of binding to a target antigen (e.g., yc, IL-2R0, or PD-1) may also be described as an antigen-binding molecule that binds to said target antigen. By way of example, an antigen-binding molecule that is capable of binding to PD-1 may also be described as an antigenbinding molecule that binds to PD-1.

[0591] 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.

[0592] 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).

[0593] 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, which is hereby incorporated by reference in its entirety). In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an antigen-binding 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).

[0594] 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.

[0595] 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).

[0596] 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.

[0597] 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.

[0598] 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.

[0599] 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-2R0. An ‘antigen-binding region’ is any fragment of an antibody that binds to the target for which the given antibody is specific.

[0600] 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.

[0601] 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.

[0602] 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. 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.

[0603] 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.

[0604] 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.

[0605] 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.

[0606] 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.

[0607] 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.

[0608] 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.

[0609] 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 al., 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.

[0610] In some embodiments, the antigen-binding molecule comprises means for binding an immune checkpoint protein.

[0611] In some embodiments, the antigen-binding molecule comprises means for binding PD-1 .

[0612] In some embodiments, the antigen-binding molecule comprises means for binding yc.

[0613] In some embodiments, the antigen-binding molecule comprises means for binding a polypeptide of a yc- containing cytokine receptor other than yc (e.g. selected from IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21Ra or IL-7Ra).

[0614] In some embodiments, the antigen-binding molecule comprises means for binding IL-2Rp.

[0615] In some embodiments, the antigen-binding molecule comprises means for binding IL-21 Ra.

[0616] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to an immune checkpoint protein. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to an immune checkpoint protein. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to an immune checkpoint protein. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to an immune checkpoint protein. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to an immune checkpoint protein.

[0617] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to PD-1 . In some embodiments, the antigen-binding molecule comprises the FRs of an antigenbinding molecule that binds to PD-1. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to PD-1. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to PD-1 . That is, in some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to PD-1.

[0618] 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.

[0619] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to a polypeptide of a yc- containing cytokine receptor other than yc. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to a polypeptide of a yc-containing cytokine receptor other than yc.

[0620] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to IL-2R0. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to IL-2R0. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to IL-2R0. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to 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 IL-2R0.

[0621] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to IL-21 Ra. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to IL-21 Ra. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to IL-21 Ra. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to IL-21 Ra. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to IL-21 Ra.

[0622] 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.

[0623] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule described Table G herein. In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule described Table I herein.

[0624] In some embodiments, a PD-1-binding antibody is selected from an antibody described in Table G, H, or I, herein. In some embodiments, the PD-1-binding antibody is selected from an antibody disclosed herein with one of the following Ab codes: PD-1-MA014, PD-1-MA005, PD-1-MA007, PD-1-MA001 , PD-1-MA003, PD-1- MA004, PD-1-MA006, PD-1-MA008, PD-1-MA009, PD-1-MA010, PD-1-MA011 , PD-1-MA013, PD-1- MA0015 and PD-1-MA016. In other words, in some embodiments, the PD-1-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2HAP55, 2HAP231 , 2HAP103, 2HAP129, 3HAP85, 2HAP226, 3HAP88, 3HAP43, 2HAP189, 2HAP178, 2HAP23, 2HAP285, 2HAP276, 2HAP158, 3HAP51 , and 3HAP3.

[0625] In some embodiments, the PD-1-binding antibody is selected from an antibody disclosed herein with one of the following Ab codes: PD-1-MA014, PD-1-MA005, PD-1-MA007.

[0626] In some embodiments, the PD-1-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2HAP55, 2HAP231 , 2HAP103. In some embodiments, the PD-1-binding antibody is 2HAP55. In some embodiments, the PD-1-binding antibody is 2HAP231. In some embodiments, the PD-1 -binding antibody 2HAP103.

[0627] In some embodiments, the PD-1-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: hu2HAP55, hu2HAP231 , hu2HAP103. In some embodiments, the PD-1- binding antibody is hu2HAP55. In some embodiments, the PD-1-binding antibody is hu2HAP231. In some embodiments, the PD-1 -binding antibody hu2HAP103.

[0628] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule described Table A herein. In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule described Table C herein.

[0629] In some embodiments, a yc-binding antibody is selected from an antibody described in Table A, B, or C, herein.

[0630] 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.

[0631] 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.

[0632] In some embodiments, the yc-binding antibody is selected from: MA081 , MA103, MA003, MA004, MA005, and MA009.

[0633] In some embodiments, the yc-binding antibody is selected from: MA081 and MA103.

[0634] In some embodiments, the yc-binding antibody is selected from: MA003, MA004, MA005, and MA009.

[0635] In some embodiments, the yc-binding antibody is MA081. In some embodiments, the yc-binding antibody is MA103. 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.

[0636] In some embodiments, the yc-binding antibody is 217P3P1_A8. In some embodiments, the yc-binding antibody is 217P3P1_D12. 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.

[0637] In some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: hu2RGT38, hu2RGT238, hu2RGT212.

[0638] In some embodiments, the yc-binding antibody is hu2RGT38. In some embodiments, the yc-binding antibody is hu2RGT238. In some embodiments, the yc-binding antibody is hu2RGT212.

[0639] In some embodiments, an IL-2Rp-binding antibody is selected from an antibody described in Table D, E, or F, herein.

[0640] 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.

[0641] In some embodiments, the IL-2Rp-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: hu3MAV81 , 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, or 2MAV263. In some embodiments, the IL-2Rp-binding antibody is selected from: MA016, MA021 , MA026, MA034, and MA040.

[0642] 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.

[0643] In some embodiments, the IL-2Rp-binding antibody is selected from: hu3MAV75, hu2MAV103, hu2MAV96, hu2MAV248, hu2MAV110, and hu3MAV81.

[0644] In some embodiments, the IL-2Rp-binding antibody is selected from: hu3MAV75, hu2MAV103, hu2MAV96, hu2MAV248, and hu2MAV110.

[0645] 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.

[0646] In some embodiments, an IL-21 Ra-binding antibody is selected from an antibody described in Table M, N, or O, herein.

[0647] In some embodiments, the IL-21 Ra-binding antibody is selected from: MA015, MA023, MA010, MA014, and MA020. In other words, in some embodiments, the IL-21 Ra-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2DAS189, 2DAS109, 3DAS22, 2DAS122, and 3DAS38.

[0648] In some embodiments, the IL-21 Ra-binding antibody is selected from: MA015 and MA020.

[0649] In some embodiments, the IL-21 Ra-binding antibody is selected from: 2DAS189 and 3DAS38.

[0650] In some embodiments, the IL-21 Ra-binding antibody is 2DAS189. In some embodiments, the IL-2R0- binding antibody is 3DAS38. In some embodiments, the IL-2Rp-binding antibody is 2DAS109. In some embodiments, the IL-2Rp-binding antibody is 3DAS22. In some embodiments, the IL-2Rp-binding antibody is 2DAS122.

[0651] In some embodiments, the antibody that binds yc and IL-2R0 is selected from: BS079, BS078, BS081 , BS083, BS084, BS092, and BS094.

[0652] In some embodiments, the antibody that binds yc and IL-2R0 is selected from: BS007, BS008, BS009, BS010, BS011 , BS012, BS013, BS014, BS015, BS016, BS017, BS018, BS019, BS020, BS021 , BS022, BS023, BS024, BS025, BS026, BS027, BS028, BS029, BS030, BS031 , BS032, BS033, BS034, BS035, BS036, BS037, BS038, BS039, BS040, BS041 , BS042, BS043, BS044, BS045, BS046, BS047, BS048,

[0653] BS049, BS050, BS051 , BS052, BS053, BS054, BS055, BS056, BS057, BS058, BS059, BS060, BS061 ,

[0654] BS062, BS063, BS064, BS065, BS066, BS067, BS068, BS069, BS070, BS071 , BS072, BS073, BS074,

[0655] BS075, BS076, BS077, BS078, BS079, BS080, BS081 , BS082, BS083, BS084, BS085, BS086, BS087,

[0656] BS088, BS089, BS090, BS091 , BS092, BS093, and BS094.

[0657] 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,

[0658] BS023, BS024, BS025, BS026, BS027, BS028, BS029, BS030, BS031 , BS032, BS033, BS034, BS035,

[0659] BS036, BS037, BS038, BS039, BS040, BS041 , BS042, BS043, BS044, BS045, BS046, BS047, BS048,

[0660] BS049, BS050, BS051 , BS052, BS053, BS054, BS055, BS056, BS057, BS058, BS059, BS060, BS061 ,

[0661] BS062, BS063, BS064, BS065, and BS066.

[0662] In some embodiments, the antibody that binds yc and IL-2Rp is selected from: BS007, BS008, BS009, BS010, BS011 , BS012, BS013, BS014, BS015, BS016, BS028, BS029, BS030, BS032, BS033, BS034, BS035, BS036.

[0663] 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.

[0664] 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.

[0665] In some embodiments, the antibody that binds yc, IL-2Rp, and PD-1 is selected from: TS101 , TS102,

[0666] TS103, TS104, TS105, TS106, TS107, TS108, TS109, TS110, TS111 , TS112, TS113, TS114, TS115,

[0667] TS116, TS117, TS118, TS119, TS120, TS121 , TS122, TS123, TS124, TS125, TS126, TS127, TS128,

[0668] TS129, TS130, TS131 , TS132, TS133, TS134, TS135, TS136, TS137, TS138, TS139, TS140, TS141 ,

[0669] TS142, TS143, and TS144.

[0670] In some embodiments, the antibody that binds yc, IL-2Rp, and PD-1 is selected from: TS101 , TS102, TS103, TS104, TS105, TS106, TS107, TS108, TS109, TS110, TS111 , TS112, TS113, TS114, TS115, TS116, TS117, TS118, TS119, TS120, TS121 , TS122, TS123, TS124, TS125, TS126, TS127, TS128, TS129, and TS130.

[0671] In some embodiments, the antibody that binds yc, IL-2Rp, and PD-1 is selected from: TS101 , TS106, TS111 , TS119, TS124, and TS129.

[0672] In some embodiments, the antibody that binds yc, IL-2Rp, and PD-1 is selected from: TS101 , TS106, and TS111. In some embodiments, the antibody that binds yc, IL-2R0, and PD-1 is selected from: TS119, TS124, and TS129.

[0673] In some embodiments, the antibody that binds yc, IL-2R0, and PD-1 is selected from: TS136, TS131 , TS132, TS133, TS134, TS135, TS137, TS138, TS139, TS140, TS141 , TS142, TS143, and TS144.

[0674] In some embodiments, the antibody that binds yc, IL-2Rp, and PD-1 is TS136.

[0675] In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is selected from: TS233, TS244, TS237, TS238, TS240, TS241 , TS242, and TS243.

[0676] In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS233 or TS244.

[0677] In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS233. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS233. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS237. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS238. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS240. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS241. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS242. In some embodiments, the antibody that binds yc, IL-21 Ra, and PD-1 is TS243.

[0678] 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.

[0679] In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 which is lower than the pSTAT5 ECso of IL-21. In some embodiments, the antigen-binding molecule has a pSTAT5 EC50 which is higher than the pSTAT5 EC50 of IL-21 .

[0680] 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’.

[0681] 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).

[0682] In some embodiments, the pSTAT5 EC50 ratio of an antigen-binding molecule is determined by comparing the pSTAT5 ECso of a human cytokine with the pSTAT5 ECso of the antigen-binding molecule in question, using the following calculation: (pSTAT5 EC50 of human cytokine / ECso of pSTAT5 on the agonist) x 100. In some embodiments, the pSTAT5 EC50 ratio of an antigen-binding molecule is determined by comparing the pSTAT5 EC50 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.

[0683] In some embodiments, the pSTAT5 EC50 ratio of an antigen-binding molecule is determined by comparing the pSTAT5 EC50 of human IL-21 with the pSTAT5 ECso of the antigen-binding molecule in question, using the following calculation: (pSTAT5 EC50 of human IL-21 / EC50 of pSTAT5 on the agonist) x 100.

[0684] 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.

[0685] 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.

[0686] 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).

[0687] 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.

[0688] 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.

[0689] 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 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 IL- 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. It will also be understood that the pSTAT5 EC50 of an antigen-binding molecule comprising a yc-binding moiety and an IL-21 Ra-binding moiety can be determined through the use of a cell-based reporter gene assay, wherein the cell expresses relevant IL-21 receptor polypeptides (e.g., cells which express IL-21 Ra and yc). In some embodiments, the cells utilised in the cell-based reporter gene assay are cells which express IL-21 Ra and yc.

[0690] 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);

[0691] 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.

[0692] 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-21 Ra and yc; ii. Stimulate reporter cells with the antigen-binding molecule, and separately stimulate cells with a human IL-21 control (both at a range of concentrations);

[0693] 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.

[0694] 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 the relevant cytokine receptors; ii. Stimulate reporter cells with the antigen-binding molecule, and separately stimulate cells with the relevant human cytokine (e.g., IL-2 or IL-21) 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 cytokine / pSTAT5 EC50 of on the antigen-binding molecule) x 100).

[0695] 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).

[0696] 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.

[0697] 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.

[0698] 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.

[0699] 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.

[0700] 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.

[0701] 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.

[0702] 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 / 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. 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-2Rp is selected from: BS008, BS009, BS010, BS011 , BS014, BS015, BS034, BS051 , and BS054.

[0703] 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.

[0704] 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.

[0705] 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.

[0706] In some embodiments, the intermediate agonist has a pSTAT5 EC50 ratio ((human IL-2 pSTAT5 EC50 / agonist pSTAT5 EC50) x 100), which is <50.

[0707] 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 1 agonist pSTAT5 EC50) x 100), which is >15.

[0708] 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 / 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.

[0709] 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.

[0710] 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.

[0711] 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.

[0712] 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, I, J, K, or L herein.

[0713] 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.

[0714] 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.

[0715] In some embodiments, the antibody that binds IL-2Rp is a humanized antibody. In some embodiments, the antibody that binds IL-2Rp is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody that binds IL-2Rp is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table D, E, or F herein.

[0716] In some embodiments, the antibody that binds PD-1 is a humanized antibody. In some embodiments, the antibody that binds PD-1 is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody that binds PD-1 is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table G, H, or I herein.

[0717] In some embodiments, the antibody that binds PD1 , yc and IL-2R0 is a humanized antibody.

[0718] 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. 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.

[0719] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety.

[0720] (A) a yc-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:760 HC-CDR2 having the amino acid sequence of SEQ ID NO:776 HC-CDR3 having the amino acid sequence of SEQ ID NO:792, 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] (B) a yc-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:761 HC-CDR2 having the amino acid sequence of SEQ ID NO:777 HC-CDR3 having the amino acid sequence of SEQ ID NO:793, 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. (C) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0724] HC-CDR1 having the amino acid sequence of SEQ ID NO:762

[0725] HC-CDR2 having the amino acid sequence of SEQ ID NO:778

[0726] HC-CDR3 having the amino acid sequence of SEQ ID NO:794, 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.

[0727] (D) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0728] HC-CDR1 having the amino acid sequence of SEQ ID NO:763

[0729] HC-CDR2 having the amino acid sequence of SEQ ID NO:779

[0730] HC-CDR3 having the amino acid sequence of SEQ ID NO:795, 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.

[0731] (E) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0732] HC-CDR1 having the amino acid sequence of SEQ ID NO:764

[0733] HC-CDR2 having the amino acid sequence of SEQ ID NQ:780

[0734] HC-CDR3 having the amino acid sequence of SEQ ID NO:796, 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.

[0735] (F) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0736] HC-CDR1 having the amino acid sequence of SEQ ID NO:765

[0737] HC-CDR2 having the amino acid sequence of SEQ ID NO:781

[0738] HC-CDR3 having the amino acid sequence of SEQ ID NO:797, 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.

[0739] (G) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0740] HC-CDR1 having the amino acid sequence of SEQ ID NO:766

[0741] HC-CDR2 having the amino acid sequence of SEQ ID NO:782

[0742] HC-CDR3 having the amino acid sequence of SEQ ID NO:798, 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.

[0743] (H) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0744] HC-CDR1 having the amino acid sequence of SEQ ID NO:767 HC-CDR2 having the amino acid sequence of SEQ ID NO:783

[0745] HC-CDR3 having the amino acid sequence of SEQ ID NO:799, 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] (I) a yc-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:768

[0748] HC-CDR2 having the amino acid sequence of SEQ ID NO:784

[0749] HC-CDR3 having the amino acid sequence of SEQ ID NQ:800, 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] (J) a yc-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:769

[0752] HC-CDR2 having the amino acid sequence of SEQ ID NO:785

[0753] HC-CDR3 having the amino acid sequence of SEQ ID NQ:801 , 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] (K) a yc-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 NQ:770

[0756] HC-CDR2 having the amino acid sequence of SEQ ID NO:786

[0757] HC-CDR3 having the amino acid sequence of SEQ ID NQ:802, 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.

[0758] (L) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0759] HC-CDR1 having the amino acid sequence of SEQ ID NO:771

[0760] HC-CDR2 having the amino acid sequence of SEQ ID NO:787

[0761] HC-CDR3 having the amino acid sequence of SEQ ID NQ:803, 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.

[0762] (M) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0763] HC-CDR1 having the amino acid sequence of SEQ ID NO:772

[0764] HC-CDR2 having the amino acid sequence of SEQ ID NO:788

[0765] HC-CDR3 having the amino acid sequence of SEQ ID NQ:804, 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.

[0766] (N) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0767] HC-CDR1 having the amino acid sequence of SEQ ID NO:773

[0768] HC-CDR2 having the amino acid sequence of SEQ ID NO:789

[0769] HC-CDR3 having the amino acid sequence of SEQ ID NQ:805, 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.

[0770] (O) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0771] HC-CDR1 having the amino acid sequence of SEQ ID NO:774

[0772] HC-CDR2 having the amino acid sequence of SEQ ID NQ:790

[0773] HC-CDR3 having the amino acid sequence of SEQ ID NQ:806, 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.

[0774] (P) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0775] HC-CDR1 having the amino acid sequence of SEQ ID NO:775

[0776] HC-CDR2 having the amino acid sequence of SEQ ID NO:791

[0777] HC-CDR3 having the amino acid sequence of SEQ ID NQ:807, 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.

[0778] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0779] (Q) a yc-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 NQ:808

[0781] HC-FR2 having the amino acid sequence of SEQ ID NO:816

[0782] HC-FR3 having the amino acid sequence of SEQ ID NO:831

[0783] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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] (R) a yc-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 NQ:809

[0786] HC-FR2 having the amino acid sequence of SEQ ID NO:817 HC-FR3 having the amino acid sequence of SEQ ID NO:832

[0787] HC-FR4 having the amino acid sequence of SEQ ID NO:849, 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.

[0788] (S) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0789] HC-FR1 having the amino acid sequence of SEQ ID NQ:810

[0790] HC-FR2 having the amino acid sequence of SEQ ID NO:818

[0791] HC-FR3 having the amino acid sequence of SEQ ID NO:833

[0792] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0793] (T) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0794] HC-FR1 having the amino acid sequence of SEQ ID NQ:809

[0795] HC-FR2 having the amino acid sequence of SEQ ID NO:819

[0796] HC-FR3 having the amino acid sequence of SEQ ID NO:834

[0797] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0798] (U) a yc-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:811

[0800] HC-FR2 having the amino acid sequence of SEQ ID NQ:820

[0801] HC-FR3 having the amino acid sequence of SEQ ID NO:835

[0802] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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] (V) a yc-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:812

[0805] HC-FR2 having the amino acid sequence of SEQ ID NO:821

[0806] HC-FR3 having the amino acid sequence of SEQ ID NO:836

[0807] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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. (W) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0808] HC-FR1 having the amino acid sequence of SEQ ID NO:809

[0809] HC-FR2 having the amino acid sequence of SEQ ID NO:817

[0810] HC-FR3 having the amino acid sequence of SEQ ID NO:837

[0811] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0812] (X) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0813] HC-FR1 having the amino acid sequence of SEQ ID NQ:809

[0814] HC-FR2 having the amino acid sequence of SEQ ID NO:822

[0815] HC-FR3 having the amino acid sequence of SEQ ID NO:838

[0816] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0817] (Y) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0818] HC-FR1 having the amino acid sequence of SEQ ID NQ:809

[0819] HC-FR2 having the amino acid sequence of SEQ ID NO:823

[0820] HC-FR3 having the amino acid sequence of SEQ ID NO:839

[0821] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0822] (Z) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0823] HC-FR1 having the amino acid sequence of SEQ ID NQ:809

[0824] HC-FR2 having the amino acid sequence of SEQ ID NO:817

[0825] HC-FR3 having the amino acid sequence of SEQ ID NQ:840

[0826] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0827] (AA) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0828] HC-FR1 having the amino acid sequence of SEQ ID NO:813

[0829] HC-FR2 having the amino acid sequence of SEQ ID NO:824

[0830] HC-FR3 having the amino acid sequence of SEQ ID NO:841

[0831] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0832] (AB) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0833] HC-FR1 having the amino acid sequence of SEQ ID NO:809

[0834] HC-FR2 having the amino acid sequence of SEQ ID NO:825

[0835] HC-FR3 having the amino acid sequence of SEQ ID NO:842

[0836] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0837] (AC) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0838] HC-FR1 having the amino acid sequence of SEQ ID NQ:809

[0839] HC-FR2 having the amino acid sequence of SEQ ID NO:826

[0840] HC-FR3 having the amino acid sequence of SEQ ID NO:843

[0841] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0842] (AD) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0843] HC-FR1 having the amino acid sequence of SEQ ID NO:814

[0844] HC-FR2 having the amino acid sequence of SEQ ID NO:827

[0845] HC-FR3 having the amino acid sequence of SEQ ID NO:844

[0846] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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] (AE) a yc-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:809

[0849] HC-FR2 having the amino acid sequence of SEQ ID NO:828

[0850] HC-FR3 having the amino acid sequence of SEQ ID NO:845

[0851] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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] (AF) a yc-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:815 HC-FR2 having the amino acid sequence of SEQ ID NO:828

[0854] HC-FR3 having the amino acid sequence of SEQ ID NO:846

[0855] HC-FR4 having the amino acid sequence of SEQ ID NQ:850, 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.

[0856] (AG) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0857] HC-FR1 having the amino acid sequence of SEQ ID NQ:809

[0858] HC-FR2 having the amino acid sequence of SEQ ID NO:829

[0859] HC-FR3 having the amino acid sequence of SEQ ID NO:845

[0860] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0861] (AH) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0862] HC-FR1 having the amino acid sequence of SEQ ID NO:815

[0863] HC-FR2 having the amino acid sequence of SEQ ID NQ:830

[0864] HC-FR3 having the amino acid sequence of SEQ ID NO:847

[0865] HC-FR4 having the amino acid sequence of SEQ ID NO:848, 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.

[0866] (Al) 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 (A) to (P) above, and the FRs according to any one of (Q) to (AH) above.

[0867] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region):

[0868] (AJ) comprising the CDRs according to (A) and the FRs according to (Q).

[0869] (AK) comprising the CDRs according to (B) and the FRs according to (R).

[0870] (AL) comprising the CDRs according to (C) and the FRs according to (S).

[0871] (AM) comprising the CDRs according to (D) and the FRs according to (T).

[0872] (AN) comprising the CDRs according to (E) and the FRs according to (U). (AO) comprising the CDRs according to (F) and the FRs according to (V).

[0873] (AP) comprising the CDRs according to (G) and the FRs according to (W).

[0874] (AQ) comprising the CDRs according to (H) and the FRs according to (X).

[0875] (AR) comprising the CDRs according to (I) and the FRs according to (Y).

[0876] (AS) comprising the CDRs according to (J) and the FRs according to (Z).

[0877] (AT) comprising the CDRs according to (K) and the FRs according to (AA).

[0878] (AU) comprising the CDRs according to (L) and the FRs according to (AB).

[0879] (AV) comprising the CDRs according to (M) and the FRs according to (AC).

[0880] (AW) comprising the CDRs according to (N) and the FRs according to (AD).

[0881] (AX) comprising the CDRs according to (N) and the FRs according to (AH).

[0882] (AY) comprising the CDRs according to (O) and the FRs according to (AE).

[0883] (AZ) comprising the CDRs according to (O) and the FRs according to (AF).

[0884] (BA) comprising the CDRs according to (P) and the FRs according to (AG).

[0885] (BB) 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:851 , SEQ ID NO:852, SEQ ID NO:853, SEQ ID NO:854, SEQ ID NO:855, SEQ ID NO:856, SEQ ID NO:857,

[0886] SEQ ID NO:858, SEQ ID NO:859, SEQ ID NQ:860, SEQ ID NO:861 , SEQ ID NO:862, SEQ ID NO:863,

[0887] SEQ ID NO:864, SEQ ID NO:865, SEQ ID NO:866, SEQ ID NO:867, or SEQ ID NO:868.

[0888] (BC) 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:851 , or SEQ ID NO:855.

[0889] (BD) 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:851. (BE) 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:855.

[0890] (BF) 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:866, or SEQ ID NO:868.

[0891] (BG) 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:866.

[0892] (BH) 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:868.

[0893] In some embodiments, the antigen-binding molecule comprises:

[0894] (1) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0895] 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.

[0896] (2) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0897] 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.

[0898] (3) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0899] HC-CDR1 having the amino acid sequence of SEQ ID NO:276 HC-CDR2 having the amino acid sequence of SEQ ID NO:277 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. (4) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0900] HC-CDR1 having the amino acid sequence of SEQ ID NO:273

[0901] HC-CDR2 having the amino acid sequence of SEQ ID NO:274

[0902] 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.

[0903] (5) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0904] HC-CDR1 having the amino acid sequence of SEQ ID NO:279

[0905] HC-CDR2 having the amino acid sequence of SEQ ID NQ:280

[0906] 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.

[0907] (6) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0908] HC-CDR1 having the amino acid sequence of SEQ ID NO:279

[0909] HC-CDR2 having the amino acid sequence of SEQ ID NQ:280

[0910] 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.

[0911] (7) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0912] HC-CDR1 having the amino acid sequence of SEQ ID NO:282

[0913] HC-CDR2 having the amino acid sequence of SEQ ID NO:283

[0914] 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.

[0915] (8) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0916] HC-CDR1 having the amino acid sequence of SEQ ID NO:285

[0917] HC-CDR2 having the amino acid sequence of SEQ ID NO:286

[0918] 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.

[0919] (9) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:288

[0920] HC-CDR2 having the amino acid sequence of SEQ ID NO:289

[0921] 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.

[0922] (10) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0923] HC-CDR1 having the amino acid sequence of SEQ ID NO:291

[0924] HC-CDR2 having the amino acid sequence of SEQ ID NO:292

[0925] 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.

[0926] (11) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0927] HC-CDR1 having the amino acid sequence of SEQ ID NO:294

[0928] HC-CDR2 having the amino acid sequence of SEQ ID NO:295

[0929] 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.

[0930] (12) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0931] HC-CDR1 having the amino acid sequence of SEQ ID NO:297

[0932] HC-CDR2 having the amino acid sequence of SEQ ID NO:298

[0933] 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.

[0934] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0935] (13) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0936] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0937] HC-FR2 having the amino acid sequence of SEQ ID NQ:400

[0938] HC-FR3 having the amino acid sequence of SEQ ID NO:462

[0939] 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. (13.1) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0940] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0941] HC-FR2 having the amino acid sequence of SEQ ID NQ:400

[0942] HC-FR3 having the amino acid sequence of SEQ ID NO:463

[0943] 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.

[0944] (14) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0945] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0946] HC-FR2 having the amino acid sequence of SEQ ID NQ:401

[0947] HC-FR3 having the amino acid sequence of SEQ ID NO:465

[0948] 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.

[0949] (15) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0950] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[0951] HC-FR2 having the amino acid sequence of SEQ ID NQ:403

[0952] HC-FR3 having the amino acid sequence of SEQ ID NO:466

[0953] 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.

[0954] (16) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0955] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[0956] HC-FR2 having the amino acid sequence of SEQ ID NQ:400

[0957] HC-FR3 having the amino acid sequence of SEQ ID NO:425

[0958] 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.

[0959] (17) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0960] HC-FR1 having the amino acid sequence of SEQ ID NO:378

[0961] HC-FR2 having the amino acid sequence of SEQ ID NQ:401

[0962] HC-FR3 having the amino acid sequence of SEQ ID NO:426

[0963] 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.

[0964] (18) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0965] HC-FR1 having the amino acid sequence of SEQ ID NO:380

[0966] HC-FR2 having the amino acid sequence of SEQ ID NO:403

[0967] HC-FR3 having the amino acid sequence of SEQ ID NO:428

[0968] 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.

[0969] (19) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0970] HC-FR1 having the amino acid sequence of SEQ ID NO:379

[0971] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0972] HC-FR3 having the amino acid sequence of SEQ ID NO:427

[0973] 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.

[0974] (20) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0975] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[0976] HC-FR2 having the amino acid sequence of SEQ ID NO:392

[0977] HC-FR3 having the amino acid sequence of SEQ ID NO:429

[0978] 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.

[0979] (21) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0980] HC-FR1 having the amino acid sequence of SEQ ID NO:395

[0981] HC-FR2 having the amino acid sequence of SEQ ID NO:392

[0982] HC-FR3 having the amino acid sequence of SEQ ID NO:429

[0983] 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.

[0984] (22) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0985] HC-FR1 having the amino acid sequence of SEQ ID NO:393 HC-FR2 having the amino acid sequence of SEQ ID NO:404

[0986] HC-FR3 having the amino acid sequence of SEQ ID NO:430

[0987] 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.

[0988] (23) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0989] HC-FR1 having the amino acid sequence of SEQ ID NO:382

[0990] HC-FR2 having the amino acid sequence of SEQ ID NQ:405

[0991] HC-FR3 having the amino acid sequence of SEQ ID NO:431

[0992] 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.

[0993] (24) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0994] HC-FR1 having the amino acid sequence of SEQ ID NO:394

[0995] HC-FR2 having the amino acid sequence of SEQ ID NQ:406

[0996] HC-FR3 having the amino acid sequence of SEQ ID NO:432

[0997] 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.

[0998] (25) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0999] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1000] HC-FR2 having the amino acid sequence of SEQ ID NQ:407

[1001] HC-FR3 having the amino acid sequence of SEQ ID NO:433

[1002] 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.

[1003] (26) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1004] HC-FR1 having the amino acid sequence of SEQ ID NO:396

[1005] HC-FR2 having the amino acid sequence of SEQ ID NQ:408

[1006] HC-FR3 having the amino acid sequence of SEQ ID NO:434

[1007] 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. (27) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1008] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1009] HC-FR2 having the amino acid sequence of SEQ ID NO:405

[1010] HC-FR3 having the amino acid sequence of SEQ ID NO:435

[1011] 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.

[1012] (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.

[1013] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region):

[1014] (29) comprising the CDRs according to (1) and the FRs according to (13).

[1015] (30) comprising the CDRs according to (1) and the FRs according to (13.1).

[1016] (31) comprising the CDRs according to (1) and the FRs according to (16).

[1017] (32) comprising the CDRs according to (2) and the FRs according to (14).

[1018] (33) comprising the CDRs according to (2) and the FRs according to (17).

[1019] (34) comprising the CDRs according to (3) and the FRs according to (15).

[1020] (35) comprising the CDRs according to (3) and the FRs according to (18).

[1021] (36) comprising the CDRs according to (4) and the FRs according to (19).

[1022] (37) comprising the CDRs according to (5) and the FRs according to (20).

[1023] (38) comprising the CDRs according to (6) and the FRs according to (21).

[1024] (39) comprising the CDRs according to (7) and the FRs according to (22).

[1025] (40) comprising the CDRs according to (8) and the FRs according to (23).

[1026] (41) comprising the CDRs according to (9) and the FRs according to (24). (42) comprising the CDRs according to (10) and the FRs according to (25).

[1027] (43) comprising the CDRs according to (11) and the FRs according to (26).

[1028] (44) comprising the CDRs according to (12) and the FRs according to (27).

[1029] (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.

[1030] (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.

[1031] (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.

[1032] (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.

[1033] (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.

[1034] (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.

[1035] In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety.

[1036] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[1037] (50) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1038] HC-CDR1 having the amino acid sequence of SEQ ID NQ:303 HC-CDR2 having the amino acid sequence of SEQ ID NQ:304 HC-CDR3 having the amino acid sequence of SEQ ID NO: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.

[1039] (51) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1040] HC-CDR1 having the amino acid sequence of SEQ ID NQ:300 HC-CDR2 having the amino acid sequence of SEQ ID NQ:301 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.

[1041] (52) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1042] HC-CDR1 having the amino acid sequence of SEQ ID NQ:303 HC-CDR2 having the amino acid sequence of SEQ ID NO:312 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.

[1043] (53) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1044] HC-CDR1 having the amino acid sequence of SEQ ID NQ:306 HC-CDR2 having the amino acid sequence of SEQ ID NQ:307 HC-CDR3 having the amino acid sequence of SEQ ID NQ: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.

[1045] (54) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1046] HC-CDR1 having the amino acid sequence of SEQ ID NQ:309 HC-CDR2 having the amino acid sequence of SEQ ID NQ:310 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.

[1047] (55) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1048] HC-CDR1 having the amino acid sequence of SEQ ID NO:314 HC-CDR2 having the amino acid sequence of SEQ ID NO:315 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.

[1049] (56) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1050] HC-CDR1 having the amino acid sequence of SEQ ID NO:317

[1051] HC-CDR2 having the amino acid sequence of SEQ ID NO:318

[1052] 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.

[1053] (57) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1054] HC-CDR1 having the amino acid sequence of SEQ ID NQ:320

[1055] HC-CDR2 having the amino acid sequence of SEQ ID NO:321

[1056] 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.

[1057] (58) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1058] HC-CDR1 having the amino acid sequence of SEQ ID NO:323

[1059] HC-CDR2 having the amino acid sequence of SEQ ID NO:324

[1060] 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.

[1061] (59) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1062] HC-CDR1 having the amino acid sequence of SEQ ID NO:326

[1063] HC-CDR2 having the amino acid sequence of SEQ ID NO:327

[1064] 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.

[1065] (60) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1066] HC-CDR1 having the amino acid sequence of SEQ ID NO:329 HC-CDR2 having the amino acid sequence of SEQ ID NQ:330 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.

[1067] (61) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1068] HC-CDR1 having the amino acid sequence of SEQ ID NO:332

[1069] HC-CDR2 having the amino acid sequence of SEQ ID NO:333

[1070] 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.

[1071] (62) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1072] HC-CDR1 having the amino acid sequence of SEQ ID NO:335

[1073] HC-CDR2 having the amino acid sequence of SEQ ID NO:336

[1074] 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.

[1075] (63) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1076] HC-CDR1 having the amino acid sequence of SEQ ID NO:338

[1077] HC-CDR2 having the amino acid sequence of SEQ ID NO:339

[1078] 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.

[1079] (64) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1080] HC-CDR1 having the amino acid sequence of SEQ ID NO:341

[1081] HC-CDR2 having the amino acid sequence of SEQ ID NO:342

[1082] 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.

[1083] (65) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1084] HC-CDR1 having the amino acid sequence of SEQ ID NO:344 HC-CDR2 having the amino acid sequence of SEQ ID NO:345 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.

[1085] (66) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1086] HC-CDR1 having the amino acid sequence of SEQ ID NO:347

[1087] HC-CDR2 having the amino acid sequence of SEQ ID NO:348

[1088] 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.

[1089] (67) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1090] HC-CDR1 having the amino acid sequence of SEQ ID NQ:350

[1091] HC-CDR2 having the amino acid sequence of SEQ ID NO:351

[1092] 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.

[1093] (68) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1094] HC-CDR1 having the amino acid sequence of SEQ ID NO:353

[1095] HC-CDR2 having the amino acid sequence of SEQ ID NO:354

[1096] 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.

[1097] (69) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1098] HC-CDR1 having the amino acid sequence of SEQ ID NO:356

[1099] HC-CDR2 having the amino acid sequence of SEQ ID NO:357

[1100] 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.

[1101] (70) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1102] HC-CDR1 having the amino acid sequence of SEQ ID NO:359 HC-CDR2 having the amino acid sequence of SEQ ID NQ:360 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.

[1103] (71) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1104] HC-CDR1 having the amino acid sequence of SEQ ID NO:362

[1105] HC-CDR2 having the amino acid sequence of SEQ ID NO:363

[1106] 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.

[1107] (72) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1108] HC-CDR1 having the amino acid sequence of SEQ ID NO:365

[1109] HC-CDR2 having the amino acid sequence of SEQ ID NO:366

[1110] 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.

[1111] (73) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1112] HC-CDR1 having the amino acid sequence of SEQ ID NO:368

[1113] HC-CDR2 having the amino acid sequence of SEQ ID NO:369

[1114] 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.

[1115] (74) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1116] HC-CDR1 having the amino acid sequence of SEQ ID NO:371

[1117] HC-CDR2 having the amino acid sequence of SEQ ID NO:372

[1118] 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.

[1119] (75) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1120] HC-CDR1 having the amino acid sequence of SEQ ID NO:374 HC-CDR2 having the amino acid sequence of SEQ ID NO:375 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.

[1121] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[1122] (76) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1123] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1124] HC-FR2 having the amino acid sequence of SEQ ID NO:402

[1125] HC-FR3 having the amino acid sequence of SEQ ID NO:468

[1126] 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.

[1127] (77) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1128] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1129] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1130] HC-FR3 having the amino acid sequence of SEQ ID NO:464

[1131] 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.

[1132] (78) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1133] HC-FR1 having the amino acid sequence of SEQ ID NO:398

[1134] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1135] HC-FR3 having the amino acid sequence of SEQ ID NO:464

[1136] 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.

[1137] (79) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1138] HC-FR1 having the amino acid sequence of SEQ ID NO:399

[1139] HC-FR2 having the amino acid sequence of SEQ ID NO:467

[1140] HC-FR3 having the amino acid sequence of SEQ ID NO:469

[1141] 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. (80) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1142] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1143] HC-FR2 having the amino acid sequence of SEQ ID NO:410

[1144] HC-FR3 having the amino acid sequence of SEQ ID NQ:470

[1145] 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.

[1146] (81) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1147] HC-FR1 having the amino acid sequence of SEQ ID NO:385

[1148] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1149] HC-FR3 having the amino acid sequence of SEQ ID NO:437

[1150] 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.

[1151] (82) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1152] HC-FR1 having the amino acid sequence of SEQ ID NO:383

[1153] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1154] HC-FR3 having the amino acid sequence of SEQ ID NO:436

[1155] 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.

[1156] (83) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1157] HC-FR1 having the amino acid sequence of SEQ ID NO:385

[1158] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1159] HC-FR3 having the amino acid sequence of SEQ ID NQ:440

[1160] 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.

[1161] (84) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1162] HC-FR1 having the amino acid sequence of SEQ ID NO:383

[1163] HC-FR2 having the amino acid sequence of SEQ ID NQ:409

[1164] HC-FR3 having the amino acid sequence of SEQ ID NO:438

[1165] 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.

[1166] (85) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1167] HC-FR1 having the amino acid sequence of SEQ ID NO:381

[1168] HC-FR2 having the amino acid sequence of SEQ ID NO:410

[1169] HC-FR3 having the amino acid sequence of SEQ ID NO:439

[1170] 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.

[1171] (86) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1172] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[1173] HC-FR2 having the amino acid sequence of SEQ ID NO:411

[1174] HC-FR3 having the amino acid sequence of SEQ ID NO:441

[1175] 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.

[1176] (87) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1177] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1178] HC-FR2 having the amino acid sequence of SEQ ID NO:412

[1179] HC-FR3 having the amino acid sequence of SEQ ID NO:442

[1180] 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.

[1181] (88) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1182] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1183] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1184] HC-FR3 having the amino acid sequence of SEQ ID NO:443

[1185] 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.

[1186] (89) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1187] HC-FR1 having the amino acid sequence of SEQ ID NO:382 HC-FR2 having the amino acid sequence of SEQ ID NO:402

[1188] HC-FR3 having the amino acid sequence of SEQ ID NO:444

[1189] 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.

[1190] (90) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1191] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1192] HC-FR2 having the amino acid sequence of SEQ ID NQ:410

[1193] HC-FR3 having the amino acid sequence of SEQ ID NO:445

[1194] 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.

[1195] (91) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1196] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1197] HC-FR2 having the amino acid sequence of SEQ ID NO:413

[1198] HC-FR3 having the amino acid sequence of SEQ ID NO:446

[1199] 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.

[1200] (92) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1201] HC-FR1 having the amino acid sequence of SEQ ID NO:384

[1202] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1203] HC-FR3 having the amino acid sequence of SEQ ID NO:447

[1204] 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.

[1205] (93) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1206] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[1207] HC-FR2 having the amino acid sequence of SEQ ID NO:414

[1208] HC-FR3 having the amino acid sequence of SEQ ID NO:448

[1209] 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. (94) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1210] HC-FR1 having the amino acid sequence of SEQ ID NO:386

[1211] HC-FR2 having the amino acid sequence of SEQ ID NO:415

[1212] HC-FR3 having the amino acid sequence of SEQ ID NO:449

[1213] 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.

[1214] (95) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1215] HC-FR1 having the amino acid sequence of SEQ ID NO:387

[1216] HC-FR2 having the amino acid sequence of SEQ ID NO:416

[1217] HC-FR3 having the amino acid sequence of SEQ ID NQ:450

[1218] 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.

[1219] (96) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1220] HC-FR1 having the amino acid sequence of SEQ ID NO:388

[1221] HC-FR2 having the amino acid sequence of SEQ ID NO:417

[1222] HC-FR3 having the amino acid sequence of SEQ ID NO:451

[1223] 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.

[1224] (96b) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1225] HC-FR1 having the amino acid sequence of SEQ ID NO:872

[1226] HC-FR2 having the amino acid sequence of SEQ ID NO:873

[1227] HC-FR3 having the amino acid sequence of SEQ ID NO:874

[1228] HC-FR4 having the amino acid sequence of SEQ ID NQ:850, 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.

[1229] (97) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1230] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[1231] HC-FR2 having the amino acid sequence of SEQ ID NO:418

[1232] HC-FR3 having the amino acid sequence of SEQ ID NO:452

[1233] 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.

[1234] (98) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1235] HC-FR1 having the amino acid sequence of SEQ ID NO:387

[1236] HC-FR2 having the amino acid sequence of SEQ ID NO:419

[1237] HC-FR3 having the amino acid sequence of SEQ ID NO:453

[1238] 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.

[1239] (99) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1240] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1241] HC-FR2 having the amino acid sequence of SEQ ID NQ:420

[1242] HC-FR3 having the amino acid sequence of SEQ ID NO:454

[1243] 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.

[1244] (100) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1245] HC-FR1 having the amino acid sequence of SEQ ID NQ:380

[1246] HC-FR2 having the amino acid sequence of SEQ ID NO:421

[1247] HC-FR3 having the amino acid sequence of SEQ ID NO:455

[1248] 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.

[1249] (101) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1250] HC-FR1 having the amino acid sequence of SEQ ID NO:389

[1251] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1252] HC-FR3 having the amino acid sequence of SEQ ID NO:456

[1253] 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.

[1254] (102) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1255] HC-FR1 having the amino acid sequence of SEQ ID NQ:390 HC-FR2 having the amino acid sequence of SEQ ID NO:422

[1256] HC-FR3 having the amino acid sequence of SEQ ID NO:457

[1257] 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.

[1258] (103) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1259] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1260] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1261] HC-FR3 having the amino acid sequence of SEQ ID NO:458

[1262] 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.

[1263] (104) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1264] HC-FR1 having the amino acid sequence of SEQ ID NO:391

[1265] HC-FR2 having the amino acid sequence of SEQ ID NO:423

[1266] HC-FR3 having the amino acid sequence of SEQ ID NO:459

[1267] 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.

[1268] (105) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1269] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1270] HC-FR2 having the amino acid sequence of SEQ ID NO:424

[1271] HC-FR3 having the amino acid sequence of SEQ ID NQ:460

[1272] 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.

[1273] (106) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1274] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1275] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1276] HC-FR3 having the amino acid sequence of SEQ ID NO:461

[1277] 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. (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.

[1278] In some embodiments, the antigen-binding molecule comprises an IL-2Rp-binding moiety (e.g., a VHH, or a VH region):

[1279] (108) comprising the CDRs according to (50) and the FRs according to (76).

[1280] (109) comprising the CDRs according to (50) and the FRs according to (81).

[1281] (110) comprising the CDRs according to (51) and the FRs according to (77).

[1282] (111) comprising the CDRs according to (51) and the FRs according to (82).

[1283] (112) comprising the CDRs according to (52) and the FRs according to (78).

[1284] (113) comprising the CDRs according to (52) and the FRs according to (83).

[1285] (114) comprising the CDRs according to (53) and the FRs according to (79).

[1286] (115) comprising the CDRs according to (53) and the FRs according to (84).

[1287] (116) comprising the CDRs according to (54) and the FRs according to (80).

[1288] (117) comprising the CDRs according to (54) and the FRs according to (85).

[1289] (118) comprising the CDRs according to (55) and the FRs according to (86).

[1290] (119) comprising the CDRs according to (56) and the FRs according to (87).

[1291] (120) comprising the CDRs according to (57) and the FRs according to (88).

[1292] (121) comprising the CDRs according to (58) and the FRs according to (89).

[1293] (122) comprising the CDRs according to (59) and the FRs according to (90).

[1294] (123) comprising the CDRs according to (60) and the FRs according to (91).

[1295] (124) comprising the CDRs according to (61) and the FRs according to (92). (125) comprising the CDRs according to (62) and the FRs according to (93).

[1296] (126) comprising the CDRs according to (63) and the FRs according to (94).

[1297] (127) comprising the CDRs according to (64) and the FRs according to (95).

[1298] (128) comprising the CDRs according to (65) and the FRs according to (96) or (96b).

[1299] (129) comprising the CDRs according to (66) and the FRs according to (97).

[1300] (130) comprising the CDRs according to (67) and the FRs according to (98).

[1301] (131) comprising the CDRs according to (68) and the FRs according to (99).

[1302] (132) comprising the CDRs according to (69) and the FRs according to (100).

[1303] (133) comprising the CDRs according to (70) and the FRs according to (101).

[1304] (134) comprising the CDRs according to (71) and the FRs according to (102).

[1305] (135) comprising the CDRs according to (72) and the FRs according to (103).

[1306] (136) comprising the CDRs according to (73) and the FRs according to (104).

[1307] (137) comprising the CDRs according to (74) and the FRs according to (105).

[1308] (138) comprising the CDRs according to (75) and the FRs according to (106).

[1309] (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 NO:479, SEQ ID NO:480, SEQ ID NO:481 , SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:141 , SEQ ID

[1310] NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID

[1311] NO:148, SEQ ID NO:149, SEQ ID NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID

[1312] NO:154, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID

[1313] NQ:160, SEQ ID NO:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ

[1314] ID NO:166.

[1315] (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. (141) In some embodiments, the antigen-binding molecule comprises:

[1316] (i) a yc-binding moiety, and

[1317] (ii) an IL-2Rp-binding moiety.

[1318] (142) In some embodiments, the antigen-binding molecule comprises:

[1319] (i) a yc-binding moiety, and

[1320] (ii) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[1321] (50) to (75) above.

[1322] (143) In some embodiments, the antigen-binding molecule comprises:

[1323] (i) a yc-binding moiety, and

[1324] (ii) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[1325] (50) to (75) above, and the FRs according to any one of (76) to (106) above.

[1326] (144) In some embodiments, the antigen-binding molecule comprises:

[1327] (i) a yc-binding moiety, and

[1328] (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, SEQ ID NO:483, SEQ ID NO:141 , SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID

[1329] NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID

[1330] NQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID

[1331] NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID

[1332] NQ:160, SEQ ID NO:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID

[1333] NO:165, or SEQ ID NO:166.

[1334] (145) In some embodiments, the antigen-binding molecule comprises:

[1335] (i) a yc-binding moiety, and

[1336] (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, or SEQ ID NO:483.

[1337] (146) In some embodiments, the antigen-binding molecule comprises:

[1338] (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[1339] (12) above, and

[1340] (iv) an IL-2Rp-binding moiety.

[1341] (147) In some embodiments, the antigen-binding molecule comprises: (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[1342] (12) above, and the FRs according to any one of (13) to (27) above, and

[1343] (iv) an IL-2Rp-binding moiety.

[1344] (148) In some embodiments, the antigen-binding molecule comprises:

[1345] (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

[1346] (iv) an IL-2Rp-binding moiety.

[1347] (149) In some embodiments, the antigen-binding molecule comprises:

[1348] (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

[1349] (iv) an IL-2Rp-binding moiety.

[1350] (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.

[1351] (151) In some embodiments, the antigen-binding molecule comprises:

[1352] (v) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[1353] (12) above, and the FRs according to any one of (13) to (27) above, and

[1354] (vi) an IL-2Rp-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[1355] (50) to (75) above, and the FRs according to any one of (76) to (106) above.

[1356] (151) 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, 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 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 NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148,

[1357] SEQ ID NO:149, SEQ ID NO:150, SEQ ID N0:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154,

[1358] SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160,

[1359] SEQ ID N0:161 , SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ ID

[1360] NO:166.

[1361] (152) 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.

[1362] (153) 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

[1363] ID NO:243, SEQ ID NO:244, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, SEQ

[1364] ID NO:249, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:259, SEQ

[1365] ID NQ:260, SEQ ID NO:261 , SEQ ID NO:262, SEQ ID NO:263, SEQ ID NO:265, SEQ ID NO:179, SEQ

[1366] ID NQ:180, SEQ ID NO:181 , SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ

[1367] ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NQ:190, SEQ ID NO:191 , SEQ

[1368] ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ

[1369] ID NO:198, SEQ ID NO:199, SEQ ID NQ:200, SEQ ID NQ:201 , SEQ ID NQ:202, SEQ ID NQ:203, SEQ

[1370] ID NQ:204, SEQ ID NQ:205, SEQ ID NQ:206, SEQ ID NQ:207, SEQ ID NQ:208, SEQ ID NQ:209, SEQ

[1371] ID NQ:210, SEQ ID NO:211 , SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ

[1372] ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NQ:220, SEQ ID NO:221 , SEQ

[1373] ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ

[1374] ID NO:228, SEQ ID NO:229, SEQ ID NQ:230, SEQ ID NO:231 , SEQ ID NO:232, SEQ ID NO:233, SEQ

[1375] ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, and / or SEQ ID NO:238.

[1376] (153.1) 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 ID NO:249, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:259, SEQ ID NQ:260, SEQ ID NO:261 , SEQ ID NO:262, SEQ ID NO:263, and / or SEQ ID NO:265.

[1377] (154) 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, and / or SEQ ID NO:266.

[1378] 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

[1379] ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NQ:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ

[1380] ID NO:123, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ

[1381] 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

[1382] NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NQ:60, SEQ ID NO:61 , SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NQ:70, SEQ ID NO:71 , SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NQ:80, SEQ ID NO:81 , SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NQ:90, SEQ ID NO:91 , SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NQ:100, SEQ ID NQ:101 , SEQ ID NQ:102, SEQ ID NQ:103, SEQ ID NQ:104, SEQ ID NQ:105, SEQ ID NQ:106, SEQ ID NQ:107, SEQ ID NQ:108, SEQ ID NQ:109, SEQ ID NQ:110, SEQ ID NO:111 , and / or SEQ ID NO:112.

[1383] 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

[1384] ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NQ:120, SEQ ID NO:121 , SEQ ID NO:122, SEQ

[1385] ID NO:123, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:131 , SEQ ID NO:132, SEQ ID NO:133, SEQ

[1386] ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, and / or SEQ ID NO:139.

[1387] 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. In some embodiments, the antigen-binding molecule comprises a PD-1-binding moiety.

[1388] In some embodiments, the antigen-binding molecule comprises:

[1389] (155) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1390] HC-CDR1 having the amino acid sequence of SEQ ID NO:669

[1391] HC-CDR2 having the amino acid sequence of SEQ ID NQ:670

[1392] HC-CDR3 having the amino acid sequence of SEQ ID NO:671 , 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.

[1393] (156) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1394] HC-CDR1 having the amino acid sequence of SEQ ID NO:649

[1395] HC-CDR2 having the amino acid sequence of SEQ ID NQ:650

[1396] HC-CDR3 having the amino acid sequence of SEQ ID NO:651 , 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.

[1397] (157) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1398] HC-CDR1 having the amino acid sequence of SEQ ID NO:643

[1399] HC-CDR2 having the amino acid sequence of SEQ ID NO:644

[1400] HC-CDR3 having the amino acid sequence of SEQ ID NO:645, 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.

[1401] (158) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1402] HC-CDR1 having the amino acid sequence of SEQ ID NO:674

[1403] HC-CDR2 having the amino acid sequence of SEQ ID NO:675

[1404] HC-CDR3 having the amino acid sequence of SEQ ID NO:676, 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.

[1405] (159) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1406] HC-CDR1 having the amino acid sequence of SEQ ID NO:646

[1407] HC-CDR2 having the amino acid sequence of SEQ ID NO:647

[1408] HC-CDR3 having the amino acid sequence of SEQ ID NO:648, 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.

[1409] (160) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1410] HC-CDR1 having the amino acid sequence of SEQ ID NO:350

[1411] HC-CDR2 having the amino acid sequence of SEQ ID NO:636

[1412] HC-CDR3 having the amino acid sequence of SEQ ID NO:637, 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.

[1413] (161) a PD-1-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1414] HC-CDR1 having the amino acid sequence of SEQ ID NO:633

[1415] HC-CDR2 having the amino acid sequence of SEQ ID NO:634

[1416] HC-CDR3 having the amino acid sequence of SEQ ID NO:635, 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.

[1417] (162) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1418] HC-CDR1 having the amino acid sequence of SEQ ID NQ:303

[1419] HC-CDR2 having the amino acid sequence of SEQ ID NO:638

[1420] HC-CDR3 having the amino acid sequence of SEQ ID NO:639, 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.

[1421] (163) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1422] HC-CDR1 having the amino acid sequence of SEQ ID NQ:640

[1423] HC-CDR2 having the amino acid sequence of SEQ ID NO:641

[1424] HC-CDR3 having the amino acid sequence of SEQ ID NO:642, 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.

[1425] (164) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1426] HC-CDR1 having the amino acid sequence of SEQ ID NQ:303

[1427] HC-CDR2 having the amino acid sequence of SEQ ID NO:652

[1428] HC-CDR3 having the amino acid sequence of SEQ ID NO:653, 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.

[1429] (165) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1430] HC-CDR1 having the amino acid sequence of SEQ ID NO:654

[1431] HC-CDR2 having the amino acid sequence of SEQ ID NO:655

[1432] HC-CDR3 having the amino acid sequence of SEQ ID NO:656, 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.

[1433] (166) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1434] HC-CDR1 having the amino acid sequence of SEQ ID NO:657

[1435] HC-CDR2 having the amino acid sequence of SEQ ID NO:658

[1436] HC-CDR3 having the amino acid sequence of SEQ ID NO:659, 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.

[1437] (167) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1438] HC-CDR1 having the amino acid sequence of SEQ ID NQ:660

[1439] HC-CDR2 having the amino acid sequence of SEQ ID NO:661

[1440] HC-CDR3 having the amino acid sequence of SEQ ID NO:662, 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.

[1441] (168) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1442] HC-CDR1 having the amino acid sequence of SEQ ID NO:663

[1443] HC-CDR2 having the amino acid sequence of SEQ ID NO:664

[1444] HC-CDR3 having the amino acid sequence of SEQ ID NO:665, 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.

[1445] (169) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1446] HC-CDR1 having the amino acid sequence of SEQ ID NO:666

[1447] HC-CDR2 having the amino acid sequence of SEQ ID NO:667

[1448] HC-CDR3 having the amino acid sequence of SEQ ID NO:668, 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.

[1449] (170) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[1450] HC-CDR1 having the amino acid sequence of SEQ ID NO:663

[1451] HC-CDR2 having the amino acid sequence of SEQ ID NQ:360

[1452] HC-CDR3 having the amino acid sequence of SEQ ID NO:673, 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.

[1453] In some embodiments, the antigen-binding molecule comprises:

[1454] (171) a PD-1-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1455] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1456] HC-FR2 having the amino acid sequence of SEQ ID NO:712

[1457] HC-FR3 having the amino acid sequence of SEQ ID NO:713

[1458] HC-FR4 having the amino acid sequence of SEQ ID NO:714, 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 amino acid in HC- FR4 are substituted with another amino acid.

[1459] (172) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1460] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1461] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1462] HC-FR3 having the amino acid sequence of SEQ ID NO:699

[1463] 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.

[1464] (173) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1465] HC-FR1 having the amino acid sequence of SEQ ID NO:694

[1466] HC-FR2 having the amino acid sequence of SEQ ID NO:695

[1467] HC-FR3 having the amino acid sequence of SEQ ID NO:696

[1468] 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.

[1469] (174) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs: HC-FR1 having the amino acid sequence of SEQ ID NO:715

[1470] HC-FR2 having the amino acid sequence of SEQ ID NO:716

[1471] HC-FR3 having the amino acid sequence of SEQ ID NO:717

[1472] 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.

[1473] (175) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1474] HC-FR1 having the amino acid sequence of SEQ ID NO:697

[1475] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1476] HC-FR3 having the amino acid sequence of SEQ ID NO:698

[1477] 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.

[1478] (176) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1479] HC-FR1 having the amino acid sequence of SEQ ID NO:687

[1480] HC-FR2 having the amino acid sequence of SEQ ID NO:688

[1481] HC-FR3 having the amino acid sequence of SEQ ID NO:689

[1482] HC-FR4 having the amino acid sequence of SEQ ID NQ:690, 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.

[1483] (177) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1484] HC-FR1 having the amino acid sequence of SEQ ID NO:683

[1485] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1486] HC-FR3 having the amino acid sequence of SEQ ID NO:685

[1487] 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.

[1488] (178) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1489] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1490] HC-FR2 having the amino acid sequence of SEQ ID NO:422

[1491] HC-FR3 having the amino acid sequence of SEQ ID NO:691

[1492] 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.

[1493] (179) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1494] HC-FR1 having the amino acid sequence of SEQ ID NO:692

[1495] HC-FR2 having the amino acid sequence of SEQ ID NO:410

[1496] HC-FR3 having the amino acid sequence of SEQ ID NO:693

[1497] 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.

[1498] (180) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1499] HC-FR1 having the amino acid sequence of SEQ ID NO:385

[1500] HC-FR2 having the amino acid sequence of SEQ ID NQ:410

[1501] HC-FR3 having the amino acid sequence of SEQ ID NQ:700

[1502] 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.

[1503] (181) a PD-1-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1504] HC-FR1 having the amino acid sequence of SEQ ID NQ:701

[1505] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1506] HC-FR3 having the amino acid sequence of SEQ ID NQ:702

[1507] 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.

[1508] (182) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1509] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1510] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1511] HC-FR3 having the amino acid sequence of SEQ ID NQ:703

[1512] 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.

[1513] (183) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1514] HC-FR1 having the amino acid sequence of SEQ ID NQ:704 HC-FR2 having the amino acid sequence of SEQ ID NO:402

[1515] HC-FR3 having the amino acid sequence of SEQ ID NO:705

[1516] HC-FR4 having the amino acid sequence of SEQ ID NQ:706, 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.

[1517] (184) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1518] HC-FR1 having the amino acid sequence of SEQ ID NQ:707

[1519] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1520] HC-FR3 having the amino acid sequence of SEQ ID NQ:708

[1521] 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.

[1522] (185) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1523] HC-FR1 having the amino acid sequence of SEQ ID NQ:709

[1524] HC-FR2 having the amino acid sequence of SEQ ID NQ:710

[1525] HC-FR3 having the amino acid sequence of SEQ ID NO:711

[1526] 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.

[1527] (186) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1528] HC-FR1 having the amino acid sequence of SEQ ID NO:377

[1529] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[1530] HC-FR3 having the amino acid sequence of SEQ ID NQ:440

[1531] 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.

[1532] (187) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1533] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1534] HC-FR2 having the amino acid sequence of SEQ ID NO:712

[1535] HC-FR3 having the amino acid sequence of SEQ ID NO:727

[1536] HC-FR4 having the amino acid sequence of SEQ ID NO:728, 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 amino acid in HC- FR4 are substituted with another amino acid. (188) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1537] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1538] HC-FR2 having the amino acid sequence of SEQ ID NO:726

[1539] HC-FR3 having the amino acid sequence of SEQ ID NO:727

[1540] HC-FR4 having the amino acid sequence of SEQ ID NO:728, 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 amino acid in HC- FR4 are substituted with another amino acid.

[1541] (189) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1542] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1543] HC-FR2 having the amino acid sequence of SEQ ID NO:729

[1544] HC-FR3 having the amino acid sequence of SEQ ID NO:727

[1545] HC-FR4 having the amino acid sequence of SEQ ID NO:728, 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 amino acid in HC- FR4 are substituted with another amino acid.

[1546] (190) a PD-1 -binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1547] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1548] HC-FR2 having the amino acid sequence of SEQ ID NQ:730

[1549] HC-FR3 having the amino acid sequence of SEQ ID NO:727

[1550] HC-FR4 having the amino acid sequence of SEQ ID NO:728, 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 amino acid in HC- FR4 are substituted with another amino acid.

[1551] (191) a PD-1-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[1552] HC-FR1 having the amino acid sequence of SEQ ID NO:397

[1553] HC-FR2 having the amino acid sequence of SEQ ID NO:731

[1554] HC-FR3 having the amino acid sequence of SEQ ID NO:727

[1555] HC-FR4 having the amino acid sequence of SEQ ID NO:728, 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 ...

Claims

1. Claims:

1. An antigen-binding molecule, optionally isolated, comprising(i) a yc-binding moiety,(ii) a moiety that binds to a polypeptide of a yc-containing cytokine receptor other than yc, and(iii) an immune checkpoint protein-binding moiety.

2. The antigen-binding molecule according to claim 1 , wherein the moiety that binds to a polypeptide of a yc-containing cytokine receptor other than yc is an IL-2Rp-binding moiety or an IL-21 Ra- binding moiety.

3. The antigen-binding molecule according to claim 1 or claim 2, wherein the immune checkpoint protein-binding moiety is a PD-1-binding moiety.

4. An antigen-binding molecule, optionally isolated, comprising a PD-1 -binding moiety.

5. The antigen-binding molecule according to claim 4, further comprising a yc-binding moiety.

6. The antigen-binding molecule according to claim 4 or claim 5, further comprising a moiety that binds to a polypeptide of a yc-containing cytokine receptor other than yc.

7. The antigen-binding molecule according to any one of claims 4 to 6, wherein the moiety that binds to a polypeptide of a yc-containing cytokine receptor other than yc is an IL-2Rp-binding moiety or an IL-21 Ra-binding moiety.

8. The antigen-binding molecule according to any one of claims 3 to 7, wherein the PD-1 -binding moiety comprises a VH sequence incorporating the following CDRs:(a) CDR1 having the amino acid sequence of SEQ ID NO:669 CDR2 having the amino acid sequence of SEQ ID NO:670 CDR3 having the amino acid sequence of SEQ ID NO:671 ;(b) CDR1 having the amino acid sequence of SEQ ID NO:649 CDR2 having the amino acid sequence of SEQ ID NQ:650 CDR3 having the amino acid sequence of SEQ ID NO:651 ;(c) CDR1 having the amino acid sequence of SEQ ID NO:643 CDR2 having the amino acid sequence of SEQ ID NO:644 CDR3 having the amino acid sequence of SEQ ID NO:645;(d) CDR1 having the amino acid sequence of SEQ ID NO:674348CDR2 having the amino acid sequence of SEQ ID NO:675 CDR3 having the amino acid sequence of SEQ ID NO:676;(e) CDR1 having the amino acid sequence of SEQ ID NO:646 CDR2 having the amino acid sequence of SEQ ID NO:647 CDR3 having the amino acid sequence of SEQ ID NO:648;(f) CDR1 having the amino acid sequence of SEQ ID NQ:350 CDR2 having the amino acid sequence of SEQ ID NO:636 CDR3 having the amino acid sequence of SEQ ID NO:637;(g) CDR1 having the amino acid sequence of SEQ ID NO:633 CDR2 having the amino acid sequence of SEQ ID NO:634 CDR3 having the amino acid sequence of SEQ ID NO:635;(h) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NO:638 CDR3 having the amino acid sequence of SEQ ID NO:639;(i) CDR1 having the amino acid sequence of SEQ ID NQ:640 CDR2 having the amino acid sequence of SEQ ID NO:641 CDR3 having the amino acid sequence of SEQ ID NO:642;(j) CDR1 having the amino acid sequence of SEQ ID NQ:303 CDR2 having the amino acid sequence of SEQ ID NO:652 CDR3 having the amino acid sequence of SEQ ID NO:653;(k) CDR1 having the amino acid sequence of SEQ ID NO:654 CDR2 having the amino acid sequence of SEQ ID NO:655 CDR3 having the amino acid sequence of SEQ ID NO:656;(l) CDR1 having the amino acid sequence of SEQ ID NO:657 CDR2 having the amino acid sequence of SEQ ID NO:658 CDR3 having the amino acid sequence of SEQ ID NO:659;(m) CDR1 having the amino acid sequence of SEQ ID NQ:660 CDR2 having the amino acid sequence of SEQ ID NO:661 CDR3 having the amino acid sequence of SEQ ID NO:662;(n) CDR1 having the amino acid sequence of SEQ ID NO:663 CDR2 having the amino acid sequence of SEQ ID NO:664 CDR3 having the amino acid sequence of SEQ ID NO:665;(o) CDR1 having the amino acid sequence of SEQ ID NO:666 CDR2 having the amino acid sequence of SEQ ID NO:667 CDR3 having the amino acid sequence of SEQ ID NO:668; or(p) CDR1 having the amino acid sequence of SEQ ID NO:663 CDR2 having the amino acid sequence of SEQ ID NQ:360 CDR3 having the amino acid sequence of SEQ ID NO:673.

9. The antigen-binding molecule according to any one of claims 3 to 8, wherein the PD-1 -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:743, SEQ ID NO:738, SEQ ID NO:739, SEQ ID NQ:740, SEQ ID NO:741 , SEQ ID NO:742, SEQ ID NO:744, SEQ ID NO:745, SEQ ID NO:746, SEQ ID NQ:630, SEQ IDNO:617, SEQ ID NO:618, SEQ ID NO:619, SEQ ID NQ:620, SEQ ID NO:621 , SEQ ID NO:622, SEQ IDNO:623, SEQ ID NO:624, SEQ ID NO:625, SEQ ID NO:626, SEQ ID NO:627, SEQ ID NO:628, SEQ IDNO:629, SEQ ID NO:631 , or SEQ ID NO:632.

10. The antigen-binding molecule according to any one of claims 3 to 9, wherein the PD-1 -binding moiety comprises a VH sequence incorporating the following FRs:(a) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:732 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(b) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:712 FR3 having the amino acid sequence of SEQ ID NO:713 FR4 having the amino acid sequence of SEQ ID NO:714;(c) 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:699 FR4 having the amino acid sequence of SEQ ID NO:471 ;(d) FR1 having the amino acid sequence of SEQ ID NO:694 FR2 having the amino acid sequence of SEQ ID NO:695 FR3 having the amino acid sequence of SEQ ID NO:696 FR4 having the amino acid sequence of SEQ ID NO:471 ;(e) FR1 having the amino acid sequence of SEQ ID NO:715 FR2 having the amino acid sequence of SEQ ID NO:716FR3 having the amino acid sequence of SEQ ID NO:717 FR4 having the amino acid sequence of SEQ ID NO:484;(f) FR1 having the amino acid sequence of SEQ ID NO:697 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:698 FR4 having the amino acid sequence of SEQ ID NO:471 ;(g) FR1 having the amino acid sequence of SEQ ID NO:687 FR2 having the amino acid sequence of SEQ ID NO:688 FR3 having the amino acid sequence of SEQ ID NO:689 FR4 having the amino acid sequence of SEQ ID NQ:690;(h) FR1 having the amino acid sequence of SEQ ID NO:683 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:685 FR4 having the amino acid sequence of SEQ ID NO:471 ;(i) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:422 FR3 having the amino acid sequence of SEQ ID NO:691 FR4 having the amino acid sequence of SEQ ID NO:471 ;(j) FR1 having the amino acid sequence of SEQ ID NO:692 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NO:693 FR4 having the amino acid sequence of SEQ ID NO:471 ;(k) FR1 having the amino acid sequence of SEQ ID NO:385 FR2 having the amino acid sequence of SEQ ID NQ:410 FR3 having the amino acid sequence of SEQ ID NQ:700 FR4 having the amino acid sequence of SEQ ID NO:471 ;(l) FR1 having the amino acid sequence of SEQ ID NQ:701 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NQ:702 FR4 having the amino acid sequence of SEQ ID NO:471 ;(m) 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 NQ:703 FR4 having the amino acid sequence of SEQ ID NO:471 ;(n) FR1 having the amino acid sequence of SEQ ID NO:704 FR2 having the amino acid sequence of SEQ ID NO:402 FR3 having the amino acid sequence of SEQ ID NQ:705 FR4 having the amino acid sequence of SEQ ID NQ:706;(o) FR1 having the amino acid sequence of SEQ ID NQ:707 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NQ:708 FR4 having the amino acid sequence of SEQ ID NO:471 ;(p) FR1 having the amino acid sequence of SEQ ID NQ:709 FR2 having the amino acid sequence of SEQ ID NQ:710 FR3 having the amino acid sequence of SEQ ID NO:711 FR4 having the amino acid sequence of SEQ ID NO:471 ;(q) 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 NQ:440 FR4 having the amino acid sequence of SEQ ID NO:471 ;(r) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:712 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(s) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:726 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(t) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:729 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(u) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:730 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(v) FR1 having the amino acid sequence of SEQ ID NO:397FR2 having the amino acid sequence of SEQ ID NO:731FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(w) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NO:733 FR3 having the amino acid sequence of SEQ ID NO:727 FR4 having the amino acid sequence of SEQ ID NO:728;(x) 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:734 FR4 having the amino acid sequence of SEQ ID NO:735; or(y) FR1 having the amino acid sequence of SEQ ID NO:694 FR2 having the amino acid sequence of SEQ ID NO:695 FR3 having the amino acid sequence of SEQ ID NO:737 FR4 having the amino acid sequence of SEQ ID NO:735.11 . The antigen-binding molecule according to any one of claims 1 to 3 or 5 to 10, wherein the yc- binding moiety comprises a VH sequence incorporating the following CDRs:(i) CDR1 having the amino acid sequence of SEQ ID NQ:760 CDR2 having the amino acid sequence of SEQ ID NO:776 CDR3 having the amino acid sequence of SEQ ID NO:792,(ii) CDR1 having the amino acid sequence of SEQ ID NO:761 CDR2 having the amino acid sequence of SEQ ID NO:777 CDR3 having the amino acid sequence of SEQ ID NO:793,(iii) CDR1 having the amino acid sequence of SEQ ID NO:762 CDR2 having the amino acid sequence of SEQ ID NO:778 CDR3 having the amino acid sequence of SEQ ID NO:794,(iv) CDR1 having the amino acid sequence of SEQ ID NO:763 CDR2 having the amino acid sequence of SEQ ID NO:779 CDR3 having the amino acid sequence of SEQ ID NO:795,(v) CDR1 having the amino acid sequence of SEQ ID NO:764 CDR2 having the amino acid sequence of SEQ ID NQ:780 CDR3 having the amino acid sequence of SEQ ID NO:796,(vi) CDR1 having the amino acid sequence of SEQ ID NO:765 CDR2 having the amino acid sequence of SEQ ID NO:781 CDR3 having the amino acid sequence of SEQ ID NO:797,(vii) CDR1 having the amino acid sequence of SEQ ID NO:766 CDR2 having the amino acid sequence of SEQ ID NO:782 CDR3 having the amino acid sequence of SEQ ID NO:798,(viii) CDR1 having the amino acid sequence of SEQ ID NO:767 CDR2 having the amino acid sequence of SEQ ID NO:783 CDR3 having the amino acid sequence of SEQ ID NO:799,(ix) CDR1 having the amino acid sequence of SEQ ID NO:768 CDR2 having the amino acid sequence of SEQ ID NO:784 CDR3 having the amino acid sequence of SEQ ID NQ:800,(x) CDR1 having the amino acid sequence of SEQ ID NO:769 CDR2 having the amino acid sequence of SEQ ID NO:785 CDR3 having the amino acid sequence of SEQ ID NQ:801 ,(xi) CDR1 having the amino acid sequence of SEQ ID NO:770 CDR2 having the amino acid sequence of SEQ ID NO:786 CDR3 having the amino acid sequence of SEQ ID NO:802,(xii) CDR1 having the amino acid sequence of SEQ ID NO:771 CDR2 having the amino acid sequence of SEQ ID NO:787 CDR3 having the amino acid sequence of SEQ ID NO:803,(xiii) CDR1 having the amino acid sequence of SEQ ID NO:772 CDR2 having the amino acid sequence of SEQ ID NO:788 CDR3 having the amino acid sequence of SEQ ID NO:804,(xiv) CDR1 having the amino acid sequence of SEQ ID NO:773 CDR2 having the amino acid sequence of SEQ ID NO:789 CDR3 having the amino acid sequence of SEQ ID NO:805,(xv) CDR1 having the amino acid sequence of SEQ ID NO:774 CDR2 having the amino acid sequence of SEQ ID NO:790 CDR3 having the amino acid sequence of SEQ ID NO:806,(xvi) CDR1 having the amino acid sequence of SEQ ID NO:775 CDR2 having the amino acid sequence of SEQ ID NO:791354CDR3 having the amino acid sequence of SEQ ID NO:807,(xvii) 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;(xviii) 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;(xix) 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;(xx) 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;(xxi) CDR1 having the amino acid sequence of SEQ ID NO:279CDR2 having the amino acid sequence of SEQ ID NQ:280CDR3 having the amino acid sequence of SEQ ID NO:281 ;(xxii) CDR1 having the amino acid sequence of SEQ ID NO:282CDR2 having the amino acid sequence of SEQ ID NO:283CDR3 having the amino acid sequence of SEQ ID NO:284;(xxiii) CDR1 having the amino acid sequence of SEQ ID NO:285CDR2 having the amino acid sequence of SEQ ID NO:286CDR3 having the amino acid sequence of SEQ ID NO:287;(xxiv) CDR1 having the amino acid sequence of SEQ ID NO:288CDR2 having the amino acid sequence of SEQ ID NO:289CDR3 having the amino acid sequence of SEQ ID NQ:290;(xxv) CDR1 having the amino acid sequence of SEQ ID NO:291CDR2 having the amino acid sequence of SEQ ID NO:292CDR3 having the amino acid sequence of SEQ ID NO:293;(xxvi) 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; or355(xxvii) 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.

12. The antigen-binding molecule according to any one of claims 1 to 3 or 5-11 , 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 NO:851 , SEQ ID NO:852, SEQ ID NO:853, SEQ ID NO:854, SEQ ID NO:855, SEQ ID NO:856, SEQ ID NO:857, SEQ ID NO:858, SEQ ID NO:859, SEQ ID NQ:860, SEQID NO:861 , SEQ ID NO:862, SEQ ID NO:863, SEQ ID NO:864, SEQ ID NO:865, SEQ ID NO:866, SEQID NO:867, SEQ ID NO:868, SEQ ID NQ:501 , SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178.

13. The antigen-binding molecule according to any one of claims 1 to 3 or 5 to 12, wherein the yc- binding moiety comprises a VH sequence incorporating the following FRs:(i) FR1 having the amino acid sequence of SEQ ID NQ:808FR2 having the amino acid sequence of SEQ ID NO:816 FR3 having the amino acid sequence of SEQ ID NO:831 FR4 having the amino acid sequence of SEQ ID NO:848,(ii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:817 FR3 having the amino acid sequence of SEQ ID NO:832 FR4 having the amino acid sequence of SEQ ID NO:849,(iii) FR1 having the amino acid sequence of SEQ ID NQ:810 FR2 having the amino acid sequence of SEQ ID NO:818 FR3 having the amino acid sequence of SEQ ID NO:833 FR4 having the amino acid sequence of SEQ ID NO:848,(iv) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:819 FR3 having the amino acid sequence of SEQ ID NO:834 FR4 having the amino acid sequence of SEQ ID NO:848,(v) FR1 having the amino acid sequence of SEQ ID NO:811 FR2 having the amino acid sequence of SEQ ID NQ:820 FR3 having the amino acid sequence of SEQ ID NO:835 FR4 having the amino acid sequence of SEQ ID NO:848,(vi) FR1 having the amino acid sequence of SEQ ID NO:812FR2 having the amino acid sequence of SEQ ID NO:821356FR3 having the amino acid sequence of SEQ ID NO:836FR4 having the amino acid sequence of SEQ ID NO:848,(vii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:817 FR3 having the amino acid sequence of SEQ ID NO:837 FR4 having the amino acid sequence of SEQ ID NO:848,(viii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:822 FR3 having the amino acid sequence of SEQ ID NO:838 FR4 having the amino acid sequence of SEQ ID NO:848,(ix) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:823 FR3 having the amino acid sequence of SEQ ID NO:839 FR4 having the amino acid sequence of SEQ ID NO:848,(x) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:817 FR3 having the amino acid sequence of SEQ ID NQ:840 FR4 having the amino acid sequence of SEQ ID NO:848,(xi) FR1 having the amino acid sequence of SEQ ID NO:813 FR2 having the amino acid sequence of SEQ ID NO:824 FR3 having the amino acid sequence of SEQ ID NO:841 FR4 having the amino acid sequence of SEQ ID NO:848,(xii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:825 FR3 having the amino acid sequence of SEQ ID NO:842 FR4 having the amino acid sequence of SEQ ID NO:848,(xiii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:826 FR3 having the amino acid sequence of SEQ ID NO:843 FR4 having the amino acid sequence of SEQ ID NO:848,(xiv) FR1 having the amino acid sequence of SEQ ID NO:814 FR2 having the amino acid sequence of SEQ ID NO:827 FR3 having the amino acid sequence of SEQ ID NO:844 FR4 having the amino acid sequence of SEQ ID NO:848,357(XV) FR1 having the amino acid sequence of SEQ ID NO:809 FR2 having the amino acid sequence of SEQ ID NO:828 FR3 having the amino acid sequence of SEQ ID NO:845 FR4 having the amino acid sequence of SEQ ID NO:848,(xvi) FR1 having the amino acid sequence of SEQ ID NO:815 FR2 having the amino acid sequence of SEQ ID NO:828 FR3 having the amino acid sequence of SEQ ID NO:846 FR4 having the amino acid sequence of SEQ ID NQ:850,(xvii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:829 FR3 having the amino acid sequence of SEQ ID NO:845 FR4 having the amino acid sequence of SEQ ID NO:848,(xviii) FR1 having the amino acid sequence of SEQ ID NO:815 FR2 having the amino acid sequence of SEQ ID NQ:830 FR3 having the amino acid sequence of SEQ ID NO:847 FR4 having the amino acid sequence of SEQ ID NO:848,(xix) 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.(xx) 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;(xxi) 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;(xxii) FR1 having the amino acid sequence of SEQ ID NO:397 FR2 having the amino acid sequence of SEQ ID NQ:403 FR3 having the amino acid sequence of SEQ ID NO:466 FR4 having the amino acid sequence of SEQ ID NO:474;(xxiii) FR1 having the amino acid sequence of SEQ ID NO:377358FR2 having the amino acid sequence of SEQ ID N0:400 FR3 having the amino acid sequence of SEQ ID NO:425 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxiv) 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 ;(xxv) 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;(xxvi) 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 ;(xxvii) 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 ;(xxviii) 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 ;(xxix) 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 ;(xxx) 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,(xxxi) 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:432359FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxxii) FR1 having the amino acid sequence of SEQ ID NO:377FR2 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 ;(xxxiii) 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 ;(xxxiv) 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 .

14. The antigen-binding molecule according to any one of claims 2 to 3 or 7 to 13, wherein the IL- 2Rp-binding moiety comprises a VH sequence incorporating the following CDRs:(i) 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;(ii) 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;(iii) 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;(iv) 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;(v) 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;(vi) CDR1 having the amino acid sequence of SEQ ID NQ:309 CDR2 having the amino acid sequence of SEQ ID NQ:310360CDR3 having the amino acid sequence of SEQ ID NO:311 ,(vii) 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;(viii) 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;(ix) 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;(x) 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;(xi) 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;(xii) 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 ;(xiii) 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;(xiv) 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;(xv) 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;(xvi) 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;361(xvii) CDR1 having the amino acid sequence of SEQ ID NO:347CDR2 having the amino acid sequence of SEQ ID NO:348 CDR3 having the amino acid sequence of SEQ ID NO:349;(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;(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;(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;(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 ;(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;(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;(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;(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(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.

15. The antigen-binding molecule according to any one of claims 2 to 3 or 7 to 14, wherein the IL- 2Rp-binding moiety comprises, or consists of, an amino acid sequence having at least 70% sequence362identity to the amino acid sequence of SEQ ID NO:875, SEQ ID NO:479, SEQ ID NO: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 IDNO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ IDNQ:150, SEQ ID NO:151 , SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ IDNO:156, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NQ:160, SEQ ID NO:161 , SEQ IDNO:162, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:165, or SEQ ID NO:166.

16. The antigen-binding molecule according to any one of claims 2 to 3 or 7 to 15, wherein the IL- 2Rp-binding moiety comprises a VH sequence incorporating the following FRs:(i) FR1 having the amino acid sequence of SEQ ID NO:872FR2 having the amino acid sequence of SEQ ID NO:873 FR3 having the amino acid sequence of SEQ ID NO:874 FR4 having the amino acid sequence of SEQ ID NQ:850;(ii) FR1 having the amino acid sequence of SEQ ID NO:397FR2 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;(iii) FR1 having the amino acid sequence of SEQ ID NO:397FR2 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:398FR2 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;(v) FR1 having the amino acid sequence of SEQ ID NO:399FR2 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;(vi) FR1 having the amino acid sequence of SEQ ID NO:397FR2 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;(vii) FR1 having the amino acid sequence of SEQ ID NO:385FR2 having the amino acid sequence of SEQ ID NQ:402363FR3 having the amino acid sequence of SEQ ID NO:437FR4 having the amino acid sequence of SEQ ID NO:471 ;(viii) 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 ;(ix) 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 ;(x) 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 ;(xi) 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 ;(xii) 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;(xiii) 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 ;(xiv) 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 ;(xv) 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:444 FR4 having the amino acid sequence of SEQ ID NO:485;364(xvi) FR1 having the amino acid sequence of SEQ ID NO:377 FR2 having the amino acid sequence of SEQ ID NO:410 FR3 having the amino acid sequence of SEQ ID NO:445 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xvii) 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 ;(xviii) 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 ;(xix) 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 ;(xx) 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 ;(xxi) 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 ;(xxii) 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 ;(xxiii) 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:471 ;(xxiv) FR1 having the amino acid sequence of SEQ ID NO:387365FR2 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 ;(xxv) 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 ;(xxvi) FR1 having the amino acid sequence of SEQ ID NQ:380 FR2 having the amino acid sequence of SEQ ID NO:421 FR3 having the amino acid sequence of SEQ ID NO:455 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxvii) FR1 having the amino acid sequence of SEQ ID NO:389 FR2 having the amino acid sequence of SEQ ID NQ:402 FR3 having the amino acid sequence of SEQ ID NO:456 FR4 having the amino acid sequence of SEQ ID NO:471 ;(xxviii) 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 ;(xxix) 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 ;(xxx) FR1 having the amino acid sequence of SEQ ID NO:391FR2 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 ;(xxxi) 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(xxxii) 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:461366FR4 having the amino acid sequence of SEQ ID NO:471 .

17. The antigen-binding molecule according to any one of claims 2 to 3 or 7 to 16, wherein the IL-21 Ra-binding moiety comprises a VH sequence incorporating the following CDRs:(i) CDR1 having the amino acid sequence of SEQ ID NO:877 CDR2 having the amino acid sequence of SEQ ID NO:882 CDR3 having the amino acid sequence of SEQ ID NO:887,(ii) CDR1 having the amino acid sequence of SEQ ID NO:876 CDR2 having the amino acid sequence of SEQ ID NO:881 CDR3 having the amino acid sequence of SEQ ID NO:886,(iii) CDR1 having the amino acid sequence of SEQ ID NO:878 CDR2 having the amino acid sequence of SEQ ID NO:883 CDR3 having the amino acid sequence of SEQ ID NO:888,(iv) CDR1 having the amino acid sequence of SEQ ID NO:879 CDR2 having the amino acid sequence of SEQ ID NO:884 CDR3 having the amino acid sequence of SEQ ID NO:889, or(v) CDR1 having the amino acid sequence of SEQ ID NQ:880 CDR2 having the amino acid sequence of SEQ ID NO:885 CDR3 having the amino acid sequence of SEQ ID NQ:890.

18. The antigen-binding molecule according to any one of claims 2 to 3 or 7 to 17, wherein the IL- 21 Ra-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:906, SEQ ID NQ:905, SEQ ID NQ:907, SEQ ID NQ:908, or SEQ ID NQ:909.

19. The antigen-binding molecule according to any one of claims 2 to 3 or 7 to 18, wherein the IL-21 Ra-binding moiety comprises a VH sequence incorporating the following FRs:(i) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:895 FR3 having the amino acid sequence of SEQ ID NQ:900 FR4 having the amino acid sequence of SEQ ID NO:848,(ii) FR1 having the amino acid sequence of SEQ ID NQ:809 FR2 having the amino acid sequence of SEQ ID NO:894 FR3 having the amino acid sequence of SEQ ID NO:899 FR4 having the amino acid sequence of SEQ ID NO:848,367(iii) FR1 having the amino acid sequence of SEQ ID NO:891 FR2 having the amino acid sequence of SEQ ID NO:896 FR3 having the amino acid sequence of SEQ ID NQ:901 FR4 having the amino acid sequence of SEQ ID NO:848,(iv) FR1 having the amino acid sequence of SEQ ID NO:892 FR2 having the amino acid sequence of SEQ ID NO:897 FR3 having the amino acid sequence of SEQ ID NQ:902 FR4 having the amino acid sequence of SEQ ID NQ:904, or(v) FR1 having the amino acid sequence of SEQ ID NO:893 FR2 having the amino acid sequence of SEQ ID NO:898 FR3 having the amino acid sequence of SEQ ID NQ:903 FR4 having the amino acid sequence of SEQ ID NO:848.

20. The antigen-binding molecule according to any previous claim, 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 NQ:910, SEQ ID NO:911 , SEQ ID NO:912, SEQ ID NO:913, SEQ ID NO:914, SEQ ID NO:915, SEQ ID NO:916, SEQ ID NO:917, SEQ ID NO:918, SEQ ID NO:919, SEQ IDNQ:920, SEQ ID NO:921 , SEQ ID NO:922, SEQ ID NO:923, SEQ ID NO:924, SEQ ID NO:925, SEQ IDNO:926, SEQ ID NO:927, SEQ ID NO:928, SEQ ID NO:929, SEQ ID NQ:930, SEQ ID NO:931 , SEQ IDNO:594, SEQ ID NO:524:, SEQ ID NO:526, SEQ ID NO:528, SEQ ID NQ:530, SEQ ID NO:532, SEQ ID NO:534, SEQ ID NO:536, SEQ ID NO:538, SEQ ID NQ:540, SEQ ID NO:542, SEQ ID NO:544, SEQ IDNO:546, SEQ ID NO:548, SEQ ID NQ:550, SEQ ID NO:552, SEQ ID NO:554, SEQ ID NO:556, SEQ IDNO:558, SEQ ID NQ:560, SEQ ID NO:562, SEQ ID NO:564, SEQ ID NO:566, SEQ ID NO:568, SEQ IDNQ:570, SEQ ID NO:572, SEQ ID NO:574, SEQ ID NO:576, SEQ ID NO:578, SEQ ID NQ:580, SEQ IDNO:582, SEQ ID NO:584, SEQ ID NO:586, SEQ ID NO:588, SEQ ID NQ:590, SEQ ID NO:592, SEQ IDNO:596, SEQ ID NO:598, or SEQ ID NQ:600, and / or an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:932, SEQ ID NO:595, SEQ ID NO:525, SEQ ID NO:527, SEQ ID NO:529, SEQ ID NO:531 , SEQ IDNO:533, SEQ ID NO:535, SEQ ID NO:537, SEQ ID NO:539, SEQ ID NO:541 , SEQ ID NO:543, SEQ IDNO:545, SEQ ID NO:547, SEQ ID NO:549, SEQ ID NO:551 , SEQ ID NO:553, SEQ ID NO:555, SEQ IDNO:557, SEQ ID NO:559, SEQ ID NO:561 , SEQ ID NO:563, SEQ ID NO:565, SEQ ID NO:567, SEQ IDNO:569, SEQ ID NO:571 , SEQ ID NO:573, SEQ ID NO:575, SEQ ID NO:577, SEQ ID NO:579, SEQ IDNO:581 , SEQ ID NO:583, SEQ ID NO:585, SEQ ID NO:587, SEQ ID NO:589, SEQ ID NO:591 , SEQ IDNO:593, SEQ ID NO:597, SEQ ID NO:599, or SEQ ID NQ:601 .21 . The antigen-binding molecule according to any previous claim, wherein the antigen-binding molecule comprises a polypeptide comprising (from N-terminal to C-terminal):(i) a binding-moiety comprising an immune checkpoint protein-binding VHH,(ii) a CH2-CH3 polypeptide,368(iii) a binding moiety comprising a yc-binding VHH or an VHH that binds to a polypeptide of a yc- containing cytokine receptor other than yc, and(iv) a binding moiety comprising a VHH that binds to a polypeptide of a yc-containing cytokine receptor other than yc or a yc-binding VHH.

22. The antigen-binding molecule according to any one of claims ant previous claim, wherein the antigen-binding molecule comprises a polypeptide comprising (from N-terminal to C-terminal):(i) a binding-moiety comprising an immune checkpoint protein-binding VHH,(ii) a CH2-CH3 polypeptide,(iii) a binding moiety comprising a yc-binding VHH, and(iv) a binding moiety comprising an IL-2Rp-binding VHH or an IL-21 Ra-binding VHH.

23. The antigen-binding molecule according to any previous claim, wherein the antigen-binding molecule comprises a polypeptide comprising (from N-terminal to C-terminal):(i) a binding-moiety comprising an immune checkpoint protein-binding VHH,(ii) a CH2-CH3 polypeptide,(iii) a binding moiety comprising a yc-binding VHH,(iv) a linker, and(iv) a binding moiety comprising an IL-2Rp-binding VHH or an IL-21 Ra-binding VHH.

24. The antigen-binding molecule according to any one of claims 21 to 23, wherein the antigenbinding molecule comprises a second CH2-CH3 polypeptide, wherein the second CH2-CH3 polypeptide forms an Fc region with the CH2-CH3 region polypeptide specified in any one of claims 17 to 19.

25. The antigen-binding molecule according to claim 24, wherein the second CH2-CH3 polypeptide is connected to an antigen-binding moiety.

26. The antigen-binding molecule according to claim 25, wherein the antigen binding moiety comprises an immune checkpoint protein-binding VHH.

27. The antigen-binding molecule according to any one of claims 21 to 25, wherein the immune checkpoint protein-binding VHH is a PD-1 -binding VHH.

28. A chimeric antigen receptor (CAR), comprising an antigen-binding molecule according to any one of claims 1 to 27.

29. A nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule according to any one of claims 1 to 27, or a CAR according to claim 28.

30. An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 29.36931 . A cell comprising an antigen-binding molecule according to any one of claims 1 to 27, a CAR according to claim 28, a nucleic acid or a plurality of nucleic acids according to claim 29, or an expression vector or a plurality of expression vectors according to claim 30.

32. A method comprising culturing a cell according to claim 31 under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

33. A composition comprising an antigen-binding molecule according to any one of claims 1 to 27, a CAR according to claim 28, a nucleic acid or a plurality of nucleic acids according to claim 29, an expression vector or a plurality of expression vectors according to claim 30, or a cell according to claim 31 , and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

34. An antigen-binding molecule according to any one of claims 1 to 27, a CAR according to claim 28, a nucleic acid or a plurality of nucleic acids according to claim 29, an expression vector or a plurality of expression vectors according to claim 30, or a cell according to claim 31 , or a composition according to claim 33, for use in a method of treatment or prophylaxis.

35. Use of an antigen-binding molecule according to any one of claims 1 to 27, a CAR according to claim 28, a nucleic acid or a plurality of nucleic acids according to claim 29, an expression vector or a plurality of expression vectors according to claim 30, or a cell according to claim 31 , or a composition according to claim 33, in the manufacture of a medicament for use in a method of treatment or prophylaxis.

36. 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 27, a CAR according to claim 28, a nucleic acid or a plurality of nucleic acids according to claim 29, an expression vector or a plurality of expression vectors according to claim 30, or a cell according to claim 31 , or a composition according to claim 33.

37. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to claim 34, the use according to claim 35 or the method according to claim 36, 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.

38. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to claim 34, the use according to claim 35 or the method according to claim 36, 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.

39. 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 38, wherein the cancer is370selected 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.

40. An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 27, a CAR according to claim 28, bound to PD-1 , yc, and / or IL-2R0.41 . A method for generating or expanding a population of cells, 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 27.

42. A method for increasing the proliferation, survival and / or effector activity of a cell expressing IL- 2Rp and / or PD-1 , comprising contacting a cell expressing yc, I L-2Rp , and / or PD-1 in vitro, in vivo or ex vivo with an antigen-binding molecule according to any one of claims 1 to 27.

43. The method according to claim 42, wherein the cell is an effector immune cell.

44. The method according to claim 42, wherein the cell is a T cell or a NK cell.

45. A method of promoting heteromultimerization of yc and I L-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 27, or a CAR according to claim 28.371

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