Antigen-binding molecules

Abstract

Antigen binding molecules comprising a γc-binding moiety, and a moiety that binds to IL-7Rα, 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 / 681732 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)). Additionally, interleukins have a critical role in autoimmune diseases (Moudgil and Choubey. J Interferon Cytokine Res. (2011) 31 (10): 695-703).

[0007] 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-7 receptor. Heterodimerization of yc and the alpha chain of the IL-7 receptor (IL-2Ra) is necessary for effective IL-7 signal transduction.

[0008] Both IL-7 and the IL-7 receptor alpha (IL-7Ra) have been shown to be overexpressed in the cerebrospinal fluid and labial salivary glands of patients with multiple sclerosis (MS) and systemic sclerosis (SS). This has led to the initiation of numerous clinical trials relating to immunotherapies which target IL-7Ra. For example, clinical trials were conducted to investigate the effects of IL-7Ra antagonists, such as NCT02045732, NCT03980080, and NCT01808482.

[0009] Results from IL-7Ra antagonist clinical trials have been mixed. NCT02045732 and NCT01808482 were stopped by corporate decision. Additionally, some unexpected results have been published following anti- IL-7Ra clinical trials. Herold et al. (JCI Insight. (2019) 4(24) :e126054) showed that antagonistic anti-IL- 7Ra treatment actually increased NK expansion. Additionally, Ellis et al. (Br J Clin Pharmacol. (2019) 85(2):304-315) state that there is unexpected agonistic potential for the anti-IL-7Ra antibody (across 3 studies), which was designed for antagonism of IL-7Ra. Furthermore, Belarif et al. (Nat. Commun. (2018) 9:4483) reported that antagonistic anti-IL-7Ra antibodies induced gene expression associated with T cell activation and inflammation.

[0010] Waickman et al. (iScience. (2020) 23(8):101421) previously found that IL-7Ra sequesters yc and suppresses IL-2 signalling. The current inventors propose that the agonistic effects seen following treatment with antagonistic anti-IL-7Ra antibodies are a result of reduced yc sequestration by IL-7Ra leading to an increased availability of yc to form complexes with other polypeptides of yc family receptors (e.g. IL-2RJ3, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra), resulting in increased signalling. Summary

[0011] In a first aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc.

[0012] In a second aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to IL-7Ra.

[0013] In a third aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc and another antigen.

[0014] In a fourth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to IL-7Ra and another antigen.

[0015] In a fifth aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to yc and IL-7Ra.

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

[0017] In some embodiments, the antigen-binding molecule comprises an IL-7Ra -binding moiety.

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

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

[0020] (ii) an IL-7Ra-binding moiety.

[0021] In some embodiments, the yc-binding moiety and / or the IL-2Rp-binding moiety comprises a VHH.

[0022] In some embodiments, the IL-7Ra-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody presented in Table D.

[0023] In some embodiments, the IL-7Ra-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody presented in Table F.

[0024] In some embodiments, the IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0025] (a) CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98,

[0026] (b) CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266

[0027] CDR3 having the amino acid sequence of SEQ ID NO:271 ,

[0028] (c) CDR1 having the amino acid sequence of SEQ ID NO:93 CDR2 having the amino acid sequence of SEQ ID NO:94 CDR3 having the amino acid sequence of SEQ ID NO:95,

[0029] (d) CDR1 having the amino acid sequence of SEQ ID NO:99 CDR2 having the amino acid sequence of SEQ ID NQ:100 CDR3 having the amino acid sequence of SEQ ID NQ:101 ,

[0030] (e) CDR1 having the amino acid sequence of SEQ ID NQ:102 CDR2 having the amino acid sequence of SEQ ID NQ:103 CDR3 having the amino acid sequence of SEQ ID NQ:104,

[0031] (f) CDR1 having the amino acid sequence of SEQ ID NQ:105 CDR2 having the amino acid sequence of SEQ ID NQ:106 CDR3 having the amino acid sequence of SEQ ID NQ:107,

[0032] (g) CDR1 having the amino acid sequence of SEQ ID NQ:108 CDR2 having the amino acid sequence of SEQ ID NQ:109 CDR3 having the amino acid sequence of SEQ ID NQ:110,

[0033] (h) CDR1 having the amino acid sequence of SEQ ID NO:111 CDR2 having the amino acid sequence of SEQ ID NO:112 CDR3 having the amino acid sequence of SEQ ID NO:113,

[0034] (i) CDR1 having the amino acid sequence of SEQ ID NO:111 CDR2 having the amino acid sequence of SEQ ID NO:114 CDR3 having the amino acid sequence of SEQ ID NO:115,

[0035] (j) CDR1 having the amino acid sequence of SEQ ID NO:116 CDR2 having the amino acid sequence of SEQ ID NO:117 CDR3 having the amino acid sequence of SEQ ID NO:118, or

[0036] (k) CDR1 having the amino acid sequence of SEQ ID NO:119 CDR2 having the amino acid sequence of SEQ ID NQ:120 CDR3 having the amino acid sequence of SEQ ID NO:118.

[0037] In some embodiments, the IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0038] CDR1 having the amino acid sequence of SEQ ID NO:96, CDR2 having the amino acid sequence of SEQ ID NO:97, and CDR3 having the amino acid sequence of SEQ ID NO:98.

[0039] In some embodiments, the IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0040] CDR1 having the amino acid sequence of SEQ ID NO:262,

[0041] CDR2 having the amino acid sequence of SEQ ID NO:266, and CDR3 having the amino acid sequence of SEQ ID NO:271 .

[0042] In some embodiments, the IL-7Ra-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:254, SEQ ID NO:379, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0043] In some embodiments, the IL-7Ra-binding moiety comprises a VH sequence incorporating the following FRs:

[0044] (a) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:126 FR3 having the amino acid sequence of SEQ ID NO:144 FR4 having the amino acid sequence of SEQ ID NO:145,

[0045] (b) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:276 FR3 having the amino acid sequence of SEQ ID NO:378 FR4 having the amino acid sequence of SEQ ID NO:282,

[0046] (c) FR1 having the amino acid sequence of SEQ ID NQ:209 FR2 having the amino acid sequence of SEQ ID NO:126 FR3 having the amino acid sequence of SEQ ID NO:134 FR4 having the amino acid sequence of SEQ ID NO:239,

[0047] (d) FR1 having the amino acid sequence of SEQ ID NQ:207 FR2 having the amino acid sequence of SEQ ID NO:125 FR3 having the amino acid sequence of SEQ ID NO:133 FR4 having the amino acid sequence of SEQ ID NO:238,

[0048] (e) FR1 having the amino acid sequence of SEQ ID NO:121

[0049] FR2 having the amino acid sequence of SEQ ID NO:127 FR3 having the amino acid sequence of SEQ ID NO:135 FR4 having the amino acid sequence of SEQ ID NO:238,

[0050] (f) FR1 having the amino acid sequence of SEQ ID NO:122 FR2 having the amino acid sequence of SEQ ID NO:128 FR3 having the amino acid sequence of SEQ ID NO:136 FR4 having the amino acid sequence of SEQ ID NO:143,

[0051] (g) FR1 having the amino acid sequence of SEQ ID NO:123 FR2 having the amino acid sequence of SEQ ID NO:129 FR3 having the amino acid sequence of SEQ ID NO:137 FR4 having the amino acid sequence of SEQ ID NO:238,

[0052] (h) FR1 having the amino acid sequence of SEQ ID NO:124 FR2 having the amino acid sequence of SEQ ID NO:130 FR3 having the amino acid sequence of SEQ ID NO:138 FR4 having the amino acid sequence of SEQ ID NO:143,

[0053] (i) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:128 FR3 having the amino acid sequence of SEQ ID NO:139 FR4 having the amino acid sequence of SEQ ID NO:238,

[0054] (j) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:131 FR3 having the amino acid sequence of SEQ ID NQ:140 FR4 having the amino acid sequence of SEQ ID NO:238,

[0055] (k) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:132 FR3 having the amino acid sequence of SEQ ID NO:141 FR4 having the amino acid sequence of SEQ ID NO:238, or

[0056] (l) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:132 FR3 having the amino acid sequence of SEQ ID NO:142 FR4 having the amino acid sequence of SEQ ID NO:238.

[0057] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody presented in Table A.

[0058] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the CDR sequences of a yc-binding antibody presented in Table C.

[0059] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs: (a) CDR1 having the amino acid sequence of SEQ ID NO:261 CDR2 having the amino acid sequence of SEQ ID NO:265 CDR3 having the amino acid sequence of SEQ ID NO:269,

[0060] (b) CDR1 having the amino acid sequence of SEQ ID NO:182 CDR2 having the amino acid sequence of SEQ ID NO:183 CDR3 having the amino acid sequence of SEQ ID NO:184,

[0061] (c) CDR1 having the amino acid sequence of SEQ ID NO:259 CDR2 having the amino acid sequence of SEQ ID NO:263 CDR3 having the amino acid sequence of SEQ ID NO:267,

[0062] (d) CDR1 having the amino acid sequence of SEQ ID NQ:260 CDR2 having the amino acid sequence of SEQ ID NO:264 CDR3 having the amino acid sequence of SEQ ID NO:268,

[0063] (e) CDR1 having the amino acid sequence of SEQ ID NO:161 CDR2 having the amino acid sequence of SEQ ID NO:162 CDR3 having the amino acid sequence of SEQ ID NO:163,

[0064] (f) CDR1 having the amino acid sequence of SEQ ID NO:164 CDR2 having the amino acid sequence of SEQ ID NO:165 CDR3 having the amino acid sequence of SEQ ID NO:166,

[0065] (g) CDR1 having the amino acid sequence of SEQ ID NO:179 CDR2 having the amino acid sequence of SEQ ID NQ:180 CDR3 having the amino acid sequence of SEQ ID NO:181 ,

[0066] (h) CDR1 having the amino acid sequence of SEQ ID NO:185 CDR2 having the amino acid sequence of SEQ ID NO:186 CDR3 having the amino acid sequence of SEQ ID NO:187,

[0067] (i) CDR1 having the amino acid sequence of SEQ ID NO:188 CDR2 having the amino acid sequence of SEQ ID NO:189 CDR3 having the amino acid sequence of SEQ ID NQ:190,

[0068] (j) CDR1 having the amino acid sequence of SEQ ID NO:191 CDR2 having the amino acid sequence of SEQ ID NO:192 CDR3 having the amino acid sequence of SEQ ID NO:193,

[0069] (k) CDR1 having the amino acid sequence of SEQ ID NO:194 CDR2 having the amino acid sequence of SEQ ID NO:195 CDR3 having the amino acid sequence of SEQ ID NO:196,

[0070] (l) CDR1 having the amino acid sequence of SEQ ID NO:197 CDR2 having the amino acid sequence of SEQ ID NO:198 CDR3 having the amino acid sequence of SEQ ID NO:199,

[0071] (m) CDR1 having the amino acid sequence of SEQ ID NQ:200 CDR2 having the amino acid sequence of SEQ ID NQ:201 CDR3 having the amino acid sequence of SEQ ID NQ:202, or

[0072] (n) CDR1 having the amino acid sequence of SEQ ID NQ:203 CDR2 having the amino acid sequence of SEQ ID NQ:204 CDR3 having the amino acid sequence of SEQ ID NQ:205.

[0073] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:261 CDR2 having the amino acid sequence of SEQ ID NO:265 CDR3 having the amino acid sequence of SEQ ID NO:269.

[0074] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:182, CDR2 having the amino acid sequence of SEQ ID NO:183, and CDR3 having the amino acid sequence of SEQ ID NO:184.

[0075] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:259, CDR2 having the amino acid sequence of SEQ ID NO:263, and CDR3 having the amino acid sequence of SEQ ID NO:267,

[0076] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NQ:260, CDR2 having the amino acid sequence of SEQ ID NO:264, and CDR3 having the amino acid sequence of SEQ ID NO:268.

[0077] 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:287, SEQ ID NO:253, SEQ ID

[0078] NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:245, SEQ ID NO:246, SEQ ID

[0079] NO:247, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID

[0080] NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ

[0081] ID NO:178.

[0082] In some embodiments, the yc-binding moiety comprises a VH sequence incorporating the following FRs: (a) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:275 FR3 having the amino acid sequence of SEQ ID NQ:280 FR4 having the amino acid sequence of SEQ ID NO:282,

[0083] (b) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NQ:220 FR3 having the amino acid sequence of SEQ ID NO:237 FR4 having the amino acid sequence of SEQ ID NO:145,

[0084] (c) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:272 FR3 having the amino acid sequence of SEQ ID NO:278 FR4 having the amino acid sequence of SEQ ID NO:282,

[0085] (d) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:273 FR3 having the amino acid sequence of SEQ ID NO:277 FR4 having the amino acid sequence of SEQ ID NO:238,

[0086] (e) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:217 FR3 having the amino acid sequence of SEQ ID NO:248 FR4 having the amino acid sequence of SEQ ID NQ:250,

[0087] (f) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:217 FR3 having the amino acid sequence of SEQ ID NO:249 FR4 having the amino acid sequence of SEQ ID NQ:250,

[0088] (g) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:218 FR3 having the amino acid sequence of SEQ ID NO:251 FR4 having the amino acid sequence of SEQ ID NO:252,

[0089] (h) FR1 having the amino acid sequence of SEQ ID NQ:209 FR2 having the amino acid sequence of SEQ ID NQ:220 FR3 having the amino acid sequence of SEQ ID NO:229 FR4 having the amino acid sequence of SEQ ID NO:239,

[0090] (i) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:217

[0091] FR3 having the amino acid sequence of SEQ ID NO:226

[0092] FR4 having the amino acid sequence of SEQ ID NO:238,

[0093] (j) FR1 having the amino acid sequence of SEQ ID NQ:207 FR2 having the amino acid sequence of SEQ ID NO:218 FR3 having the amino acid sequence of SEQ ID NO:227 FR4 having the amino acid sequence of SEQ ID NO:238,

[0094] (k) FR1 having the amino acid sequence of SEQ ID NQ:208 FR2 having the amino acid sequence of SEQ ID NO:128 FR3 having the amino acid sequence of SEQ ID NO:228 FR4 having the amino acid sequence of SEQ ID NO:238,

[0095] (l) FR1 having the amino acid sequence of SEQ ID NQ:209 FR2 having the amino acid sequence of SEQ ID NO:211 FR3 having the amino acid sequence of SEQ ID NQ:230 FR4 having the amino acid sequence of SEQ ID NO:238,

[0096] (m) FR1 having the amino acid sequence of SEQ ID NO:212 FR2 having the amino acid sequence of SEQ ID NO:221 FR3 having the amino acid sequence of SEQ ID NO:231 FR4 having the amino acid sequence of SEQ ID NO:238,

[0097] (n) FR1 having the amino acid sequence of SEQ ID NQ:210 FR2 having the amino acid sequence of SEQ ID NO:222 FR3 having the amino acid sequence of SEQ ID NO:232 FR4 having the amino acid sequence of SEQ ID NO:241 ,

[0098] (o) FR1 having the amino acid sequence of SEQ ID NO:213 FR2 having the amino acid sequence of SEQ ID NO:223 FR3 having the amino acid sequence of SEQ ID NO:233 FR4 having the amino acid sequence of SEQ ID NO:238,

[0099] (p) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:224 FR3 having the amino acid sequence of SEQ ID NO:234 FR4 having the amino acid sequence of SEQ ID NO:238,

[0100] (q) FR1 having the amino acid sequence of SEQ ID NO:214 FR2 having the amino acid sequence of SEQ ID NO:211 FR3 having the amino acid sequence of SEQ ID NQ:230 FR4 having the amino acid sequence of SEQ ID NO:238,

[0101] (r) FR1 having the amino acid sequence of SEQ ID NO:215 FR2 having the amino acid sequence of SEQ ID NO:225 FR3 having the amino acid sequence of SEQ ID NO:235 FR4 having the amino acid sequence of SEQ ID NO:238, or

[0102] (s) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:222 FR3 having the amino acid sequence of SEQ ID NO:236 FR4 having the amino acid sequence of SEQ ID NO:238.

[0103] In some embodiments, the antigen-binding molecule comprises:

[0104] (a) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:

[0105] CDR1 having the amino acid sequence of SEQ ID NO:182 CDR2 having the amino acid sequence of SEQ ID NO:183 CDR3 having the amino acid sequence of SEQ ID NO:184, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98,

[0106] (b) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:

[0107] CDR1 having the amino acid sequence of SEQ ID NO:261 CDR2 having the amino acid sequence of SEQ ID NO:265 CDR3 having the amino acid sequence of SEQ ID NO:269, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98,

[0108] (c) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:

[0109] CDR1 having the amino acid sequence of SEQ ID NO:182 CDR2 having the amino acid sequence of SEQ ID NO:183 CDR3 having the amino acid sequence of SEQ ID NO:184, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266 CDR3 having the amino acid sequence of SEQ ID NO:271 , or

[0110] (d) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:

[0111] CDR1 having the amino acid sequence of SEQ ID NO:261 CDR2 having the amino acid sequence of SEQ ID NO:265

[0112] CDR3 having the amino acid sequence of SEQ ID NO:269, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:

[0113] CDR1 having the amino acid sequence of SEQ ID NO:262

[0114] CDR2 having the amino acid sequence of SEQ ID NO:266

[0115] CDR3 having the amino acid sequence of SEQ ID NO:271 .

[0116] In some embodiments, the antigen-binding molecule comprises a further IL-7Ra-binding moiety.

[0117] In some embodiments, the further IL-7Ra-binding moiety comprises:

[0118] (a) a VH sequence incorporating the following CDRs:

[0119] CDR1 having the amino acid sequence of SEQ ID NO:262

[0120] CDR2 having the amino acid sequence of SEQ ID NO:266

[0121] CDR3 having the amino acid sequence of SEQ ID NO:271 , or

[0122] (b) a VH sequence incorporating the following CDRs:

[0123] CDR1 having the amino acid sequence of SEQ ID NO:261

[0124] CDR2 having the amino acid sequence of SEQ ID NO:265

[0125] CDR3 having the amino acid sequence of SEQ ID NO:269.

[0126] In some embodiments, the antigen-binding molecule comprises:

[0127] (a) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:

[0128] CDR1 having the amino acid sequence of SEQ ID NO:182

[0129] CDR2 having the amino acid sequence of SEQ ID NO:183

[0130] CDR3 having the amino acid sequence of SEQ ID NO:184, a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:

[0131] CDR1 having the amino acid sequence of SEQ ID NO:96

[0132] CDR2 having the amino acid sequence of SEQ ID NO:97

[0133] CDR3 having the amino acid sequence of SEQ ID NO:98, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:

[0134] CDR1 having the amino acid sequence of SEQ ID NO:262

[0135] CDR2 having the amino acid sequence of SEQ ID NO:266

[0136] CDR3 having the amino acid sequence of SEQ ID NO:271 , or

[0137] (b) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:

[0138] CDR1 having the amino acid sequence of SEQ ID NO:261

[0139] CDR2 having the amino acid sequence of SEQ ID NO:265

[0140] CDR3 having the amino acid sequence of SEQ ID NO:269, a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:

[0141] CDR1 having the amino acid sequence of SEQ ID NO:96

[0142] CDR2 having the amino acid sequence of SEQ ID NO:97

[0143] CDR3 having the amino acid sequence of SEQ ID NO:98, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:

[0144] CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266 CDR3 having the amino acid sequence of SEQ ID NO:271

[0145] 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:377, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:291 , SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:294, SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298, SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301 , SEQ ID NQ:302, SEQ ID NO:88, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NQ:40, SEQ ID NO:53, SEQ ID 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:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

[0146] An antigen-binding molecule comprising a first antigen-binding moiety, a second antigen-binding moiety, and a CH2-CH3 polypeptide is provided.

[0147] In some embodiments, the antigen-binding molecule comprises a polypeptide chain comprising, from N- terminus to C-terminus:

[0148] (a) a first antigen-binding moiety,

[0149] (b) a CH2-CH3 polypeptide, and

[0150] (c) a second antigen-binding moiety.

[0151] In some embodiments, the antigen-binding molecule comprises:

[0152] (i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:

[0153] (a) a first antigen-binding moiety,

[0154] (b) a CH2-CH3 polypeptide, and

[0155] (c) a second antigen-binding moiety; and

[0156] (ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

[0157] In some embodiments, polypeptide chain B comprises an antigen-binding moiety.

[0158] In some embodiments, polypeptide chain B comprises, from N-terminus to C-terminus:

[0159] (a) a first antigen-binding moiety,

[0160] (b) a CH2-CH3 polypeptide, and

[0161] (c) a second antigen-binding moiety. In some embodiments, the first antigen-binding moiety and / or the second antigen-binding moiety comprises a yc-binding moiety.

[0162] In some embodiments, the first antigen-binding moiety or the second antigen-binding moiety binds to a polypeptide of a yc-containing cytokine receptor other than yc.

[0163] In some embodiments, the first antigen-binding moiety or the second antigen-binding moiety comprises an IL-7Ra-binding moiety.

[0164] In some embodiments, the first antigen-binding moiety of polypeptide chain A binds the same target antigen as the first antigen-binding moiety of polypeptide chain B, and / or wherein the second antigenbinding moiety of polypeptide chain A binds the same target antigen as the second antigen-binding moiety of polypeptide chain B.

[0165] In some embodiments, the antigen-binding molecule comprises: a polypeptide chain comprising, from N-terminus to C-terminus:

[0166] (a) a yc-binding moiety,

[0167] (b) a CH2-CH3 polypeptide, and

[0168] (c) an IL-7Ra-binding moiety.

[0169] In some embodiments, the antigen-binding molecule comprises: a polypeptide chain comprising, from N-terminus to C-terminus:

[0170] (a) an IL-7Ra-binding moiety,

[0171] (b) a CH2-CH3 polypeptide, and

[0172] (c) a yc-binding moiety.

[0173] In some embodiments, the antigen-binding molecule comprises:

[0174] (i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:

[0175] (a) a yc-binding moiety,

[0176] (b) a CH2-CH3 polypeptide, and

[0177] (c) an IL-7Ra-binding moiety; and

[0178] (ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

[0179] In some embodiments, the antigen-binding molecule comprises:

[0180] (i) a polypeptide chain (chain A) comprising, from N-terminus to C-terminus:

[0181] (a) an IL-7Ra-binding moiety,

[0182] (b) a CH2-CH3 polypeptide, and

[0183] (c) a yc-binding moiety; and

[0184] (ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

[0185] In some embodiments, the antigen-binding molecule comprises:

[0186] (i) a polypeptide chain (chain A) comprising, from N-terminus to C-terminus: (a) a yc-binding moiety,

[0187] (b) a CH2-CH3 polypeptide, and

[0188] (c) an IL-7Ra-binding moiety; and

[0189] (ii) a polypeptide chain (chain B) comprising, from N-terminus to C-terminus:

[0190] (a) a yc-binding moiety,

[0191] (b) a CH2-CH3 polypeptide,

[0192] (c) an IL-7Ra-binding moiety.

[0193] In some embodiments, the antigen-binding molecule comprises:

[0194] (i) a polypeptide chain (chain A) comprising, from N-terminus to C-terminus:

[0195] (a) an IL-7Ra-binding moiety,

[0196] (b) a CH2-CH3 polypeptide, and

[0197] (c) a yc-binding moiety; and

[0198] (ii) a polypeptide chain (chain B) comprising, from N-terminus to C-terminus:

[0199] (a) an IL-7Ra-binding moiety,

[0200] (b) a CH2-CH3 polypeptide, and

[0201] (c) a yc-binding moiety.

[0202] In some embodiments, the antigen-binding molecule comprises:

[0203] (i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:

[0204] (a) a yc-binding moiety,

[0205] (b) a CH2-CH3 polypeptide, and

[0206] (c) a first IL-7Ra-binding moiety; and

[0207] (ii) a polypeptide chain (polypeptide chain B) comprising, from N-terminus to C-terminus:

[0208] (a) a yc-binding moiety,

[0209] (b) a CH2-CH3 polypeptide, and

[0210] (c) a second IL-7Ra-binding moiety, wherein the first IL-7Ra-binding moiety and the second IL-7Ra-binding moiety comprise different VH sequences.

[0211] In some embodiments, the first IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0212] CDR1 having the amino acid sequence of SEQ ID NO:96

[0213] CDR2 having the amino acid sequence of SEQ ID NO:97

[0214] CDR3 having the amino acid sequence of SEQ ID NO:98, and the second IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0215] CDR1 having the amino acid sequence of SEQ ID NO:262

[0216] CDR2 having the amino acid sequence of SEQ ID NO:266

[0217] CDR3 having the amino acid sequence of SEQ ID NO:271 .

[0218] In some embodiments, the first IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266 CDR3 having the amino acid sequence of SEQ ID NO:271 , and the second IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:

[0219] CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98.

[0220] A chimeric antigen receptor (CAR) is provided, comprising an antigen-binding molecule according to the present disclosure.

[0221] A nucleic acid, or a plurality of nucleic acids, is provided, encoding an antigen-binding molecule according to the present disclosure, or a CAR according to the present disclosure.

[0222] 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.

[0223] A cell 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, or an expression vector or a plurality of expression vectors according to the present disclosure.

[0224] A method is provided, the method comprising culturing a cell according to the present disclosure under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

[0225] A composition 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 is provided.

[0226] In some embodiments, 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.

[0227] A use is provided, wherein the use is a 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.

[0228] 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 autoimmune disease.

[0229] In some embodiments, the autoimmune disease is selected from Crohn’s disease, Sjogren’s syndrome, lupus, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, alopecia areata, psoriasis, psoriatic arthritis, myasthenia gravis, sarcoidosis, type 1 diabetes, ulcerative colitis, Addison’s disease, Graves’ disease, Hashimoto’s thyroiditis, autoimmune vasculitis, pernicious anemia, or celiac disease.

[0230] In some embodiments, the method of treatment or prophylaxis is a method of treating or preventing a disease / condition characterised by inflammation.

[0231] In some embodiments, yc is sequestered by the antigen binding molecule.

[0232] In some embodiments, the frequency of yc forming a complex with IL-2Ra, IL-2Rp, IL-4Ra, IL-9Ra, IL- 15Ra, and / or IL-21 Ra is reduced. In some embodiments, the formation of a complex between yc and IL- 2Ra, IL-2RP, IL-4Ra, IL-9Ra, IL-15Ra, and / or IL-21 Ra is inhibited.

[0233] 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 yc and a polypeptide of a yc-containing cytokine receptor other than yc.

[0234] A method for decreasing the proliferation, survival and / or effector activity of a cell expressing a yc- containing cytokine receptor 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, or a CAR according to the present disclosure.

[0235] In some embodiments, the cell is an effector immune cell.

[0236] A method for inhibiting signalling mediated by a yc-containing cytokine receptor is provided, comprising contacting a cell expressing a polypeptide of a yc-containing cytokine receptor 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.

[0237] In some embodiments, the yc-containing cytokine receptor is a yc:IL-7Ra receptor. A method of sequestering yc is provided, comprising contacting yc 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.

[0238] A method of inhibiting the formation of a heteromeric complex of (i) yc and (ii) IL-2Ra, IL-2Rp, IL-4Ra, IL- 9Ra, IL-15Ra, and / or IL-21 Ra is provided, comprising contacting yc 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.

[0239] A method for reducing the number / proportion of cells expressing a yc-containing cytokine receptor 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 any one of claims xx, or a cell comprising a CAR according to the present disclosure.

[0240] A method for decreasing the proliferation, survival and / or effector activity of a cell expressing a yc- containing cytokine receptor 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.

[0241] A method of inhibiting the formation of a heteromeric complex of yc and IL-2Ra, IL-2R0, IL-4Ra, IL-9Ra, IL-15Ra, and / or IL-21 Ra is provided, comprising contacting yc in vitro, in vivo or ex vivo with an antigenbinding molecule according to the present disclosure.

[0242] A method for inhibiting signalling mediated by a yc-containing cytokine receptor is provided, comprising contacting a cell expressing a polypeptide of a yc-containing cytokine receptor in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure.

[0243] A method for inhibiting the proliferation, survival and / or effector activity of a cell expressing a polypeptide of a yc-containing cytokine receptor is provided, comprising contacting a cell expressing a polypeptide of a yc-containing cytokine receptor in vitro, in vivo or ex vivo with an antigen-binding molecule according to the present disclosure.

[0244] In some embodiments, the frequency of yc forming a complex with IL-2Ra, IL-2R0, IL-4Ra, IL-9Ra, IL- 15Ra, and / or IL-21 Ra is reduced.

[0245] Description

[0246] The present disclosure provides antigen-binding molecules that bind to common y chain (yc; CD132), and antigen-binding molecules that bind to IL-7Ra (CD127), having novel biophysical and / or functional properties as compared to antigen-binding molecules disclosed in the prior art.

[0247] The present disclosure also encompasses the nucleotide and amino acid sequences of antigen-binding molecules with specificity for both yc and IL-7Ra. In one aspect, this disclosure describes IL-7 receptor antagonists in which antagonism is achieved by preventing heterodimerization of the IL-7 receptor components by multispecific antigen binding molecules (e.g. bispecific antibodies or bi-functional proteins) possessing anti-yc specificity and anti-IL-7Ra specificity.

[0248] Clinical studies looking into the effects of IL-7 receptor antagonists (e.g. anti-IL-7Ra antagonistic antibodies), such as NCT02045732, NCT03980080, and NCT01808482 have shown results that are not ideal.

[0249] Anti-IL-7Ra antagonistic antibodies are designed to inhibit signalling mediated by IL-7Ra with the aim of reducing immune responses in diseases, such as inflammatory diseases and autoimmune diseases. However, clinical studies examining the effects of IL-7Ra antagonists (e.g. anti-IL-7Ra antagonistic antibodies) have shown results suggesting increased immune responses, the opposite of the desired effect.

[0250] Herold et al. (JCI Insight. (2019) 4(24):e126054) showed that antagonistic anti-IL-7Ra treatment actually increased NK expansion. Additionally, Ellis et al. (Br J Clin Pharmacol. (2019) 85(2):304-315) state that there is unexpected agonistic potential for the anti-IL-7Ra antibody (across 3 studies), which was designed for antagonism of IL-7Ra. Furthermore, Belarif et al. (Nat. Commun. (2018) 9:4483) reported that some antagonistic anti-IL-7Ra mAbs induced gene expression associated with T cell activation and inflammation. Additionally, patients have developed anti-drug antibodies (ADAs) against multiple different anti-IL-7Ra treatments.

[0251] The current inventors propose that the agonistic effects seen following treatment with antagonistic anti-IL- 7Ra antibodies are a result of reduced yc sequestration by IL-7Ra. IL-7Ra strongly binds yc, but treatment with antagonistic anti-IL-7Ra antibodies affects the ability of IL-7Ra to bind yc. This leads to an increased availability of yc to form complexes with other polypeptides of yc family receptors (e.g. IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra), resulting in increased signalling (Figure 1).

[0252] In some embodiments, the IL-7Ra-binding moiety as disclosed herein inhibits signalling mediated by IL- 7Ra, and the yc-binding moiety reduces the availability of yc by binding and sequestering yc.

[0253] Sequestering yc reduces the availability of yc to form a heteromeric complex with a polypeptide of the yc receptor family (e.g. IL-2Ra, IL-2R0, IL-4Ra, IL-7Ra, IL-9Ra, IL-15Ra, or IL-21 Ra). Therefore, the disclosed antigen binding molecules may affect the signalling of multiple yc-associated cytokine receptors, not just IL-7Ra. As a result, non-specific agonism is reduced. In some embodiments, the disclosed antigen-binding molecules inhibit signalling mediated by IL-2Ra, IL-2RJ3, IL-4Ra, IL-7Ra, IL- 9Ra, IL-15Ra, and / or IL-21 Ra. In some embodiments, IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL-21 mediated signalling is inhibited. Common v chain (yc)

[0254] 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.

[0255] 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.

[0256] 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.

[0257] All receptors of the yc receptor family comprise yc as a constituent polypeptide. Janus kinas 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.

[0258] 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.

[0259] 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.

[0260] 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).

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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. 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.

[0269] Interleukin-7 receptor-a (IL-7Ra) lnterleukin-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 signalling leading to profound immunodeficiency. Elevated IL-7 levels have been associated with diseases associated with inflammation, autoimmune diseases, and also with poor prognosis of a number of cancers (Zarogoulidis et al., J Cancer. (2014) 5(9):765-773).

[0270] 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, which are responsible for differentiation and survival, respectively (EIKassar and Gress, J Immunotoxicol. (2010) 7(1):1— 7). When IL-7 binds to IL-7Ra, it recruits yc. This brings together the IL-7 and IL-7Ra intracellular domains, which bear JAK1 and JAK3, respectively. 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 etal. 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.

[0271] Sequence, structure and functional information relating to Human IL-7Ra may be identified on publically available databases such as UniProt (P16871), Genbank (AAA59157.1), and PDB / Alpha fold (AF- P16871-F1). Human IL-7Ra (also known as IL-7R, CD127) is the protein identified by UniProt P16871. The canonical isoform of human IL-7Ra (Uniprot P16871-1) has the amino acid sequence of SEQ ID NO:9. The N-terminal 20 amino acids of SEQ ID NO:9 constitute a signal peptide (SEQ ID NQ:10), and so the mature form ( / .e. after processing to remove the signal peptide) of human IL-7Ra has the amino acid sequence shown in SEQ ID NO:11 . The mature canonical isoform of human IL-7Ra comprises an extracellular domain (SEQ ID NO:12), a transmembrane domain (SEQ ID NO:13), and a cytoplasmic domain (SEQ ID NO:14).

[0272] 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.

[0273] Sequence, structure and functional information relating to cynomolgous IL-7Ra may be identified on publically available databases such as UniProt (Q38IC7), Genbank (ABB13531 .1), and PDB / Alpha fold (AF-Q38IC7-F1). The amino acid sequence of the cynomolgous IL-7Ra extracellular domain has 96.4% identity to the amino acid sequence of the Human IL-7Ra extracellular domain.

[0274] Sequence, structure and functional information relating to rat IL-7Ra may be identified on publically available databases such as UniProt (A6KGJ9) and Genbank (EDL75666.1). The amino acid sequence of the rat IL-7Ra extracellular domain has 66.8% identity to the amino acid sequence of the Human IL-7Ra extracellular domain.

[0275] Sequence, structure and functional information relating to mouse IL-7Ra may be identified on publically available databases such as UniProt (P16872), Genbank (AAA39304.1), and PDB / Alpha fold (AF- P16872-F1). The amino acid sequence of the mouse IL-7Ra extracellular domain has 67.3% identity to the amino acid sequence of the Human IL-7Ra extracellular domain.

[0276] An isoform, fragment, variant or homologue of IL-7Ra 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.

[0277] In some embodiments, the IL-7Ra 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 any one of SEQ ID NOs: 9 or 11 . In some embodiments, a fragment of IL-7Ra 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.

[0278] IL-7Ra binds the yc with high affinity, outcompeting other yc-associated cytokine receptors (e.g. IL-2Ra, IL-2RP, IL-15Ra, IL-4Ra, IL-9Ra, and IL-21 Ra) (Waickman et al. iScience. (2020) 23(8):101421).

[0279] Therefore, when IL-7Ra binds yc, the yc is unavailable to form a heteromeric complex with another polypeptide of the yc receptor family (e.g. IL-2Ra, IL-2RJ3, IL-4Ra, IL-7Ra, IL-9Ra, IL-15Ra, or IL-21 Ra), and therefore the signalling of cytokines that signal through cytokine receptors comprising yc (e.g. IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL21) is inhibited.

[0280] Antibodies that bind to IL-7Ra include e.g. Lusvertikimab (OSE-127; described in e.g. Belarif et al, Nature Communications 9, 4483. 2018), RN168 (PF-06342674; described in e.g. Herold et al., JCI Insight. 2019 Dec 19; 4(24): e126054), 4A10 (described in e.g. Hixon et al, Leukemia. 2020 Jan; 34(1): 35-49), GSK2618960 (described in e.g. Ellis et al., Br J Clin Pharmacol. (2019) 85(2):304-315), B12 (described in e.g. Akkapeddi et al., Leukemia. (2019) 33(9);2155-2168) and A7R34 (described in e.g. Sudo et al., Proc Natl Acad Sci USA. (1993) 90(19):9125-9129).

[0281] Signalling through cytokine receptors comprising yc

[0282] 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.

[0283] 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.

[0284] 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-2Rp), 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-2Rp and yc binds IL-2 with intermediate affinity (KD ~ 1 nM), although IL-2Rp 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-2Rp, 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 IL-2R0, but not IL-2Ra), they are not tuneable in the same way as the presently disclosed antigen binding molecules, and they do not have the same levels of low immunogenicity.

[0285] 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, most cells carry at least low numbers of this receptor chain. Upon IL-4 binding to IL-4Ra, the IL-4 / IL-4Ra complex will bind a secondary receptor chain, either yc or IL-13Ra1 (Junttila. Front Immunol. (2018) 9:888). The expression of these secondary chains varies among different cell types. In non-hematopoietic cells, yc expression is low or absent, whereas higher amounts of IL-13Ra1 are expressed in these cells. By contrast, lymphocytes express only low levels of IL- 13Ra1 and relatively large amounts of yc. Finally, myeloid cells fall in between non-hematopoietic cells and lymphocytes, as they express both IL-13Ra1 and yc. IL-4 activates multiple signalling pathways. IL-4 activates JAK1 and JAK3 via the type I IL-4 receptor (yc:IL-4Ra); however, IL-4 activates JAK1 and either JAK2 or TYK2 (depending on the cell type) via type II IL-4 receptors (yc:IL-4RcclL-13Ra1) (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, subsequently activating various pathways including Sos / Ras, PI3K / Akt, PKB / mTOR, or PKC.

[0286] 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, which are responsible for differentiation and survival, respectively (EIKassar and Gress, J Immunotoxicol. (2010) 7(1 ) : 1 — 7) . When IL-7 binds to IL-7Ra, it recruits yc. This brings together the IL-7 and IL-7Ra intracellular domains, which bear JAK1 and JAK3, respectively. IL-7 binding to the IL-7 receptor complex results in downstream STAT1 , STAT3, and STAT5 signalling. Under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in IL-7-dependent STAT1 and STAT5 activation (Le Saout et al. JCI Insight. (2017) 2(22):e96228).

[0287] 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, respectively (EIKassar and Gress, J Immunotoxicol. (2010) 7(1): 1-7). When IL-7 binds to IL-7Ra, it recruits yc, bringing together their intracellular domains bearing JAK1 and JAK3, respectively. IL-7 binding to the IL-7 receptor complex results in downstream STAT1 , STAT3, and STAT5 signalling. Under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in IL-7-dependent STAT1 and STAT5 activation (Le Saout et al. JCI Insight. (2017) 2(22): e96228). Activation by IL-7 results in phosphorylation of the Y449 residue on IL-7Ra (Jiang et al., Cytokine Growth Factor Rev. (2005) 16:513-533). The p85a subunit of PI3K binds directly to phosphorylated Y449 via an SH2 domain. This is followed by the allosteric activation of the catalytic subunit P110. PI3K is recruited to the membrane where it produces the phosphatidyl-inositol PIP3 by phosphorylating PIP2. PIP3 activates downstream genes with a plekstrin homology domain such as PDK1 and Akt (Shiroki et al., J Immunol. (2007) 178:1349-1356). Akt, in turn, phosphorylates genes that regulate cell metabolism, cell cycle progression and survival, such as GSK3p, P27 and the death protein BAD.

[0288] Interleukin-9 (IL-9) is a cytokine which stimulates cell proliferation and prevents apoptosis. IL-9 is a pleiotropic cytokine and was primarily studied in the context of T helper 2 (TH2)-associated immuno- pathological conditions such as asthma and parasitic infections. There was a paradigm shift in the biology of IL-9 after the recent discovery of TH9 cells, a new subtype of TH cells which secrete IL-9 in copious amounts. This has resulted in renewed interest in this cytokine, which was neglected since discovery because it was considered it to be just another TH2 cytokine. Recent studies have shown that it has multiple cellular sources and is critically involved in the immune pathogenesis of inflammatory diseases and in guarding immune tolerance (Chakraborty et al. Int J Mol Sci. (2019) 20(9): 2113). IL-9 functions through the interleukin-9 receptor complex, which comprises IL-9 receptor alpha (IL-9Ra) and yc. When IL-9 binds to the IL-9 receptor complex, it activates different signal transducer and activator (STAT) proteins namely 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, mast cells, as well as airway smooth muscle cells and epithelial cells (Lee at al. Pathology & Oncology Research (2020) 26:2017-2022). IL-9 also activates insulin receptor substrates (IRS) 1 and 2. Following JAK mediated phosphorylation, IRS proteins interact with other SH2- containing signaling proteins, such as the regulatory subunit of Phosphatidylinositol-3 Kinase (PI3K) p85, causing the activation of the PI3K catalytic subunit p110. PI3K then activates downstream signaling molecules like PI3K-dependent kinase (PDK) and Akt. Akt then phosphorylates BAD and protects cells by preventing caspase-mediated apoptosis. IL-9 also activates the MAPK pathway in several cell lines of lymphoid and hematopoietic origin, but the IL-9 mediated MAPK activation is weak compared to other cytokines like IL-3.

[0289] Interleukin-15 (IL-15) has structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through a complex composed of IL-2 / IL-15 receptor beta chain (CD122) and yc (CD132). Interleukin 15 is considered as a powerful pro-inflammatory cytokine and has the ability to destabilize chromosomes and induce tumorigenesis (Zarogoulidis et al., J Cancer. (2014) 5(9): 765-773). IL-15 utilizes three distinct receptor chains in at least two different combinations to signal and exert its effects on the immune system. Despite the lack of homology in the amino acid sequence between IL-15 and IL-2, the mature IL- 15 protein binds to the IL-2Rpy heterodimer, activating the intracellular signal leading to cell activation (Mishra et al., Clin Cancer Res. (2014) 20(8): 2044-2050). The third component of the IL-15R complex is a unique a-chain (IL-15Ra). In contrast to the IL-2Ra chain that binds IL-2 with low affinity and confers high affinity for IL-2 only when non-covalently linked the IL-2Rpy complex, IL-15Ra is by itself a high affinity receptor for IL-15 (Giri et al., EMBO J. (1995) 14:3654-63).

[0290] Binding of IL-15 to the IL-2 / 15Rpy heterodimer induces JAK1 activation via its p chain, and induces JAK3 activation via its y chain. Activated JAK1 then phosphorylates STAT3, while activated JAK3 phosphorylates STAT5. Phosphorylated STAT3 and STAT5 proteins subsequently form heterodimers that translocate to the nucleus where they activate transcription of the anti-apoptotic protein bcl-2 and protooncogenes c-myc, c-fos, and c-jun.

[0291] The Akt signaling mechanism utilizes an adaptor protein, She, which binds to a phosphotyrosine residue on IL-2 / 15Rp, resulting in activation of Grb2 and .subsequently, AKT via the Shc^Grb2^Gab2^PI3K^Akt signaling pathway. This increases cell proliferation, survival and / or effector activity (Gu etal. 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.

[0292] 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 a 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, MAPK and PI3K pathways.

[0293] IL-21 binding stabilizes the complex between IL-21 R 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 R can also activate the MAPK 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.

[0294] In this specification ‘yc-containing cytokine receptor-mediated signalling’ refers to signalling mediated by multimeric receptor complexes comprising yc (e.g. comprising yc and another member of the yc receptor family other than yc). ‘Signalling’ refers to signal transduction and other cellular processes governing cellular activity. yc-containing cytokine receptor-mediated signalling is signalling mediated by a yc-containing polypeptide complex ( / .e. a polypeptide complex comprising one or more yc polypeptides, and another member of the yc receptor family other than yc). Polypeptide complexes according to the present disclosure may be characterised by non-covalent, proteimprotein interaction between constituent polypeptide(s) / peptide(s). In some embodiments, the association comprises electrostatic interaction (e.g. ionic bonding, hydrogen bonding) and / or Van der Waals forces. yc-containing cytokine receptor-mediated signalling may be mediated by heteromultimeric polypeptide complexes comprising one or more yc polypeptides, and additionally comprising one or more polypeptides of the yc receptor family other than yc (e.g. selected from IL-2Rp, 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. In some embodiments, yc-containing cytokine receptor- mediated signalling is mediated by a polypeptide complex forming a receptor for IL-7.

[0295] 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).

[0296] 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. a 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).

[0297] 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. a IL-2:yc:IL-2Rp:IL-2Ra complex). Such signalling may be referred to as IL-2: yc:l L-2Rp:l L- 2Ra-mediated signalling ( / .e. signalling mediated by binding of IL-2 to the high-affinity IL-2 receptor).

[0298] 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. a 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).

[0299] 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. a 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).

[0300] 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. a 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).

[0301] 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. a 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).

[0302] 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. a 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).

[0303] The present disclosure relates to antigen-binding molecules that selectively bind to more than one component of yc-containing cytokine receptors. In particular, the antigen-binding molecules of the present disclosure are multispecific antigen-binding molecules comprising (i) a yc-binding moiety, and (ii) a moiety that binds to one or more polypeptides of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra). That is, the antigen binding molecule binds to (i) yc, and (ii) at least one of: IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra or IL-7Ra.

[0304] Antigen-binding molecules

[0305] The present disclosure provides antigen-binding molecules capable of binding to yc. An antigen-binding molecule that is capable of binding to yc may also be described as an antigen-binding molecule that binds to yc.

[0306] The present disclosure also provides antigen-binding molecules capable of binding to IL-7Ra. An antigenbinding molecule that is capable of binding to IL-7Ra may also be described as an antigen-binding molecule that binds to IL-7Ra.

[0307] The present disclosure also provides antigen-binding molecules capable of binding to yc and IL-7Ra. An antigen-binding molecule that is capable of binding to yc and IL-7Ra may also be described as an antigen-binding molecule that binds to yc and IL-7Ra.

[0308] 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.

[0309] 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). The antigen-binding molecule of the present disclosure comprises a moiety or moieties capable of binding to a target antigen(s). In some embodiments, the moiety capable of binding to a target antigen comprises an antibody heavy chain variable region (VH). In some embodiments, the moiety capable of binding to a target antigen comprises a Variable domain of the Heavy chain of a Heavy-chain antibody (VHH). In some embodiments, the moiety capable of binding to a target antigen comprises an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specific binding to the target antigen. In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an aptamer capable of binding to the target antigen, e.g. a nucleic acid aptamer (reviewed, for example, in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202). In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an antigenbinding peptide / polypeptide, e.g. a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, fynomer, atrimer, DARPin, affibody, nanobody ( / .e. a single-domain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody or fibronectin - reviewed e.g. in Reverdatto et al., Curr Top Med Chem. 2015; 15(12): 1082-1101 , which is hereby incorporated by reference in its entirety (see also e.g. Boersma et al., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).

[0310] 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.

[0311] 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).

[0312] 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.

[0313] 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.

[0314] 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. 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-7Ra. An ‘antigen-binding region’ is any fragment of an antibody that binds to the target for which the given antibody is specific.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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. 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] In some embodiments, the antigen-binding molecule comprises means for binding yc.

[0326] In some embodiments, the antigen-binding molecule comprises means for binding IL-7Ra.

[0327] 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.

[0328] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to IL-7Ra. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to IL-7Ra. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to IL-7Ra. In some embodiments, the antigen-binding molecule comprises the VH region of an antigen-binding molecule that binds to IL-7Ra. In some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigen-binding molecule that binds to IL-7Ra.

[0329] In some embodiments, the antigen-binding molecule comprises an antigen-binding moiety that binds to IL-7Ra. In some embodiments, the antigen-binding moiety comprises the CDRs of an antibody that binds to IL-7Ra. In some embodiments, the antigen-binding moiety comprises the FRs of an antibody that binds to IL-7Ra. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that binds to IL-7Ra. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that binds to IL-7Ra. In some embodiments, the antigenbinding moiety comprises or consists of an Fv moiety or Fab moiety comprising the VH region and the VL region of an antibody that binds to IL-7Ra.

[0330] 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.

[0331] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the CDRs of a yc-binding VHH antibody disclosed in Table A, 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.

[0332] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the CDRs of a yc-binding VHH antibody disclosed in Table C, 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.

[0333] In some embodiments, the antigen-binding molecule comprises a IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the CDRs of a yc-binding VHH antibody disclosed in Table D, 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.

[0334] In some embodiments, the antigen-binding molecule comprises a IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the CDRs of a yc-binding VHH antibody disclosed in Table F, 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.

[0335] 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 a yc-binding VHH antibody disclosed in Table C.

[0336] In some embodiments, the antigen-binding molecule comprises a IL-7Ra-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 a yc-binding VHH antibody disclosed in Table F.

[0337] In some embodiments, a yc-binding antibody is selected from an antibody described in Table A, B, or C herein.

[0338] In some embodiments, the yc-binding antibody is hu2RGT212.

[0339] In some embodiments, the yc-binding antibody is Hu217P2P2_E2.

[0340] In some embodiments, the yc-binding antibody is hu217P2P2_A6.

[0341] In some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Ab codes: MA009, MA003, MA004, MA005, MA006, MA007, MA008, 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: 2RGT212, 2RGT38, 2RGT238, 2RGT30, 2RGT123, 3RGT35, 3RGT83, 2RGT12, 2RGT50, 2RGT222, 3RGT31 , and 2RGT156.

[0342] In some embodiments, the yc-binding antibody is selected from an antibody disclosed herein with one of the following Ab codes: MA093, MA089, MA090, MA009, MA003, MA004, MA005, MA006, MA007, MA008, 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: 217P2P2_E2, 217P2P2_A6, 217P2P2_C3, 2RGT212, 2RGT38, 2RGT238, 2RGT30, 2RGT123, 3RGT35, 3RGT83, 2RGT12, 2RGT50, 2RGT222, 3RGT31 , and 2RGT156.

[0343] In some embodiments, the yc-binding antibody is selected from: 2RGT212, 2RGT38, 2RGT238, or 2RGT30. In some embodiments, the yc-binding antibody is 2RGT212. 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 2RGT30.

[0344] In some embodiments, the yc-binding antibody is selected from: 217P2P2_E2, 217P2P2_A6, 217P2P2_C3, and 2RGT212. In some embodiments, the yc-binding antibody is 217P2P2_E2. In some embodiments, the yc-binding antibody is 217P2P2_A6. In some embodiments, the yc-binding antibody is 217P2P2_C3. In some embodiments, the yc-binding antibody is 2RGT212.

[0345] In some embodiments, the yc-binding antibody is selected from: hu217P2P2_E2, hu217P2P2_A6, hu2RGT212, hu2RGT38-1 , hu2RGT38-2, or hu2RGT238. In some embodiments, the yc-binding antibody is selected from: hu2RGT212, hu2RGT38-1 , hu2RGT38- 2, or hu2RGT238.

[0346] In some embodiments, the yc-binding antibody is selected from: hu217P2P2_E2, hu217P2P2_A6, and hu2RGT212.

[0347] In some embodiments, the yc-binding antibody is hu217P2P2_E2.

[0348] In some embodiments, the yc-binding antibody is hu217P2P2_A6.

[0349] In some embodiments, the yc-binding antibody is hu2RGT212.

[0350] In some embodiments, the yc-binding antibody is hu2RGT38-1.

[0351] In some embodiments, the yc-binding antibody is hu2RGT38-2.

[0352] In some embodiments, the yc-binding antibody is hu2RGT238.

[0353] In some embodiments, an IL-7Ra-binding antibody is selected from an antibody described in Table D, E, or F, herein.

[0354] In some embodiments, the IL-7Ra-binding antibody is selected from: MA002, MA001 , MA003, MA004, MA005, MA006, MA007, MA008, MA009, and MA010. In other words, in some embodiments, the IL-7Ra- binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2WOM37, 3WOM22, 2WOM277, 2WOM180, 2WOM222, 3WOM47, 2WOM217, 2WOM241 , 2WOM166, and 3WOM5.

[0355] In some embodiments, the IL-7Ra-binding antibody is selected from: MA002, MA028, MA001 , MA003, MA004, MA005, MA006, MA007, MA008, MA009, and MA010. In other words, in some embodiments, the IL-7Ra-binding antibody is selected from an antibody disclosed herein with one of the following Clone IDs: 2WOM37, 6#P3P2_A9, 3WOM22, 2WOM277, 2WOM180, 2WOM222, 3WOM47, 2WOM217, 2WOM241 , 2WOM166, and 3WOM5.

[0356] In some embodiments, the IL-7Ra-binding antibody is 2WOM37.

[0357] In some embodiments, the IL-7Ra-binding antibody is hu2WOM37.

[0358] In some embodiments, the IL-7Ra-binding antibody is 6#P3P2_A9.

[0359] In some embodiments, the IL-7Ra-binding antibody is huMA028. In some embodiments, the antibody that binds yc and IL-7Ra is selected from: BS033, BS001 , BS002, BS003, BS004, BS005, BS006, 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, BS034, BS035, BS036, BS037, BS038, BS039, BS040, BS041 , and BS042.

[0360] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: TS022, TS011 , TS021 , TS023, BS047, BS095, BS096, BS097, BS099, BS100, BS125, BS033, BS001 , BS002, BS003, BS004, BS005, BS006, 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, BS034, BS035, BS036, BS037, BS038, BS039, BS040, BS041 , and BS042.

[0361] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: TS022, TS011 , TS021 , TS023, BS047, BS095, BS096, BS097, BS099, BS100, and BS125.

[0362] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: BS033, BS031 , BS021 , BS032, BS039, BS040, BS041 , and BS042.

[0363] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: BS033, BS032, BS041 , and BS042.

[0364] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: BS033, and BS032.

[0365] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: BS041 , and BS042.

[0366] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: TS022, TS011 , TS021 , TS023, BS047.

[0367] In some embodiments, the antibody that binds yc and IL-7Ra is selected from: BS047, BS095, BS096, BS097, BS099, BS100, and BS125.

[0368] In some embodiments, the antibody that binds yc and IL-7Ra is TS022. In some embodiments, the antibody that binds yc and IL-7Ra is TS011 . In some embodiments, the antibody that binds yc and IL-7Ra is TS021 . In some embodiments, the antibody that binds yc and IL-7Ra is TS023. In some embodiments, the antibody that binds yc and IL-7Ra is BS047. In some embodiments, the antibody that binds yc and IL- 7Ra is BS095. In some embodiments, the antibody that binds yc and IL-7Ra is BS096. In some embodiments, the antibody that binds yc and IL-7Ra is BS097. In some embodiments, the antibody that binds yc and IL-7Ra is BS099. In some embodiments, the antibody that binds yc and IL-7Ra is BS100. In some embodiments, the antibody that binds yc and IL-7Ra is BS125. In some embodiments, the antibody that binds yc and IL-7Ra is BS031 . In some embodiments, the antibody that binds yc and IL-7Ra is BS021. In some embodiments, the antibody that binds yc and IL-7Ra is BS032. In some embodiments, the antibody that binds yc and IL-7Ra is BS033. In some embodiments, the antibody that binds yc and IL- 7Ra is BS039. In some embodiments, the antibody that binds yc and IL-7Ra is BS040. In some embodiments, the antibody that binds yc and IL-7Ra is BS041 . In some embodiments, the antibody that binds yc and IL-7Ra is BS042.

[0369] In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table A, B, C, D, E, F, G, H, or I herein.

[0370] By way of example, BS031 is a humanized antibody, and BS021 is the corresponding parental antibody. In other words, BS021 underwent humanization, and this humanization resulted in humanized antibody BS031.

[0371] 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.

[0372] In some embodiments, the antibody that binds IL-7Ra is a humanized antibody. In some embodiments, the antibody that binds IL-7Ra is a humanized antibody, wherein the corresponding parental antibody is an antibody described herein. In some embodiments, the antibody that binds IL-7Ra is a humanized antibody, wherein the corresponding parental antibody is an antibody described in Table D, E, or F herein.

[0373] In some embodiments, the antibody that binds yc and IL-7Ra is a humanized antibody.

[0374] 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.

[0375] 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.

[0376] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety.

[0377] In some embodiments, the antigen-binding molecule comprises:

[0378] (A) 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:261 HC-CDR2 having the amino acid sequence of SEQ ID NO:265 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.

[0379] (B) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0380] HC-CDR1 having the amino acid sequence of SEQ ID NO:182 HC-CDR2 having the amino acid sequence of SEQ ID NO:183 HC-CDR3 having the amino acid sequence of SEQ ID NO:184, 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.

[0381] (C) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0382] HC-CDR1 having the amino acid sequence of SEQ ID NO:259 HC-CDR2 having the amino acid sequence of SEQ ID NO:263 HC-CDR3 having the amino acid sequence of SEQ ID NO:267, 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.

[0383] (D) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0384] HC-CDR1 having the amino acid sequence of SEQ ID NQ:260 HC-CDR2 having the amino acid sequence of SEQ ID NO:264 HC-CDR3 having the amino acid sequence of SEQ ID NO:268, 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.

[0385] In some embodiments, the antigen-binding molecule comprises:

[0386] (E) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0387] HC-FR1 having the amino acid sequence of SEQ ID NO:216 HC-FR2 having the amino acid sequence of SEQ ID NO:275 HC-FR3 having the amino acid sequence of SEQ ID NQ:280 HC-FR4 having the amino acid sequence of SEQ ID NO:282, 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.

[0388] (F) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0389] HC-FR1 having the amino acid sequence of SEQ ID NO:216 HC-FR2 having the amino acid sequence of SEQ ID NQ:220 HC-FR3 having the amino acid sequence of SEQ ID NO:237

[0390] HC-FR4 having the amino acid sequence of SEQ ID NO:145, 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.

[0391] (G) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0392] HC-FR1 having the amino acid sequence of SEQ ID NO:216 HC-FR2 having the amino acid sequence of SEQ ID NO:272 HC-FR3 having the amino acid sequence of SEQ ID NO:278 HC-FR4 having the amino acid sequence of SEQ ID NO:282, 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.

[0393] (H) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0394] HC-FR1 having the amino acid sequence of SEQ ID NQ:206 HC-FR2 having the amino acid sequence of SEQ ID NO:273 HC-FR3 having the amino acid sequence of SEQ ID NO:277 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0395] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region):

[0396] (I) comprising the CDRs according to (A) and the FRs according to (E).

[0397] (J) comprising the CDRs according to (B) and the FRs according to (F).

[0398] (K) comprising the CDRs according to (C) and the FRs according to (G).

[0399] (L) comprising the CDRs according to (D) and the FRs according to (H).

[0400] (M) 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:287, SEQ

[0401] ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:364, SEQ

[0402] ID NO:365, SEQ ID NO:366, SEQ ID NO:367, SEQ ID NO:368, SEQ ID NO:369, SEQ ID NQ:370, SEQ

[0403] ID NO:371 , SEQ ID NO:372, SEQ ID NO:373, SEQ ID NO:374, SEQ ID NO:375, or SEQ ID NO:376. (N) 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:287, SEQ ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285.

[0404] (O) 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:287.

[0405] (P) 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:253.

[0406] (Q) 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:286.

[0407] (R) 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:284.

[0408] (S) 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:283.

[0409] (T) 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:285.

[0410] In some embodiments, the antigen-binding molecule comprises an IL-7Ra-binding moiety.

[0411] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0412] (U) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0413] HC-CDR1 having the amino acid sequence of SEQ ID NO:96 HC-CDR2 having the amino acid sequence of SEQ ID NO:97 HC-CDR3 having the amino acid sequence of SEQ ID NO:98, 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.

[0414] (V) an IL-7Ra-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:262 HC-CDR2 having the amino acid sequence of SEQ ID NO:266 HC-CDR3 having the amino acid sequence of SEQ ID NO:271 , 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.

[0415] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0416] (W) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0417] HC-FR1 having the amino acid sequence of SEQ ID NO:216 HC-FR2 having the amino acid sequence of SEQ ID NO:126 HC-FR3 having the amino acid sequence of SEQ ID NO:144 HC-FR4 having the amino acid sequence of SEQ ID NO:145, 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.

[0418] (X) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0419] HC-FR1 having the amino acid sequence of SEQ ID NO:216 HC-FR2 having the amino acid sequence of SEQ ID NO:276 HC-FR3 having the amino acid sequence of SEQ ID NO:378 HC-FR4 having the amino acid sequence of SEQ ID NO:282, 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.

[0420] In some embodiments, the antigen-binding molecule comprises an IL-7Ra-binding moiety (e.g., a VHH, or a VH region):

[0421] (Y) comprising the CDRs according to (U) and the FRs according to (W)-

[0422] (Z) comprising the CDRs according to (V) and the FRs according to (X).

[0423] In some embodiments, the antigen-binding molecule comprises:

[0424] (AA) an IL-7Ra-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:254 or SEQ ID NO:379. (AB) an IL-7Ra-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:254.

[0425] (AC) an IL-7Ra-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:379.

[0426] In some embodiments, the antigen-binding molecule comprises:

[0427] (AD) an IL-7Ra-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:254 or SEQ ID NO:379, and another IL-7Ra-binding moiety.

[0428] (AE) an IL-7Ra-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:254 or SEQ ID NO:379, and an IL-7Ra-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 a VHH antibody defined in Table F herein.

[0429] (AF) an IL-7Ra-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:254, and an IL-7Ra-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:379.

[0430] (AG) In some embodiments, the antigen-binding molecule comprises:

[0431] (i) a yc-binding moiety, and

[0432] (ii) an IL-7Ra-binding moiety.

[0433] (AH) In some embodiments, the antigen-binding molecule comprises:

[0434] (i) a yc-binding moiety, and

[0435] (ii) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0436] (U) to (V) above. (Al) In some embodiments, the antigen-binding molecule comprises:

[0437] (i) a yc-binding moiety, and

[0438] (ii) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0439] (U) to (V) above, and the FRs according to any one of (W) to (X) above.

[0440] (AJ) In some embodiments, the antigen-binding molecule comprises:

[0441] (i) a yc-binding moiety, and

[0442] (ii) an IL-7Ra-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:254, SEQ ID NO:379, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0443] (AK) In some embodiments, the antigen-binding molecule comprises:

[0444] (i) a yc-binding moiety, and

[0445] (ii) an IL-7Ra-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:254 or SEQ ID NO:379.

[0446] (AL) In some embodiments, the antigen-binding molecule comprises:

[0447] (i) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (A) to

[0448] (D) above, and

[0449] (ii) an IL-7Ra-binding moiety.

[0450] (AM) In some embodiments, the antigen-binding molecule comprises:

[0451] (i) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (A) to

[0452] (D) above, and the FRs according to any one of (E) to (H) above, and

[0453] (ii) an IL-7Ra-binding moiety.

[0454] (AN) In some embodiments, the antigen-binding molecule comprises:

[0455] (i) 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:287, SEQ ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:364, SEQ ID NO:365, SEQ ID NO:366, SEQ ID

[0456] NO:367, SEQ ID NO:368, SEQ ID NO:369, SEQ ID NQ:370, SEQ ID NO:371 , SEQ ID

[0457] NO:372, SEQ ID NO:373, SEQ ID NO:374, SEQ ID NO:375, or SEQ ID NO:376, SEQ ID

[0458] NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID 1X10:170, 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 (ii) an IL-7Ra-binding moiety.

[0459] (AO) In some embodiments, the antigen-binding molecule comprises:

[0460] (i) 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:287, SEQ ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, and

[0461] (ii) an IL-7Ra-binding moiety.

[0462] (AP) In some embodiments, the antigen-binding molecule comprises CDRs according to one of (A) to (D) above, and CDRs according to one of (U) to (V) above.

[0463] (AQ) In some embodiments, the antigen-binding molecule comprises:

[0464] (i) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (A) to

[0465] (D) above, and the FRs according to any one of (E) to (H) above, and

[0466] (ii) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0467] (U) to (V) above, and the FRs according to any one of (W) to (X) above.

[0468] (AR) In some embodiments, the antigen-binding molecule comprises:

[0469] (i) 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:287, SEQ ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:364, SEQ ID NO:365, SEQ ID NO:366, SEQ ID NO:367, SEQ ID NO:368, SEQ ID NO:369, SEQ ID NQ:370, SEQ ID NO:371 , SEQ ID NO:372, SEQ ID NO:373, SEQ ID NO:374, SEQ ID NO:375, or SEQ ID NO:376, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, 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

[0470] (ii) an IL-7Ra-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:254, SEQ ID NO:379, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0471] (AS) In some embodiments, the antigen-binding molecule comprises:

[0472] (i) 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:287, SEQ ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, and (ii) an IL-7Ra-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:254 or SEQ ID NO:379.

[0473] (AT) 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:377, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:291 , SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:294, SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298, SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301 , SEQ ID NQ:302, SEQ ID NO:88, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NQ:40, SEQ ID NO:53, SEQ ID 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:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

[0474] (AU) 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:377, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:291 , SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:294, SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298, SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301 , SEQ ID NQ:302.

[0475] (AV) 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:377, SEQ ID NO:289, SEQ ID NQ:290, SEQ ID NO:291 , SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:294.

[0476] (AW) 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:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298, SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301 , SEQ ID NQ:302

[0477] (AX) 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:293. (AY) 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:294.

[0478] (AZ) In some embodiments, the antigen-binding molecule comprises a polypeptide 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:295, and a polypeptide 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:296.

[0479] (BA) In some embodiments, the antigen-binding molecule comprises a polypeptide 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:297, and a polypeptide 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:298.

[0480] (BB) In some embodiments, the antigen-binding molecule comprises a polypeptide 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:299, and a polypeptide 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:300.

[0481] (BC) In some embodiments, the antigen-binding molecule comprises a polypeptide 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:301 , and a polypeptide 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:302.

[0482] In some embodiments, the antigen-binding molecule comprises:

[0483] (1) 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:182 HC-CDR2 having the amino acid sequence of SEQ ID NO:183

[0484] HC-CDR3 having the amino acid sequence of SEQ ID NO:184, 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.

[0485] (2) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0486] HC-CDR1 having the amino acid sequence of SEQ ID NO:161 HC-CDR2 having the amino acid sequence of SEQ ID NO:162 HC-CDR3 having the amino acid sequence of SEQ ID NO:163, 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.

[0487] (3) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0488] HC-CDR1 having the amino acid sequence of SEQ ID NO:164 HC-CDR2 having the amino acid sequence of SEQ ID NO:165 HC-CDR3 having the amino acid sequence of SEQ ID NO:166, 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.

[0489] (4) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0490] HC-CDR1 having the amino acid sequence of SEQ ID NO:179 HC-CDR2 having the amino acid sequence of SEQ ID NQ:180 HC-CDR3 having the amino acid sequence of SEQ ID NO:181 , 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.

[0491] (5) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0492] HC-CDR1 having the amino acid sequence of SEQ ID NO:185 HC-CDR2 having the amino acid sequence of SEQ ID NO:186 HC-CDR3 having the amino acid sequence of SEQ ID NO:187, 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.

[0493] (6) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0494] HC-CDR1 having the amino acid sequence of SEQ ID NO:188 HC-CDR2 having the amino acid sequence of SEQ ID NO:189 HC-CDR3 having the amino acid sequence of SEQ ID NQ:190, 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.

[0495] (7) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0496] HC-CDR1 having the amino acid sequence of SEQ ID NO:191 HC-CDR2 having the amino acid sequence of SEQ ID NO:192 HC-CDR3 having the amino acid sequence of SEQ ID NO:193, 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.

[0497] (8) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0498] HC-CDR1 having the amino acid sequence of SEQ ID NO:194 HC-CDR2 having the amino acid sequence of SEQ ID NO:195 HC-CDR3 having the amino acid sequence of SEQ ID NO:196, 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.

[0499] (9) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0500] HC-CDR1 having the amino acid sequence of SEQ ID NO:197 HC-CDR2 having the amino acid sequence of SEQ ID NO:198 HC-CDR3 having the amino acid sequence of SEQ ID NO:199, 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.

[0501] (10) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0502] HC-CDR1 having the amino acid sequence of SEQ ID NO:185 HC-CDR2 having the amino acid sequence of SEQ ID NO:186 HC-CDR3 having the amino acid sequence of SEQ ID NO:187, 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.

[0503] (11) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0504] HC-CDR1 having the amino acid sequence of SEQ ID NQ:200 HC-CDR2 having the amino acid sequence of SEQ ID NQ:201 HC-CDR3 having the amino acid sequence of SEQ ID NQ:202, 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.

[0505] (12) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0506] HC-CDR1 having the amino acid sequence of SEQ ID NQ:203 HC-CDR2 having the amino acid sequence of SEQ ID NQ:204 HC-CDR3 having the amino acid sequence of SEQ ID NQ:205, 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.

[0507] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0508] (13) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0509] HC-FR1 having the amino acid sequence of SEQ ID NO:216

[0510] HC-FR2 having the amino acid sequence of SEQ ID NQ:220

[0511] HC-FR3 having the amino acid sequence of SEQ ID NO:237

[0512] HC-FR4 having the amino acid sequence of SEQ ID NO:145, 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.

[0513] (14) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0514] HC-FR1 having the amino acid sequence of SEQ ID NO:216

[0515] HC-FR2 having the amino acid sequence of SEQ ID NO:217

[0516] HC-FR3 having the amino acid sequence of SEQ ID NO:248

[0517] HC-FR4 having the amino acid sequence of SEQ ID NQ:250, 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.

[0518] (15) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0519] HC-FR1 having the amino acid sequence of SEQ ID NO:216

[0520] HC-FR2 having the amino acid sequence of SEQ ID NO:217

[0521] HC-FR3 having the amino acid sequence of SEQ ID NO:249

[0522] HC-FR4 having the amino acid sequence of SEQ ID NQ:250, 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.

[0523] (16) a yc-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:216

[0524] HC-FR2 having the amino acid sequence of SEQ ID NO:218 HC-FR3 having the amino acid sequence of SEQ ID NO:251 HC-FR4 having the amino acid sequence of SEQ ID NO:252, 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.

[0525] (17) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0526] HC-FR1 having the amino acid sequence of SEQ ID NQ:209 HC-FR2 having the amino acid sequence of SEQ ID NQ:220 HC-FR3 having the amino acid sequence of SEQ ID NO:229 HC-FR4 having the amino acid sequence of SEQ ID NO:239, 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.

[0527] (18) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0528] HC-FR1 having the amino acid sequence of SEQ ID NQ:206 HC-FR2 having the amino acid sequence of SEQ ID NO:217 HC-FR3 having the amino acid sequence of SEQ ID NO:226 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0529] (19) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0530] HC-FR1 having the amino acid sequence of SEQ ID NQ:207 HC-FR2 having the amino acid sequence of SEQ ID NO:218 HC-FR3 having the amino acid sequence of SEQ ID NO:227 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0531] (20) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0532] HC-FR1 having the amino acid sequence of SEQ ID NQ:208 HC-FR2 having the amino acid sequence of SEQ ID NO:128 HC-FR3 having the amino acid sequence of SEQ ID NO:228 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0533] (21) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0534] HC-FR1 having the amino acid sequence of SEQ ID NO:209 HC-FR2 having the amino acid sequence of SEQ ID NO:211 HC-FR3 having the amino acid sequence of SEQ ID NQ:230 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0535] (22) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0536] HC-FR1 having the amino acid sequence of SEQ ID NO:212 HC-FR2 having the amino acid sequence of SEQ ID NO:221 HC-FR3 having the amino acid sequence of SEQ ID NO:231 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0537] (23) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0538] HC-FR1 having the amino acid sequence of SEQ ID NQ:210 HC-FR2 having the amino acid sequence of SEQ ID NO:222 HC-FR3 having the amino acid sequence of SEQ ID NO:232 HC-FR4 having the amino acid sequence of SEQ ID NO:241 , 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.

[0539] (24) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0540] HC-FR1 having the amino acid sequence of SEQ ID NO:213 HC-FR2 having the amino acid sequence of SEQ ID NO:223 HC-FR3 having the amino acid sequence of SEQ ID NO:233 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0541] (25) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0542] HC-FR1 having the amino acid sequence of SEQ ID NQ:206 HC-FR2 having the amino acid sequence of SEQ ID NO:224

[0543] HC-FR3 having the amino acid sequence of SEQ ID NO:234

[0544] HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0545] (26) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0546] HC-FR1 having the amino acid sequence of SEQ ID NO:214 HC-FR2 having the amino acid sequence of SEQ ID NO:211 HC-FR3 having the amino acid sequence of SEQ ID NQ:230 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0547] (27) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0548] HC-FR1 having the amino acid sequence of SEQ ID NO:215 HC-FR2 having the amino acid sequence of SEQ ID NO:225 HC-FR3 having the amino acid sequence of SEQ ID NO:235 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0549] (28) a yc-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0550] HC-FR1 having the amino acid sequence of SEQ ID NQ:206 HC-FR2 having the amino acid sequence of SEQ ID NO:222 HC-FR3 having the amino acid sequence of SEQ ID NO:236 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0551] (29) 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 (28) above.

[0552] In some embodiments, the antigen-binding molecule comprises a yc-binding moiety (e.g., a VHH, or a VH region):

[0553] (30) comprising the CDRs according to (1) and the FRs according to (13). (31) comprising the CDRs according to (1) and the FRs according to (17).

[0554] (32) comprising the CDRs according to (2) and the FRs according to (14).

[0555] (33) comprising the CDRs according to (2) and the FRs according to (15).

[0556] (34) comprising the CDRs according to (2) and the FRs according to (18).

[0557] (35) comprising the CDRs according to (3) and the FRs according to (16).

[0558] (36) comprising the CDRs according to (3) and the FRs according to (19).

[0559] (37) comprising the CDRs according to (4) and the FRs according to (20).

[0560] (38) comprising the CDRs according to (5) and the FRs according to (21).

[0561] (39) comprising the CDRs according to (6) and the FRs according to (22).

[0562] (40) comprising the CDRs according to (7) and the FRs according to (23).

[0563] (41) comprising the CDRs according to (8) and the FRs according to (24).

[0564] (42) comprising the CDRs according to (9) and the FRs according to (25).

[0565] (43) comprising the CDRs according to (10) and the FRs according to (26).

[0566] (44) comprising the CDRs according to (11) and the FRs according to (27).

[0567] (45) comprising the CDRs according to (12) and the FRs according to (28).

[0568] (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 NO:253, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, 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.

[0569] (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 NO:253, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, or SEQ ID NO:173. (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:253, SEQ ID NO:245, SEQ ID NO:246, or SEQ ID NO:247.

[0570] (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:253.

[0571] (50) 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:173.

[0572] In some embodiments, the antigen-binding molecule comprises an IL-7Ra-binding moiety.

[0573] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0574] (51) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0575] HC-CDR1 having the amino acid sequence of SEQ ID NO:96 HC-CDR2 having the amino acid sequence of SEQ ID NO:97 HC-CDR3 having the amino acid sequence of SEQ ID NO:98, 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.

[0576] (52) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0577] HC-CDR1 having the amino acid sequence of SEQ ID NO:93 HC-CDR2 having the amino acid sequence of SEQ ID NO:94 HC-CDR3 having the amino acid sequence of SEQ ID NO:95, 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.

[0578] (53) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0579] HC-CDR1 having the amino acid sequence of SEQ ID NO:99 HC-CDR2 having the amino acid sequence of SEQ ID NQ:100 HC-CDR3 having the amino acid sequence of SEQ ID NQ:101 , 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. (54) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0580] HC-CDR1 having the amino acid sequence of SEQ ID NO:102 HC-CDR2 having the amino acid sequence of SEQ ID NO:103 HC-CDR3 having the amino acid sequence of SEQ ID NQ:104, 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.

[0581] (55) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0582] HC-CDR1 having the amino acid sequence of SEQ ID NQ:105

[0583] HC-CDR2 having the amino acid sequence of SEQ ID NQ:106

[0584] HC-CDR3 having the amino acid sequence of SEQ ID NQ:107, 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.

[0585] (56) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0586] HC-CDR1 having the amino acid sequence of SEQ ID NQ:108

[0587] HC-CDR2 having the amino acid sequence of SEQ ID NQ:109

[0588] HC-CDR3 having the amino acid sequence of SEQ ID NO:110, 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.

[0589] (57) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0590] HC-CDR1 having the amino acid sequence of SEQ ID NO:111 HC-CDR2 having the amino acid sequence of SEQ ID NO:112 HC-CDR3 having the amino acid sequence of SEQ ID NO:113, 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.

[0591] (58) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0592] HC-CDR1 having the amino acid sequence of SEQ ID NO:111 HC-CDR2 having the amino acid sequence of SEQ ID NO:114 HC-CDR3 having the amino acid sequence of SEQ ID NO:115, 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.

[0593] (59) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0594] HC-CDR1 having the amino acid sequence of SEQ ID NO:116 HC-CDR2 having the amino acid sequence of SEQ ID NO:117

[0595] HC-CDR3 having the amino acid sequence of SEQ ID NO:118, 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.

[0596] (60) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following CDRs:

[0597] HC-CDR1 having the amino acid sequence of SEQ ID NO:119 HC-CDR2 having the amino acid sequence of SEQ ID NQ:120 HC-CDR3 having the amino acid sequence of SEQ ID NO:118, 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.

[0598] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0599] (61) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0600] HC-FR1 having the amino acid sequence of SEQ ID NO:216

[0601] HC-FR2 having the amino acid sequence of SEQ ID NO:126

[0602] HC-FR3 having the amino acid sequence of SEQ ID NO:144

[0603] HC-FR4 having the amino acid sequence of SEQ ID NO:145, 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.

[0604] (62) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0605] HC-FR1 having the amino acid sequence of SEQ ID NQ:209

[0606] HC-FR2 having the amino acid sequence of SEQ ID NO:126

[0607] HC-FR3 having the amino acid sequence of SEQ ID NO:134

[0608] HC-FR4 having the amino acid sequence of SEQ ID NO:239, 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.

[0609] (63) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0610] HC-FR1 having the amino acid sequence of SEQ ID NQ:207

[0611] HC-FR2 having the amino acid sequence of SEQ ID NO:125

[0612] HC-FR3 having the amino acid sequence of SEQ ID NO:133

[0613] HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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. (64) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0614] HC-FR1 having the amino acid sequence of SEQ ID NO:121 HC-FR2 having the amino acid sequence of SEQ ID NO:127 HC-FR3 having the amino acid sequence of SEQ ID NO:135 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0615] (65) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0616] HC-FR1 having the amino acid sequence of SEQ ID NO:122

[0617] HC-FR2 having the amino acid sequence of SEQ ID NO:128 HC-FR3 having the amino acid sequence of SEQ ID NO:136 HC-FR4 having the amino acid sequence of SEQ ID NO:143, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0618] (66) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0619] HC-FR1 having the amino acid sequence of SEQ ID NO:123

[0620] HC-FR2 having the amino acid sequence of SEQ ID NO:129 HC-FR3 having the amino acid sequence of SEQ ID NO:137 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0621] (67) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0622] HC-FR1 having the amino acid sequence of SEQ ID NO:124

[0623] HC-FR2 having the amino acid sequence of SEQ ID NQ:130 HC-FR3 having the amino acid sequence of SEQ ID NO:138 HC-FR4 having the amino acid sequence of SEQ ID NO:143, 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.

[0624] (68) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0625] HC-FR1 having the amino acid sequence of SEQ ID NQ:206

[0626] HC-FR2 having the amino acid sequence of SEQ ID NO:128 HC-FR3 having the amino acid sequence of SEQ ID NO:139 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0627] (69) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0628] HC-FR1 having the amino acid sequence of SEQ ID NO:206 HC-FR2 having the amino acid sequence of SEQ ID NO:131 HC-FR3 having the amino acid sequence of SEQ ID NQ:140 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0629] (70) a IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0630] HC-FR1 having the amino acid sequence of SEQ ID NQ:206

[0631] HC-FR2 having the amino acid sequence of SEQ ID NO:132 HC-FR3 having the amino acid sequence of SEQ ID NO:141 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0632] (71) a IL-7Ra-binding moiety (e.g., a VHH, or a VH region) incorporating the following FRs:

[0633] HC-FR1 having the amino acid sequence of SEQ ID NQ:206

[0634] HC-FR2 having the amino acid sequence of SEQ ID NO:132 HC-FR3 having the amino acid sequence of SEQ ID NO:142 HC-FR4 having the amino acid sequence of SEQ ID NO:238, 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.

[0635] (72) In some embodiments, the antigen-binding molecule comprises an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (51) to (60) above, and the FRs according to any one of (61) to (71) above.

[0636] In some embodiments, the antigen-binding molecule comprises an IL-7Ra-binding moiety (e.g., a VHH, or a VH region):

[0637] (73) comprising the CDRs according to (51) and the FRs according to (61).

[0638] (74) comprising the CDRs according to (51) and the FRs according to (62). (75) comprising the CDRs according to (52) and the FRs according to (63).

[0639] (76) comprising the CDRs according to (53) and the FRs according to (64).

[0640] (77) comprising the CDRs according to (54) and the FRs according to (65).

[0641] (78) comprising the CDRs according to (55) and the FRs according to (66).

[0642] (79) comprising the CDRs according to (56) and the FRs according to (67).

[0643] (80) comprising the CDRs according to (57) and the FRs according to (68).

[0644] (81) comprising the CDRs according to (58) and the FRs according to (69).

[0645] (82) comprising the CDRs according to (59) and the FRs according to (70).

[0646] (83) comprising the CDRs according to (60) and the FRs according to (71).

[0647] (84) an IL-7Ra-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:254, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0648] (85) an IL-7Ra-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:254 or SEQ ID NO:26.

[0649] (86) an IL-7Ra-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:254.

[0650] (87) an IL-7Ra-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:26.

[0651] (88) In some embodiments, the antigen-binding molecule comprises:

[0652] (iii) a yc-binding moiety, and

[0653] (iv) an IL-7Ra-binding moiety. (89) In some embodiments, the antigen-binding molecule comprises:

[0654] (iii) a yc-binding moiety, and

[0655] (iv) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0656] (51) to (60) above.

[0657] (90) In some embodiments, the antigen-binding molecule comprises:

[0658] (iii) a yc-binding moiety, and

[0659] (iv) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0660] (51) to (60) above, and the FRs according to any one of (61) to (71) above.

[0661] (91) In some embodiments, the antigen-binding molecule comprises:

[0662] (iii) a yc-binding moiety, and

[0663] (iv) an IL-7Ra-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:254, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0664] (92) In some embodiments, the antigen-binding molecule comprises:

[0665] (iii) a yc-binding moiety, and

[0666] (iv) an IL-7Ra-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:254 or SEQ ID NO:26.

[0667] (93) In some embodiments, the antigen-binding molecule comprises:

[0668] (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[0669] (12) above, and

[0670] (iv) an IL-7Ra-binding moiety.

[0671] (94) In some embodiments, the antigen-binding molecule comprises:

[0672] (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[0673] (12) above, and the FRs according to any one of (13) to (28) above, and

[0674] (iv) an IL-7Ra-binding moiety.

[0675] (95) In some embodiments, the antigen-binding molecule comprises:

[0676] (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:253, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID 1X10:170, 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

[0677] (iv) an IL-7Ra-binding moiety.

[0678] (96) In some embodiments, the antigen-binding molecule comprises:

[0679] (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:253, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, or SEQ ID NO:173, and

[0680] (iv) an IL-7Ra-binding moiety.

[0681] (97) In some embodiments, the antigen-binding molecule comprises CDRs according to one of (1) to (12) above, and CDRs according to one of (51) to (60) above.

[0682] (98) In some embodiments, the antigen-binding molecule comprises:

[0683] (iii) a yc-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of (1) to

[0684] (12) above, and the FRs according to any one of (13) to (28) above, and

[0685] (iv) an IL-7Ra-binding moiety (e.g., a VHH, or a VH region) comprising the CDRs according to one of

[0686] (51) to (60) above, and the FRs according to any one of (61) to (71) above.

[0687] (99) In some embodiments, the antigen-binding molecule comprises:

[0688] (i) 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

[0689] NO:253, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:167, SEQ ID NO:168, SEQ ID

[0690] NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID

[0691] NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178, and

[0692] (ii) an IL-7Ra-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:254, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

[0693] (100) In some embodiments, the antigen-binding molecule comprises:

[0694] (i) 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:253, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, or SEQ ID NO:173, and

[0695] (ii) an IL-7Ra-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:254 or SEQ ID NO:26.

[0696] (101) 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:88, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NQ:40, SEQ ID NO:53, SEQ ID 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:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

[0697] (102) 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:88, SEQ ID NO:77, SEQ ID NO:67, SEQ ID NO:87, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

[0698] (103) 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:88, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

[0699] (104) 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:88 or SEQ ID NO:87

[0700] (105) 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:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

[0701] (106) 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:88. (107) 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:87.

[0702] (108) In some embodiments, the antigen-binding molecule comprises:

[0703] (i) 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:89, and

[0704] (ii) 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:90

[0705] (109) In some embodiments, the antigen-binding molecule comprises:

[0706] (i) 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:91 , and

[0707] (ii) 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:92.

[0708] In embodiments in accordance with the present disclosure, one or more amino acids are substituted with another amino acid. A substitution comprises substitution of an amino acid residue with a non-identical 'replacement' amino acid residue. A replacement amino acid residue of a substitution according to the present disclosure may be a naturally-occurring amino acid residue ( / .e. encoded by the genetic code) which is non-identical to the amino acid residue at the relevant position of the equivalent, unsubstituted amino acid sequence, selected from: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie): leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Vai). In some embodiments, a replacement amino acid may be a non-naturally occurring amino acid residue - i.e. an amino acid residue other than those recited in the preceding sentence. Examples of non-naturally occurring amino acid residues include norleucine, ornithine, norvaline, homoserine, aib, and other amino acid residue analogues such as those described in Ellman, et al., Meth. Enzym. 202 (1991) 301-336.

[0709] In some embodiments, a substitution may be biochemically conservative. In some embodiments, where an amino acid to be substituted is provided in one of rows 1 to 5 of the table below, the replacement amino acid of the substitution is another, non-identical amino acid provided in the same row:

[0710] By way of illustration, in some embodiments wherein substitution is of a Met residue, the replacement amino acid may be selected from Ala, Vai, Leu, lie, Trp, Tyr, Phe and Norleucine. In some embodiments, a replacement amino acid in a substitution may have the same side chain polarity as the amino acid residue it replaces. In some embodiments, a replacement amino acid in a substitution may have the same side chain charge (at pH 7.4) as the amino acid residue it replaces: That is, in some embodiments, a nonpolar amino acid is substituted with another, non-identical nonpolar amino acid. In some embodiments, a polar amino acid is substituted with another, non-identical polar amino acid. In some embodiments, an acidic polar amino acid is substituted with another, non-identical acidic polar amino acid. In some embodiments, a basic polar amino acid is substituted with another, nonidentical basic polar amino acid. In some embodiments, a neutral amino acid is substituted with another, non-identical neutral amino acid. In some embodiments, a positive amino acid is substituted with another, non-identical positive amino acid. In some embodiments, a negative amino acid is substituted with another, non-identical negative amino acid.

[0711] In some embodiments, substitution(s) may be functionally conservative. That is, in some embodiments, the substitution may not affect (or may not substantially affect) one or more functional properties (e.g. target binding) of the antigen-binding molecule comprising the substitution as compared to the equivalent unsubstituted molecule.

[0712] In some embodiments, substitution(s) may prevent / reduce degradation of the antigen-binding molecule. Degradation of an antigen-binding molecule may occur during manufacturing, processing, storage, handling and / or administration. The degradation may be physical and / or chemical. Degradation processes, e.g. chemical degradation processes, include oxidation, fragmentation, deamination, isomerisation, hydrolysis, deglycosylation, racemization, disulphide bond breakage and formation, Maillard reaction, and p-elimination.

[0713] Oxidation is one of the most common chemical modifications in monoclonal antibodies and may be induced by reactive oxygen species. Oxidation may occur at cysteine, methionine, tryptophan, tyrosine, lysine and other amino acid residues. Oxidation of amino acid residues may impact protein structure and / or function. In some embodiments, one or more amino acids are substituted with another amino acid to remove an oxidation site. In some embodiments, one or more amino acids susceptible to oxidation are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptible to oxidation). In some embodiments, one or more amino acids identified as being oxidised, or identified as being susceptible to oxidation, are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptible to oxidation).

[0714] Amino acid residues susceptible to oxidation may be identified e.g. by in silica methods (e.g. as reviewed in Vatsa S, Mabs, 2022, 14(1):2023938, which is hereby incorporated by reference in its entirety) or by forced oxidation assays (e.g. as reviewed in Nowak C et al, Mabs, 2017, 9(8): 1217-1230, and Dyck YFK et al, Bioengineering (Basel), 2019, 6(3):62, which are hereby incorporated by reference in their entirety).

[0715] The VH and VL region of an antigen-binding region of an antibody together constitute the Fv region. In some embodiments, the antigen-binding molecule according to the present disclosure comprises, or consists of, an Fv region. In some embodiments, the VH and VL regions of the Fv are provided as single polypeptide joined by a linker sequence, i.e. a single chain Fv (scFv).

[0716] The VL and light chain constant (CL) region, and the VH region and heavy chain constant 1 (CH1) region of an antigen-binding region of an antibody together constitute the Fab region. In some embodiments, the antigen-binding molecule comprises a Fab region comprising a VH, a CH1 , a VL and a CL (e.g. CK or CA). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CH1 (e.g. a VH-CH1 fusion polypeptide), and a polypeptide comprising a VL and a CL (e.g. a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CL (e.g. a VH-CL fusion polypeptide) and a polypeptide comprising a VL and a CH (e.g. a VL-CH1 fusion polypeptide); that is, in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1 , VL and CL regions of the Fab or CrossFab are provided as single polypeptides joined by linker regions, i.e. as a single chain Fab (scFab) or a single chain CrossFab (scCrossFab).

[0717] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, a whole antibody. As used herein, ‘whole antibody’ refers to an antibody having a structure which is substantially similar to the structure of an immunoglobulin (Ig). Different kinds of immunoglobulins and their structures are described e.g. in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202): S41-S52, which is hereby incorporated by reference in its entirety.

[0718] Immunoglobulins of type G (i.e. IgG) are -150 kDa glycoproteins comprising two heavy chains and two light chains. From N- to C-terminus, the heavy chains comprise a VH followed by a heavy chain constant region comprising three constant domains (CH1 , CH2, and CH3), and similarly the light chains comprise a VL followed by a CL. Depending on the heavy chain, immunoglobulins may be classed as IgG (e.g.

[0719] IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, Ig E, or IgM. The light chain may be kappa (K) or lambda (A).

[0720] Herein, a ‘CH2 domain’ refers to an amino acid sequence corresponding to the CH2 domain of an immunoglobulin (Ig). The CH2 domain is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant domain, according to the EU numbering system (described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85). A ‘CH3 domain’ refers to an amino acid sequence corresponding to the CH3 domain of an immunoglobulin (Ig). The CH3 domain is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant domain, according to the EU numbering system. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 domains of an immunoglobulin (Ig). The CH2-CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant domain, according to the EU numbering system.

[0721] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, Ig E, or IgM that binds to a target antigen.

[0722] In some embodiments, the antigen-binding molecule of the present disclosure comprises one or more regions (e.g. CH1 , CH2, CH3, etc.) of an immunoglobulin heavy chain constant sequence. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of an IgG (e.g. lgG1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE or IgM, e.g. a human IgG (e.g. hlgG1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlgE or hlgM. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of a human IgG 1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17). In some embodiments, the antigen-binding molecule is, or comprises, a monoclonal antibody, or an antigen-binding fragment thereof.

[0723] In some embodiments, the antigen-binding molecule is or comprises a fully human antibody / antibody fragment. A fully human antibody / antibody fragment may be encoded by human nucleic acid sequence(s). A fully human antibody / antibody fragment may be devoid of non-human amino acid sequences. Commonly employed techniques for the production of fully human antibodies include (i) phage display, in which human antibody genes are expressed in phage display libraries, and (ii) production of antibodies in transgenic mice engineered to have human antibody genes (described in Park and Smolen, Advances in Protein Chemistry (2001) 56: 369-421). Briefly, in the human antibody genephage display technique, genes encoding the VH and VL chains are generated by PCR amplification and cloning from ‘naive’ human lymphocytes, before being assembled into a library from which they can be expressed either as disulfide-linked Fab fragments or as single-chain Fv (scFv) fragments. The Fab- or scFv-encoding genes are fused to a surface coat protein of filamentous bacteriophage and Fab or scFv capable of binding to the target of interest can then be identified by screening the library with antigen. Molecular evolution or affinity maturation procedures can be employed to enhance the affinity of the Fab / scFv fragment. In the transgenic mouse technique, mice in which the endogenous murine Ig gene loci have been replaced by homologous recombination with their human homologues, are immunised with antigen, and monoclonal antibody is prepared by conventional hybridoma technology, to yield a fully human monoclonal antibody.

[0724] In some embodiments, the antigen-binding molecule of the present disclosure is a mouse antibody / antibody fragment. In some embodiments, the antibody / antibody fragment is obtained from phage display using a human naive antibody gene library.

[0725] In some embodiments, the antigen-binding molecule is a mouse / human chimeric antigen-binding molecule ( / .e. an antigen-binding molecule comprising mouse antibody variable domains and human antibody constant regions). In some embodiments, the antigen-binding molecule is a humanised antigenbinding molecule ( / .e. an antigen-binding molecule comprising variable domains derived by humanisation of the variable domains of an antibody from a non-human animal, e.g. a mouse) comprising mouse antibody variable domains and human antibody constant regions. In some embodiments, the antigenbinding molecule comprises mouse antibody CDRs and human antibody framework and constant regions.

[0726] Mouse / human chimeric antigen-binding molecules can be prepared from mouse antibodies by the process of chimerization, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 8 thereof, in particular section 3 of Chapter 8.

[0727] Humanised antigen-binding molecules can be prepared from mouse antibodies by the process of humanisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 7 thereof, in particular section 3.1 of Chapter 7 entitled ‘Antibody Humanization’. Techniques for antibody humanisation are also described e.g. in Safdari et al., Biotechnol Genet Eng Rev (2013) 29:175- 86.

[0728] Aspects of the present disclosure relate to multispecific antigen-binding molecules. By ‘multispecific’ it is meant that the antigen-binding molecule displays specific binding to more than one target. In some embodiments, the antigen-binding molecule is a bispecific antigen-binding molecule. In some embodiments, the antigen-binding molecule comprises at least two different antigen-binding domains ( / .e. at least two antigen-binding domains, e.g. comprising non-identical VHs and VLs).

[0729] In some embodiments, the antigen-binding molecule binds to yc and another target (e.g. an antigen other than yc), and so is at least bispecific. The term ‘bispecific’ means that the antigen-binding molecule is able to bind specifically to at least two distinct antigenic determinants.

[0730] It will be appreciated that an antigen-binding molecule according to the present disclosure (e.g. a multispecific antigen-binding molecule) may comprise antigen-binding molecules capable of binding to the targets for which the antigen-binding molecule is specific. For example, an antigen-binding molecule that binds to yc and an antigen other than yc may comprise: (i) an antigen-binding molecule that binds to yc, and (ii) an antigen-binding molecule that binds to an antigen other than yc.

[0731] It will also be appreciated that an antigen-binding molecule according to the present disclosure (e.g. a multispecific antigen-binding molecule) may comprise antigen-binding polypeptides or antigen-binding polypeptide complexes capable of binding to the targets for which the antigen-binding molecule is specific.

[0732] In some embodiments, a component antigen-binding molecule of a larger antigen-binding molecule (e.g. a multispecific antigen-binding molecule) may be referred to e.g. as an ‘antigen-binding domain’ or ‘antigen-binding region’ of the larger antigen-binding molecule.

[0733] In some embodiments, the antigen-binding molecule is an immune cell engager. Immune cell engagers are reviewed e.g. in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17: 418-434 and Ellerman, Methods (2019) 154:102-117, both of which are hereby incorporated by reference in their entirety.

[0734] Immune cell engager molecules comprise an antigen-binding region for a target antigen of interest, and an antigen-binding region for recruiting / engaging an immune cell of interest. Immune cell engagers recruit / engage immune cells through an antigen-binding region specific for an immune cell surface molecule.

[0735] Multispecific antigen-binding molecules according to the present disclosure may be provided in any suitable format, such as those formats described in described in Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212, which is hereby incorporated by reference in its entirety. Suitable formats include those shown in Figure 2 of Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212: antibody conjugates, e.g. lgG2, F(ab’)2 or CovX-Body; IgG or IgG-like molecules, e.g. IgG, chimeric IgG, KA-body common HC; CH1 / CL fusion proteins, e.g. scFv2-CH1 / CL, VHH2-CH1 / CL; ‘variable domain only’ bispecific antigen- binding molecules, e.g. tandem scFv (taFV), triplebodies, diabodies (Db), dsDb, Db(kih), DART, scDB, dsFv-dsFv, tandAbs, triple heads, tandem dAbA / HH, tertravalent dAb.VHH; Non-lg fusion proteins, e.g. scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL- Fab2-lgG-cytokine2, ImmTAC (TCR-scFv); modified Fc and CH3 fusion proteins, e.g. scFv-Fc(kih), scFv- Fc(CH3 charge pairs), scFv-Fc (EW-RVT), scFv-fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc(kih), scFv- Fc(kih)-Fv, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc (SEEDbody), DART- Fc, scFv-CH3(kih), TriFabs; Fc fusions, e.g. Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-lg, scFv2-Fcab; CH3 fusions, e.g. Dia-diabody, scDb-CH3; IgE / IgM CH2 fusions, e.g. scFv-EHD2-scFv, scFvMHD2-scFv; Fab fusion proteins, e.g. Fab-scFv (bibody), Fab-scFv2 (tribody), Fab- Fv, Fab-dsFv, Fab-VHH, orthogonal Fab-Fab; non-lg fusion proteins, e.g. DNL-Fabs, DNL-Fab2-scFv, DNL-Fab2-lgG-cytokine2; asymmetric IgG or IgG-like molecules, e.g. IgG(kih), IgG(kih) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMab, CrossMab(kih), scFab-lgG(kih), Fab-scFab-lgG(kih), orthogonal Fab IgG(kih), DuetMab, CH3 charge pairs + CH1 / CL charge pairs, hinge / CH3 charge pairs, SEED-body, Duobody, four-in-one-CrossMab(kih), LUZ-Y common LC; LUZ-Y scFab-IgG, FcFc*; appended and Fc-modified IgGs, e.g. lgG(kih)-Fv, IgG HA-TF-Fv, lgG(kih)scFab, scFab-Fc(kih)-scFv2, scFab-Fc(kih)-scFv, half DVD-lg, DVI-lg (four-in-one), CrossMab-Fab; modified Fc and CH3 fusion proteins, e.g. Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc-SEEDbody, TriFab; appended IgGs - HC fusions, e.g. IgG-HC, scFv, IgG-dAb, IgG-taFV, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaCp) Fab, scFv-HC-IgG, tandem Fab-IgG (orthogonal Fab), Fab-lgG(CaCp Fab), Fab-lgG(CR3), Fab-hinge-lgG(CR3); appended IgGs - LC fusions, e.g. IgG-scFv(LC), scFv(LC)-lgG, dAb-IgG; appended IgGs - HC and LC fusions, e.g. DVD-lg, TVD-lg, CODV-lg, scFv4-lgG, Zybody; Fc fusions, e.g. Fab-scFv- Fc, scFv4-lg; F(ab’)2 fusions, e.g. F(ab’)2-scFv2; CH1 / CL fusion proteins e.g. scFv2-CH1-hinge / CL; modified IgGs, e.g. DAF (two-in one-IgG), DutaMab, Mab2; and non-lg fusions, e.g. DNL-Fab4-lgG. The skilled person is readily able to design and produce multispecific antigen-binding molecules.

[0736] The present disclosure also provides Chimeric Antigen Receptors (CARs). CARs are recombinant receptors that provide both antigen-binding and T cell activating functions. CAR structure and engineering is reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1), hereby incorporated by reference in its entirety. CARs comprise an antigen-binding region linked to a cell membrane anchor region and a signalling region. An optional hinge region may provide separation between the antigen-binding region and cell membrane anchor region, and may act as a flexible linker.

[0737] The antigen-binding domain of a CAR according to the present disclosure comprises, or consists of, an antigen-binding molecule described herein. Accordingly, a CAR according to the present disclosure comprises an antigen-binding molecule as described herein.

[0738] It will be appreciated that an antigen-binding molecule according to the present disclosure forms, or is comprised in, the antigen-binding domain of the CAR. Accordingly, in some embodiments, the antigenbinding molecule of the present disclosure is comprised in a CAR.

[0739] It will also be appreciated that an antigen-binding molecule according to the present disclosure may be a CAR. A CAR having an antigen-binding domain comprising, or consisting of, an antigen-binding molecule of the present disclosure is an antigen-binding molecule. The antigen-binding domain of the CAR of the present disclosure may be provided with any suitable format, e.g. scFv, scFab, etc.

[0740] The cell membrane anchor region is provided between the antigen-binding region and the signalling region of the CAR and provides for anchoring the CAR to the cell membrane of a cell expressing a CAR, with the antigen-binding region in the extracellular space, and signalling region inside the cell. In some embodiments, the CAR comprises a cell membrane anchor region comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the transmembrane region amino acid sequence for one of CD3- , CD4, CD8 or CD28. As used herein, a region which is ‘derived from’ a reference amino acid sequence comprises an amino acid sequence having at least 60%, e.g. one of at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the reference sequence.

[0741] The signalling region of a CAR allows for activation of the T cell. The CAR signalling regions may comprise the amino acid sequence of the intracellular domain of CD3- , which provides immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation and activation of the CAR-expressing T cell. Signalling regions comprising sequences of other ITAM-containing proteins such as FcyRI have also been employed in CARs (Haynes et al., 2001 J Immunol 166(1 ):182-187). Signalling regions of CARs may also comprise co-stimulatory sequences derived from the signalling region of co-stimulatory molecules, to facilitate activation of CAR-expressing T cells upon binding to the target protein. Suitable co-stimulatory molecules include CD28, 0X40, 4-1 BB, ICOS and CD27. In some cases, CARs are engineered to provide for co-stimulation of different intracellular signalling pathways. For example, signalling associated with CD28 costimulation preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway, whereas 4-1 BB-mediated signalling is through TNF receptor associated factor (TRAF) adaptor proteins. Signalling regions of CARs therefore sometimes contain co-stimulatory sequences derived from signalling regions of more than one co-stimulatory molecule. In some embodiments, the CAR of the present disclosure comprises one or more co-stimulatory sequences comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the intracellular domain of one or more of CD28, 0X40, 4-1 BB, ICOS and CD27.

[0742] An optional hinge region may provide separation between the antigen-binding domain and the transmembrane domain, and may act as a flexible linker. Hinge regions may be derived from IgG 1 or lgG4. In some embodiments, the CAR of the present disclosure comprises a hinge region comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the hinge region of IgG 1 or lgG4.

[0743] Also provided is a cell comprising a CAR according to the present disclosure. The CAR according to the present disclosure may be used to generate CAR-expressing immune cells, e.g. CAR-T or CAR-NK cells. Engineering of CARs into immune cells may be performed during culture, in vitro.

[0744] Fc regions

[0745] In some embodiments, the antigen-binding molecules of the present disclosure comprise an Fc region. In some embodiments, the antigen-binding molecules of the present disclosure do not comprise an Fc region.

[0746] As used herein, an ‘Fc region’ refers to a polypeptide complex formed by interaction between two polypeptides, each polypeptide comprising the CH2-CH3 region of an immunoglobulin (Ig) heavy chain constant sequence.

[0747] Herein, a ‘CH2 region’ refers to an amino acid sequence corresponding to the CH2 region of an immunoglobulin (Ig). The CH2 region is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1):78-85. A ‘CH3 region’ refers to an amino acid sequence corresponding to the CH3 region of an immunoglobulin (Ig). The CH3 region is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1):78-85. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 regions of an immunoglobulin (Ig). The CH2- CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1)78-85.

[0748] In some embodiments, a CH2 region, CH3 region and / or a CH2-CH3 region according to the present disclosure corresponds to the CH2 region / CH3 region / CH2-CH3 region of an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE or IgM. In some embodiments, the CH2 region, CH3 region and / or the CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human IgG (e.g. hlgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlgE or hlgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human IgG 1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17).

[0749] In some embodiments, a CH2-CH3 polypeptide is a polypeptide comprising the amino acid sequence of a CH2-CH3 region described herein. In some embodiments, a CH2-CH3 polypeptide is a polypeptide comprising the amino acid sequence of an IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE or IgM CH2-CH3 region. In some embodiments, a CH2-CH3 polypeptide comprises a substitution that is disclosed herein (relative to the amino acid sequence of a CH2-CH3 region of a reference Fc region).

[0750] In some embodiments, the antigen-binding molecule of the present disclosure is provided with an Fc region comprising the ‘knob-into-hole’ or ‘KiH ’ modification, e.g. as described e.g. in US 7,695,936 and Carter, J Immunol Meth. (2001) 2487-15. In some embodiments, the CH2-CH3 polypeptide comprises a ‘knob’ modification. In some embodiments, the CH2-CH3 polypeptide comprises a ‘hole’ modification. In some embodiments, the antigen-binding molecule comprises a CH2-CH3 polypeptide comprising a ‘knob’ modification and a CH2-CH3 polypeptide comprising a ‘hole’ modification. In some embodiments, the CH2-CH3 polypeptide comprises a substitution at position N297. In some embodiments, the CH2-CH3 polypeptide comprises a modification corresponding to N297A or N297Q or N297G as described in Leabman et al., MAbs. (2013) 5:896-903.

[0751] In some embodiments, the CH2-CH3 polypeptide comprises a YTE mutation. In some embodiments, the CH2-CH3 polypeptide comprises a substitution at position M252, S254, and / or T256. In some embodiments, the CH2-CH3 polypeptide comprises a modification corresponding to M252Y, S254T, and / or T256E. In some embodiments, the CH2-CH3 polypeptide comprises modification corresponding to the combination of substitutions M252Y / S254T / T256E as described in Dall’Acqua et al. J Immunol. (2002) 169:5171-5180.

[0752] In some embodiments, the CH2-CH3 polypeptide 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:242.

[0753] In some embodiments, the CH2-CH3 polypeptide 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:243.

[0754] In some embodiments, the CH2-CH3 polypeptide 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:244.

[0755] Fc regions provide for interaction with Fc receptors and other molecules of the immune system to bring about functional effects. Fc-mediated effector functions are reviewed e.g. in Jefferis et al., Immunol Rev (1998) 163:59-76 (hereby incorporated by reference in its entirety), and are brought about through Fc- mediated recruitment and activation of immune cells (e.g. macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells and T cells) through interaction between the Fc region and Fc receptors expressed by the immune cells, recruitment of complement pathway components through binding of the Fc region to complement protein C1q, and consequent activation of the complement cascade. Fc-mediated functions include Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), formation of the membrane attack complex (MAC), cell degranulation, cytokine and / or chemokine production, and antigen processing and presentation.

[0756] Modifications to antibody Fc regions that influence Fc-mediated functions are known in the art, such as those described e.g. in Wang et al., Protein Cell (2018) 9(1):63-73, which is hereby incorporated by reference in its entirety. Exemplary Fc region modifications known to influence antibody effector function are summarised in Table 1 of Wang et al., Protein Cell (2018) 9(1):63-73. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification to increase or reduce an Fc-mediated function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0757] Where an Fc region / CH2 / CH3 is described as comprising modification(s) ‘corresponding to’ reference substitution(s), equivalent substitution(s) in the homologous Fc / CH2 / CH3 are contemplated. By way of illustration, L234A / L235A substitutions in human IgG 1 (numbered according to the EU numbering system as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) correspond to L to A substitutions at positions 117 and 118 of the mouse Ig gamma-2A chain C region (UniProtKB: P01863-1 , v1).

[0758] Where an Fc region is described as comprising a modification, the modification may be present in one or both of the polypeptide chains which together form the Fc region.

[0759] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification in one or more of the CH2 and / or CH3 regions.

[0760] In some embodiments, the Fc region comprises modification to increase an Fc-mediated function. In some embodiments, the Fc region comprises modification to increase ADCC. In some embodiments, the Fc region comprises modification to increase ADCP. In some embodiments, the Fc region comprises modification to increase CDC. An antigen-binding molecule comprising an Fc region comprising modification to increase an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces an increased level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0761] In some embodiments, the Fc region comprises modification to increase binding to an Fc receptor. In some embodiments, the Fc region comprises modification to increase binding to an Fey receptor. In some embodiments, the Fc region comprises modification to increase binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region comprises modification to increase binding to FcyRllla. In some embodiments, the Fc region comprises modification to increase binding to FcyRlla. In some embodiments, the Fc region comprises modification to increase binding to FcyRllb. In some embodiments, the Fc region comprises modification to increase binding to FcRn. In some embodiments, the Fc region comprises modification to increase binding to a complement protein. In some embodiments, the Fc region comprises modification to increase binding to C1q. In some embodiments, the Fc region comprises modification to promote hexamerisation of the antigen-binding molecule. In some embodiments, the Fc region comprises modification to increase antigen-binding molecule half-life. In some embodiments, the Fc region comprises modification to increase coengagement.

[0762] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions F243L / R292P / Y300L / V305I / P396L as described in Stavenhagen et al. Cancer Res. (2007) 67:8882-8890. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S239D / I332E or S239D / I332E / A330L as described in Lazar et al., Proc Natl Acad Sci USA. (2006) 103:4005-4010. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S298A / E333A / K334A as described in Shields et al., J Biol Chem. (2001) 276:6591-6604. In some embodiments, the Fc region comprises modification to one of heavy chain polypeptides corresponding to the combination of substitutions L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and modification to the other heavy chain polypeptide corresponding to the combination of substitutions D270E / K326D / A330M / K334E, as described in Mimoto et al., MAbs. (2013) 5:229-236. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions G236A / S239D / I332E as described in Richards et al., Mol Cancer Ther. (2008) 7:2517-2527.

[0763] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions K326W / E333S as described in Idusogie et al. J Immunol. (2001) 166(4):2571-5. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / H268F / S324T as described in Moore et al. MAbs. (2010) 2(2):181-9. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Natsume et al., Cancer Res. (2008) 68(10):3863-72. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions E345R / E430G / S440Y as described in Diebolder et al. Science (2014) 343(6176):1260-3.

[0764] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M252Y / S254T / T256E as described in Dall’Acqua et al. J Immunol. (2002) 169:5171-5180. These so called ‘YTE’ modifications located at the CH2-CH3 interface of the Fc region have been shown to increase the binding affinity at pH 6.0 to the MHC Class I neonatal Fc receptor (FcRn), localised within the acidic endosomes of endothelial and haematopoietic cells, which increases efficient recycling of administered mAb and half-life in the plasma.

[0765] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M428L / N434S as described in Zalevsky et al. Nat Biotechnol. (2010) 28:157-159.

[0766] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / L328F as described in Chu et al., Mol Immunol. (2008) 45:3926-3933. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions N325S / L328F as described in Shang et al. Biol Chem. (2014) 289:15309-15318.

[0767] In some embodiments, the Fc region comprises modification to reduce / prevent an Fc-mediated function. In some embodiments, the Fc region comprises modification to reduce / prevent ADCC. In some embodiments, the Fc region comprises modification to reduce / prevent ADCP. In some embodiments, the Fc region comprises modification to reduce / prevent CDC. An antigen-binding molecule comprising an Fc region comprising modification to reduce / prevent an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces a reduced level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0768] In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fc receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fey receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRI I lb. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRllla. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRlla. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRllb. In some embodiments, the Fc region comprises modification to reduce / prevent binding to a complement protein. In some embodiments, the Fc region comprises modification to reduce / prevent binding to C1q. In some embodiments, the Fc region comprises modification to reduce / prevent glycosylation of the amino acid residue corresponding to N297.

[0769] In some embodiments, the Fc region is not able to induce one or more Fc-mediated functions ( / .e. lacks the ability to elicit the relevant Fc-mediated function(s)). Accordingly, antigen-binding molecules comprising such Fc regions also lack the ability to induce the relevant function(s). Such antigen-binding molecules may be described as being devoid of the relevant function(s).

[0770] In some embodiments, the Fc region is not able to induce ADCC. In some embodiments, the Fc region is not able to induce ADCP. In some embodiments, the Fc region is not able to induce CDC. In some embodiments, the Fc region is not able to induce ADCC and / or is not able to induce ADCP and / or is not able to induce CDC.

[0771] In some embodiments, the Fc region is not able to bind to an Fc receptor. In some embodiments, the Fc region is not able to bind to an Fey receptor. In some embodiments, the Fc region is not able to bind to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region is not able to bind to FcyRllla. In some embodiments, the Fc region is not able to bind to FcyRlla. In some embodiments, the Fc region is not able to bind to FcyRllb. In some embodiments, the Fc region is not able to bind to FcRn. In some embodiments, the Fc region is not able to bind to a complement protein. In some embodiments, the Fc region is not able to bind to C1q. In some embodiments, the Fc region is not glycosylated at the amino acid residue corresponding to N297.

[0772] In some embodiments, the Fc region comprises a modification corresponding to N297A, N297Q or N297G as described in Leabman et al., MAbs. (2013) 5:896-903. In some embodiments, the Fc region comprises a modification corresponding to L235E as described in Alegre et al., J Immunol. (1992) 148:3461-3468. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235A or F234A / L235A as described in Xu et al., Cell Immunol. (2000) 200:16-26. In some embodiments, the Fc region comprises modification corresponding to P329A or P329G as described in Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235A / P329G as described in Lo et al. J. Biol. Chem (2017) 292(9):3900-3908. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions described in Rother et al., Nat Biotechnol. (2007) 25:1256-1264. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions S228P / L235E as described in Newman et al., Clin. Immunol. (2001) 98:164-174. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions H268Q / V309L / A330S / P331S as described in An et al., MAbs. (2009) 1 :572-579. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions V234A / G237A / P238S / H268A / V309L / A330S / P331 S as described in Vafa et al., Methods. (2014) 65:114- 126. In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S as described in US 2015 / 0044231 A1.

[0773] The combination of substitutions ‘L234A / L235A’ and corresponding substitutions (such as e.g. F234A / L235A in human lgG4) are known to disrupt binding of Fc to Fey receptors and inhibit ADCC, ADCP, and also to reduce C1q binding and thus CDC (Schlothauer et al., Protein Engineering, Design and Selection (2016) 29(10):457-466, hereby incorporated by reference in entirety). The substitutions ‘P329G’ and ‘P329A’ reduce C1q binding (and thereby CDC). Substitution of ‘N297’ with ‘A’, ‘G’ or ‘Q’ is known to eliminate glycosylation, and thereby reduce Fc binding to C1q and Fey receptors, and thus CDC and ADCC. Lo et al. J. Biol. Chem (2017) 292(9) :3900-3908 (hereby incorporated by reference in its entirety) reports that the combination of substitutions L234A / L235A / P329G eliminated complement binding and fixation as well as Fey receptor dependent, antibody-dependent, cell-mediated cytotoxicity in both murine lgG2a and human lgG1.

[0774] The combination of substitutions L234A / L235E / G237A / A330S / P331S in lgG1 Fc is disclosed in US 2015 / 0044231 A1 to abolish induction of phagocytosis, ADCC and CDC.

[0775] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P as described in Silva et al., J Biol Chem. (2015) 290(9) :5462-5469. The substitution S228P in lgG4 Fc reduces Fab-arm exchange (Fab-arm exchange can be undesirable).

[0776] In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235A. In some embodiments, the Fc region comprises modification corresponding to the substitution P329G. In some embodiments, the Fc region comprises modification corresponding to the substitution N297Q.

[0777] In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235A / P329G.

[0778] In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235A / P329G / N297Q.

[0779] In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S. In some embodiments, the Fc region comprises a modification corresponding to the substitution S228P, e.g. in lgG4.

[0780] In some embodiments, the Fc region comprises a CH2-CH3 region comprising an amino acid difference at one or more of the following positions, relative to the amino acid sequence of a CH2-CH3 region of a reference Fc region: 234 or 235 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following specified amino acid residues: A234 or A235 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising A234 and A235. In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following amino acid substitutions, relative to the amino acid sequence of a CH2-CH3 region of the reference Fc region: L234A or L235A (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising the following amino acid substitutions, relative to the amino acid sequence of a CH2-CH3 region of the reference Fc region: L234A and L235A (according to the EU numbering system).

[0781] In some embodiments - particularly embodiments in which the antigen-binding molecule is a multispecific (e.g. bispecific) antigen-binding molecule - the antigen-binding molecule comprises an Fc region comprising modification in one or more of the CH2 and CH3 regions, promoting association of the Fc region. Recombinant co-expression of constituent polypeptides of an antigen-binding molecule and subsequent association leads to several possible combinations. To improve the yield of the desired combinations of polypeptides in antigen-binding molecules during recombinant production, it is advantageous to introduce Fc region modification(s) to promote association of the desired combination of heavy chain polypeptides. Modifications may promote e.g. hydrophobic and / or electrostatic interaction between CH2 and / or CH3 regions of different polypeptide chains. Suitable modifications are described e.g. in Ha et al., Front Immnol. (2016) 7:394, which is hereby incorporated by reference in its entirety.

[0782] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising paired substitutions in the CH3 regions of the Fc region according to one of the following formats, as shown in Table 1 of Ha et al., Front Immnol. (2016) 7:394: KiH, KiHs-s, HA-TF, ZW1 , 7.8.60, DD-KK, EW-RVT, EW-RVTs-s, SEED or A107.

[0783] In some embodiments, the multispecific (e.g. bispecific) antigen-binding molecule of the present disclosure is provided with an Fc region comprising the ‘knob-into-hole’ or ‘KiH’ modification, e.g. as described e.g. in US 7,695,936 and Carter, J Immunol Meth. (2001) 248:7-15. In such embodiments, one of the CH3 regions of the Fc region comprises a ‘knob’ modification, and the other CH3 region comprises a ‘hole’ modification. The ‘knob’ and ‘hole’ modifications are positioned within the respective CH3 regions so that the ‘knob’ can be positioned in the ‘hole’ in order to promote heterodimerisation (and inhibit homodimerisation) of the polypeptides, and / or stabilise heterodimers. Knobs are constructed by substituting amino acids having small chains with those having larger side chains (e.g. tyrosine or tryptophan). Holes are created by substituting amino acids having large side chains with those having smaller side chains (e.g. alanine or threonine). In some embodiments, one of the CH3 regions of the Fc region of the antigen-binding molecule of the present disclosure comprises the substitution (numbering of positions / substitutions in the Fc region herein is according to the EU numbering system as described in Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) T366W, and the other CH3 region of the Fc region comprises the substitution Y407V. In some embodiments, one of the CH3 regions of the Fc region of the antigen-binding molecule comprises the substitution T366W, and the other CH3 region of the Fc region comprises the substitutions T366S and L368A. In some embodiments, one of the CH3 regions of the Fc region of the antigen-binding molecule comprises the substitution T366W, and the other CH3 region of the Fc region comprises the substitutions Y407V, T366S and L368A.

[0784] In some embodiments, one of the CH3 regions comprises the substitution S354C, and the other CH3 region of the Fc region comprises the substitution Y349C. Introduction of these cysteine residues results in formation of a disulfide bridge between the two CH3 regions of the Fc region, further stabilizing the heterodimer (Carter, J Immunol Methods (2001) 248:7-15).

[0785] In some embodiments, one of the CH3 regions comprises the substitutions K392D and K409D, and the other CH3 region of the Fc region comprises the substitutions E356K and D399K. ‘DDKK’ knob-into-hole technology is described e.g. in WO 2014 / 131694 A1 , and promotes assembly of the heavy chains providing the complementary amino acid residues.

[0786] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region modified as described in Labrijn et al., Proc Natl Acad Sci USA. (2013) 110(13):5145-50, referred to as ‘Duobody’ format. In some embodiments one of the CH3 regions comprises the substitution K409R, and the other CH3 region of the Fc region comprises the substitution K405L.

[0787] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region modified as described in Strop et al., J Mol Biol. (2012) 420(3):204-19, so-called ‘EEE-RRR’ format. In some embodiments one of the CH3 regions comprises the substitutions D221 E, P228E and L368E, and the other CH3 region of the Fc region comprises the substitutions D221 R, P228R and K409R.

[0788] In some embodiments, the antigen-binding molecule comprises an Fc region comprising the ‘EW-RVT’ modification described in Choi et al., Mol Cancer Ther. (2013) 12(12):2748-59. In some embodiments one of the CH3 regions comprises the substitutions K360E and K409W, and the other CH3 region of the Fc region comprises the substitutions Q347R, D399V and F405T.

[0789] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising the ‘SEED’ modification as described in Davis et al., Protein Eng Des Sei. (2010) 23(4):195- 202, in which p-strand segments of human lgG1 CH3 and IgA CH3 are exchanged. In some embodiments, one of the CH3 regions of the Fc region comprises the substitutions S364H and F405A, and the other CH3 region of the Fc region comprises the substitutions Y349T and T394F (see e.g. Moore et al., MAbs (2011) 3(6):546-57).

[0790] In some embodiments, one of the CH3 regions of the Fc region comprises the substitutions T350V, L351 Y, F405A and Y407V, and the other CH3 region of the Fc region comprises the substitutions T350V, T366L, K392L and T394W (see e.g. Von Kreudenstein et al., MAbs (2013) 5(5):646-54).

[0791] In some embodiments, one of the CH3 regions of the Fc region comprises the substitutions K360D, D399M and Y407A, and the other CH3 region of the Fc region comprises the substitutions E345R, Q347R, T366V and K409V (see e.g. Leaver-Fay et al., Structure (2016) 24(4):641-51).

[0792] In some embodiments, one of the CH3 regions of the Fc region comprises the substitutions K370E and K409W, and the other CH3 region of the Fc region comprises the substitutions E357N, D399V and F405T (see e.g. Choi et al., PLoS One (2015) 10(12):e0145349).

[0793] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification to increase stability (e.g. thermostability and / or freeze-thaw stability). In some embodiments, the antigen-binding molecule comprises modification to one or more of the CH2 and CH3 regions to increase stability (e.g. thermostability and / or freeze-thaw stability).

[0794] In some embodiments, the antigen-binding molecule of the present disclosure comprises CH3 regions (e.g. within an Fc region, e.g. within CH2-CH3 regions forming an Fc region) comprising paired CH3 region 'KiH' or 'KiHs-s' modifications. Such paired CH3 regions may comprise a CH3 region comprising a knob modification, and a CH3 region comprising a hole modification.

[0795] In some embodiments, a CH3 region comprising a knob modification comprises a tryptophan or tyrosine residue at position 366 ( / .e. 366W or 366Y). In some embodiments, the knob modification is, or comprises, T366W or T366Y. In some embodiments, a CH3 region comprising a knob modification comprises 366W. In some embodiments, the knob modification is, or comprises, T366W.

[0796] In some embodiments, a CH3 region comprising a hole modification comprises 407V, 407A, 407S or 407T; 366S, 366V or 366A; and 368A, 368V, 368S or 368T. In some embodiments, the hole modification is, or comprises, Y407V, Y407A, Y407S or Y407T; T366S, T366V or T366A; and L368A, L368V, L368S or L368T. In some embodiments, a CH3 region comprising a hole modification comprises 407V, 366S and 368A. In some embodiments, the hole modification is, or comprises, Y407V, T366S, and L368A.

[0797] In some embodiments, the antigen-binding molecule of the present disclosure comprises a CH3 region(s) (e.g. within an Fc region, e.g. within CH2-CH3 region(s) of an Fc region) comprising modification for the formation of an interchain disulfide bond ( / .e. between polypeptides comprising CH2-CH3 regions forming the Fc region). Such modification may comprise the introduction of one or more cysteine residues into one or both of the CH3 regions of the constituent polypeptides of a polypeptide complex of the present disclosure. More particularly, such modification may have the result that the CH3:CH3 interface formed between the CH3 regions of polypeptides of polypeptide complexes of the present disclosure, comprises a disulfide bond formed between cysteine residues (one from each polypeptide). In some embodiments, one of the CH3 regions comprises 349C, and the other CH3 region comprises 354C. In some embodiments, one of the CH3 regions comprises Y349C, and the other CH3 region comprises S354C.

[0798] In some embodiments, a CH3 region comprising a knob modification comprises 366W and S354C. In some embodiments, a CH3 region comprising a hole modification comprises Y407V, T366S, L368A and Y349C.

[0799] Particular exemplary polypeptides and antigen-binding molecules

[0800] Multispecific antigen-binding molecules are provided. By ‘multispecific’ it is meant that the antigen-binding molecule displays specific binding to more than one target. In some embodiments, the antigen-binding molecule is a bispecific antigen-binding molecule.

[0801] In some embodiments, antigen-binding molecule binds to a first target antigen and a second target antigen. In some embodiments, the antigen-binding molecule comprises a first antigen-binding moiety, and a second antigen-binding moiety. In some embodiments, the first antigen-binding moiety binds a first target antigen, and the second antigen-binding moiety binds a second target antigen.

[0802] The target for the first antigen-binding moiety, and / or the second antigen-binding moiety may be any target antigen. In some embodiments, the first target antigen and / or the second target antigen is 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.

[0803] In some embodiments, the target antigen is a disease-associated antigen, or an antigen expressed by an immune cell.

[0804] 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.

[0805] 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. 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.

[0806] 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. 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.

[0807] 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.

[0808] 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.

[0809] In some embodiments, the first antigen is yc. In some embodiments, the first antigen is a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the first antigen is IL-7Ra, IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra. In some embodiments, the first antigen is IL-7Ra.

[0810] In some embodiments, the second antigen is yc. In some embodiments, the second antigen is a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the second antigen is IL-7Ra, IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra. In some embodiments, the second antigen is IL-7Ra.

[0811] In some embodiments, the first antigen is yc, and the second antigen is a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the first antigen is yc, and the second antigen is IL-7Ra, IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra. In some embodiments, the first antigen is yc, and the second antigen is IL-7Ra.

[0812] In some embodiments, the second antigen is yc, and the first antigen is a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the second antigen is yc, and the first antigen is IL-7Ra, IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra. In some embodiments, the second antigen is yc, and the first antigen is IL-7Ra.

[0813] Multispecific antigen-binding molecules may be provided in any format known to the skilled person. In some embodiments, the antigen-binding molecule is provided in a format shown in Figure 3. In some embodiments, the antigen-binding molecule is provided in a format disclosed in the Examples herein.

[0814] In some embodiments, the antigen-binding molecule is provided in Format B-1 , Format B-2, Format A-1 , Format A-2, or Format A-3 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format B-1 , Format B-2, Format A1 , Format A-2, or Format A-3 described herein.

[0815] In some embodiments, the antigen-binding molecule is provided in Format B-1 , Format B-2, Format A-2, or Format A-3 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format B-1 , Format B-2, Format A-2, or Format A-3 described herein.

[0816] In some embodiments, the antigen-binding molecule is provided in Format A-2 or Format A-3 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format A-2 or Format A-3 described herein.

[0817] In some embodiments, the antigen-binding molecule is provided in Format B-1 or Format B-2 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format B-1 or Format B-2 described herein.

[0818] In some embodiments, the antigen-binding molecule is provided in Format B-1 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format B-2 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format A-1 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format A-2 shown in Figure 2. In some embodiments, the antigen-binding molecule is provided in Format A-3 shown in Figure 2.

[0819] In some embodiments, the antigen-binding molecule is provided in Format B-1 described herein. In some embodiments, the antigen-binding molecule is provided in Format B-2 described herein. In some embodiments, the antigen-binding molecule is provided in Format A-1 described herein. In some embodiments, the antigen-binding molecule is provided in Format A-2 described herein. In some embodiments, the antigen-binding molecule is provided in Format A-3 described herein.

[0820] Format A-1 , Format A-2, and Format A-3 antigen-binding molecules comprise two symmetrical polypeptide chains. In some embodiments, Format A-1 , Format A-2, and Format A-3 antigen-binding molecules comprise two identical polypeptide chains.

[0821] Format B-1 and Format B-2 antigen-binding molecules comprise two non-identical polypeptide chains. Format B-1 and Format B-2 antigen-binding molecules are asymmetrical. In some embodiments, Format B-1 and Format B-2 antigen-binding molecules comprise two non-identical polypeptide chains, wherein one polypeptide chain comprises two antigen-binding moieties and the other polypeptide chain comprises zero antigen-binding moieties. In some embodiments, Format B-1 and Format B-2 antigen-binding molecules comprise two non-identical polypeptide chains, wherein one polypeptide chain comprises two antigen-binding VHH moieties, and the other polypeptide chain comprises zero VHH antigen-binding moieties. In some embodiments, the first polypeptide chain is designated as polypeptide chain A, and the second polypeptide chain is designated as polypeptide chain B.

[0822] In some embodiments, the antigen-binding molecule is provided in the format shown in Figure 11A. The format of the antigen-binding molecule shown in Figure 11A was designed by replacing one IL-7R binding arm of format A-3 (Figure 2) with a different IL-7Ra-binding VHH, meaning that the antigen-binding molecule comprises two different IL-7Ra-binding VHH molecules.

[0823] In some embodiments, the antigen-binding molecule comprises (i) a yc-binding moiety, (ii) a first IL-7Ra- binding moiety, and (iii) a second IL-7Ra-binding moiety.

[0824] In some embodiments, the antigen-binding molecule comprises a polypeptide chain comprising, from N- terminus to C-terminus:

[0825] (d) a first antigen-binding moiety,

[0826] (e) a CH2-CH3 polypeptide, and

[0827] (f) a second antigen-binding moiety.

[0828] In some embodiments, the antigen-binding molecule comprises a polypeptide chain comprising, from N- terminus to C-terminus:

[0829] (i) a first antigen-binding moiety (e.g., a yc-binding moiety),

[0830] (ii) a CH2-CH3 polypeptide, and

[0831] (iii) a second antigen-binding moiety (e.g., an IL-7Ra-binding moiety).

[0832] In some embodiments, the antigen-binding molecule comprises a polypeptide chain comprising, from N- terminus to C-terminus:

[0833] (i) a yc-binding moiety,

[0834] (ii) a CH2-CH3 polypeptide, and

[0835] (iii) an IL-7Ra-binding moiety.

[0836] In some embodiments, the antigen-binding molecule comprises a polypeptide chain (chain A) comprising, from N-terminus to C-terminus:

[0837] (i) a yc-binding moiety,

[0838] (ii) a CH2-CH3 polypeptide, and

[0839] (iii) an IL-7Ra-binding moiety. and a polypeptide chain (chain B) comprising, from N-terminus to C-terminus:

[0840] (i) a yc-binding moiety,

[0841] (ii) a CH2-CH3 polypeptide, and (iii) an IL-7Ra-binding moiety.

[0842] In some embodiments, the antigen-binding molecule comprises a polypeptide chain (chain A) comprising a first antigen-binding moiety, and a polypeptide chain (chain B) comprising a second antigen-binding moiety which binds to the same antigen as the first antigen-binding moiety of chain A (e.g., both bind to IL-7).

[0843] In some embodiments, the antigen-binding molecule comprises a polypeptide chain (chain A) comprising a first antigen-binding moiety, and a polypeptide chain (chain B) comprising a second antigen-binding moiety, wherein the first and second antigen-binding moieties bind to different regions of the same antigen (e.g., different regions of IL-7Ra).

[0844] In some embodiments, the antigen-binding molecule comprises a polypeptide chain (chain A) comprising a first IL-7Ra-binding moiety, and a polypeptide chain (chain B) comprising a second IL-7Ra-binding moiety. In some embodiments, the first and second anti IL-7Ra-binding moieties bind to different regions of IL-7Ra.

[0845] In some embodiments, the antigen-binding molecule comprises a polypeptide chain (chain A) comprising a first yc-binding moiety, and a polypeptide chain (chain B) comprising a second yc-binding moiety. In some embodiments, the first and second yc-binding moieties bind to different regions of yc.

[0846] In some embodiments, the antigen-binding molecule comprises a polypeptide chain (chain A) comprising, from N-terminus to C-terminus:

[0847] (i) a yc-binding moiety,

[0848] (ii) a CH2-CH3 polypeptide, and

[0849] (iii) a first IL-7Ra-binding moiety. and a polypeptide chain (chain B) comprising, from N-terminus to C-terminus:

[0850] (i) a yc-binding moiety,

[0851] (ii) a CH2-CH3 polypeptide, and

[0852] (iii) a second IL-7Ra-binding moiety.

[0853] In some embodiments, the first and second anti IL-7Ra-binding moieties bind to different regions of IL- 7Ra.

[0854] In some embodiments, a CH2-CH3 polypeptide is a polypeptide comprising the amino acid sequence of a CH2-CH3 region described herein.

[0855] In some embodiments, the chain A CH2-CH3 polypeptide comprises a ‘knob’ modification, and the chain B CH2-CH3 polypeptide comprises a ‘hole’ modification. In some embodiments, the chain B CH2-CH3 polypeptide comprises a ‘knob’ modification, and the chain A CH2-CH3 polypeptide comprises a ‘hole’ modification. In some embodiments, the second CH2-CH3 polypeptide is connected to an antigen-binding moiety. An example of this can be seen in Figure 2, for example on Chain A of the Format B-1 antigen binding molecule. In some embodiments, the second CH2-CH3 polypeptide is connected to two antigen-binding moieties.

[0856] In some embodiments, the CH2-CH3 polypeptide is connected to an antigen-binding moiety by a linker. In some embodiments, the CH2-CH3 polypeptide is connected to an antigen-binding moiety by a linker described herein. In some embodiments, the linker sequence has the structure: (GxS)n or (GxS)nGm; wherein G = glycine, S = serine, x = 3 or 4, n = 2, 3, 4, 5 or 6, and m = 0, 1 , 2 or 3. In some embodiments, the antigen-binding moiety is connected to an antigen-binding moiety by a GS linker, a GGGGS (SEQ ID NO:146) linker, a GGGGSGGGGS (SEQ ID NO:147) linker, a GGGGSGGGGSGGGGS (SEQ ID NO:219) linker, or a GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:148) linker.

[0857] In some embodiments, the CH2-CH3 polypeptide is connected to a first antigen-binding moiety by a GS linker or a GGGGS (SEQ ID NO:146) linker, and is connected to a second antigen-binding moiety by a GGGGSGGGGS (SEQ ID NO:147) linker, a GGGGSGGGGSGGGGS (SEQ ID NO:219) linker, or a GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:148) linker.

[0858] In some embodiments, the CH2-CH3 polypeptide is connected to a first antigen-binding moiety by a GGGGS (SEQ ID NO:146) linker, and is connected to a second antigen-binding moiety by a GGGGSGGGGSGGGGS (SEQ ID NO:219) linker.

[0859] In some embodiments, the CH2-CH3 polypeptide is connected to a second antigen-binding moiety by a GS linker or a GGGGS (SEQ ID NO:146) linker, and is connected to a first antigen-binding moiety by a GGGGSGGGGS (SEQ ID NO:147) linker, a GGGGSGGGGSGGGGS (SEQ ID NO:219) linker, or a GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:148) linker.

[0860] In some embodiments, the CH2-CH3 polypeptide is connected to a second antigen-binding moiety by a GGGGS (SEQ ID NO:146) linker, and is connected to a first antigen-binding moiety by a GGGGSGGGGSGGGGS (SEQ ID NO:219) linker.

[0861] In some embodiments, the second CH2-CH3 region polypeptide is not connected to an antigen-binding moiety. An example of this can be seen in Figure 2, for example on Chain B of the Format B-1 antigen binding molecule.

[0862] In some embodiments, the multispecific antigen-binding molecule comprises two polypeptide chains: polypeptide chain A and polypeptide chain B.

[0863] In some embodiments, the chain A polypeptide (or polypeptide chain A) comprises an antigen-binding moiety, and a CH2-CH3 polypeptide. In some embodiments, the chain A polypeptide (or polypeptide chain A) comprises one antigen-binding moiety, and a CH2-CH3 polypeptide. In some embodiments, the chain A polypeptide (or polypeptide chain A) comprises two antigen-binding moieties, and a CH2-CH3 polypeptide.

[0864] In some embodiments, the chain B polypeptide (or polypeptide chain B) comprises two antigen-binding moieties, and a CH2-CH3 polypeptide. In some embodiments, the chain B polypeptide (or polypeptide chain B) comprises an antigen-binding moiety, and a CH2-CH3 polypeptide. In some embodiments, the chain B polypeptide (or polypeptide chain B) comprises one antigen-binding moiety, and a CH2-CH3 polypeptide. In some embodiments, the chain B polypeptide (or polypeptide chain B) comprises two antigen-binding moieties, and a CH2-CH3 polypeptide.

[0865] In some embodiments, chain A is longer than chain B. In some embodiments, chain A comprises a yc- binding moiety, and chain B does not comprise a yc-binding moiety. In some embodiments, chain A comprises an IL-7Ra-binding moiety, and chain B does not comprise an IL-7Ra-binding moiety.

[0866] In some embodiments, the antigen-binding molecule comprises:

[0867] (i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:

[0868] (c) a first antigen-binding moiety,

[0869] (d) a CH2-CH3 polypeptide, and

[0870] (c) a second antigen-binding moiety; and

[0871] (ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

[0872] In some embodiments, the polypeptide chain B comprises an antigen-binding moiety.

[0873] In some embodiments, polypeptide chain B comprises, from N-terminus to C-terminus:

[0874] (a) a first antigen-binding moiety,

[0875] (b) a CH2-CH3 polypeptide, and

[0876] (c) a second antigen-binding moiety.

[0877] In some embodiments, the first antigen-binding moiety or the second antigen-binding moiety comprises a yc-binding moiety.

[0878] In some embodiments, the first antigen-binding moiety or the second antigen-binding moiety binds to a polypeptide of a yc-containing cytokine receptor other than yc. In some embodiments, the first antigenbinding moiety or the second antigen-binding moiety binds to IL-7Ra, IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, or IL-21 Ra. In some embodiments, the first antigen-binding moiety or the second antigen-binding moiety binds to IL-7Ra.

[0879] In some embodiments, the first antigen-binding moiety of polypeptide chain A binds the same target antigen as first antigen-binding moiety of polypeptide chain B. In some embodiments, the second antigenbinding moiety of chain A binds the same target antigen as second antigen-binding moiety of chain B. In some embodiments, the second antigen-binding moiety of chain A binds the same target antigen as second antigen-binding moiety of chain B. In some embodiments, the second antigen-binding moiety of chain A and the second antigen-binding moiety of chain B bind to different regions of the same target antigen. In some embodiments, the second antigen-binding moiety of chain A and the second antigenbinding moiety of chain B bind to different epitopes of the same target antigen.

[0880] In some embodiments, the second antigen-binding moiety of chain A and the second antigen-binding moiety of chain B both bind to IL-7Ra. In some embodiments, the second antigen-binding moiety of chain A and the second antigen-binding moiety of chain B bind to different regions of IL-7Ra. In some embodiments, the second antigen-binding moiety of chain A and the second antigen-binding moiety of chain B bind to different epitopes of IL-7Ra.

[0881] In some embodiments, the first antigen-binding moiety of polypeptide chain A and the first antigen-binding moiety of polypeptide chain B comprise the same CDR sequences. In some embodiments, the first antigen-binding moiety of polypeptide chain A and the first antigen-binding moiety of polypeptide chain B comprise the same FR sequences. In some embodiments, the first antigen-binding moiety of polypeptide chain A and the first antigen-binding moiety of polypeptide chain B comprise the same VHH sequences.

[0882] In some embodiments, the first antigen-binding moiety of polypeptide chain A and the first antigen-binding moiety of polypeptide chain B comprise different CDR sequences. In some embodiments, the first antigen-binding moiety of polypeptide chain A and the first antigen-binding moiety of polypeptide chain B comprise different FR sequences. In some embodiments, the first antigen-binding moiety of polypeptide chain A and the first antigen-binding moiety of polypeptide chain B comprise different VHH sequences.

[0883] In some embodiments, the second antigen-binding moiety of polypeptide chain A and the second antigenbinding moiety of polypeptide chain B comprise the same CDR sequences. In some embodiments, the second antigen-binding moiety of polypeptide chain A and the second antigen-binding moiety of polypeptide chain B comprise the same FR sequences. In some embodiments, the second antigenbinding moiety of polypeptide chain A and the second antigen-binding moiety of polypeptide chain B comprise the same VHH sequences.

[0884] In some embodiments, the second antigen-binding moiety of polypeptide chain A and the second antigenbinding moiety of polypeptide chain B comprise different CDR sequences. In some embodiments, the second antigen-binding moiety of polypeptide chain A and the second antigen-binding moiety of polypeptide chain B comprise different FR sequences. In some embodiments, the second antigen-binding moiety of polypeptide chain A and the second antigen-binding moiety of polypeptide chain B comprise different VHH sequences.

[0885] Functional properties of the antigen-binding molecules

[0886] Antigen-binding molecules described herein may be characterised by reference to certain functional properties. In some embodiments, an antigen-binding molecule described herein may possess one or more of the following properties: binds to a target antigen, binds to a first target antigen and a second target antigen, binds to yc; binds to a polypeptide of a yc-containing cytokine receptor other than yc; binds to IL-7Ra; binds to yc and a polypeptide of a yc-containing cytokine receptor other than yc; binds to yc and IL-7Ra; binds to human yc and a non-human primate yc, binds to human yc and rhesus yc, binds to human IL-7Ra and a non-human primate IL-7Ra, binds to human IL-7Ra and cynomolgous (cyno) IL-7Ra, binds to two different regions of IL-7Ra; competes with hu2RGT212 for yc binding; competes with 217P2P2_A6 for yc binding; competes with 217P2P2_C3 for yc binding; competes with Hu217P2P2_E2 for yc binding; competes with hu2WOM37 for IL-7Ra binding; competes with 6#P3P2_A9 for IL-7Ra binding; reduced cellular internalization; binds to yc-expressing cells; binds to cells expressing a polypeptide of a yc-containing cytokine receptor other than yc; binds to IL-7Ra-expressing cells; binds to cells expressing yc and a polypeptide of a yc-containing cytokine receptor other than yc; binds to cells expressing yc and IL-7Ra; binds to cells expressing a receptor comprising yc and a polypeptide of a yc-containing cytokine receptor other than yc; binds to cells expressing yc:IL-7Ra receptor; sequesters yc; decreases the amount of unbound yc; inhibits multimerization of yc; inhibits multimerization of yc and a polypeptide of IL-2Rp, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, and / or IL-21 Ra; inhibits multimerization of yc with another component of a yc-containing cytokine receptor, other than yc IL-7Ra; inhibits the formation of a heteromeric complex of yc and IL-2Ra, IL-2R0, IL-4Ra, IL-9Ra, IL- 15Ra, and / or IL-21 Ra; inhibits the formation of a heteromeric complex of yc and another component of a yc-containing cytokine receptor, other than IL-7Ra; inhibits signalling mediated by a polypeptide of the yc receptor family (e.g. selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21Ra and IL-7Ra); inhibits signalling mediated by IL-7Ra; inhibits signalling mediated by IL-4Ra; inhibits signalling mediated by IL-21 Ra; inhibits signalling mediated by IL-7Ra and signalling mediated by one or more of IL-2Ra, IL-2R0, IL-15Ra, IL-4Ra, IL-9Ra, and / or IL-21 Ra; inhibits IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL-21 mediated signalling; inhibits IL-7 mediated signalling; inhibits IL-4 mediated signalling; inhibits IL-21 mediated signalling; inhibits IL-7 mediated signalling and inhibits IL-2, IL-4, IL-9, IL-15, and / or IL-21 mediated signalling; inhibits IL-7 mediated signalling and inhibits IL-4 mediated signalling; inhibits IL-7 mediated signalling and inhibits IL-21 mediated signalling; does not agonise signalling mediated by one or more of IL-2Ra, IL-2RJ3, IL-15Ra, IL-4Ra, IL-9Ra, and / or IL-21 Ra; does not agonise signalling mediated by IL-4Ra; does not agonise signalling mediated by L-21 Ra;does not agonise IL-2, IL-4, IL-9, IL-15, and / or IL-21 mediated signalling; does not agonise IL-4 mediated signalling; does not agonise IL-21 mediated signalling; reduces non-specific agonism ( / .e., agonism of a polypeptide of the yc receptor family which is not IL-7Ra); reduces non-specific agonism of one or more of IL-2Ra, IL-2R0, IL-15Ra, IL-4Ra, IL-9Ra, and / or IL-21 Ra; reduces non-specific agonism of IL-4Ra; reduces non-specific agonism of IL-21 Ra; decreases multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R , IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra); decreases multimerization of yc and IL-7Ra; decreases signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor); decreases signalling mediated by a yc:IL-7Ra receptor; decreases proliferation, survival and / or effector activity of cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL- 21 Ra receptor and yc:IL-7Ra receptor); decreases proliferation, survival and / or effector activity of cells expressing IL-7Ra; reduces expression of one or more markers of immune cell exhaustion by cells expressing a yc- containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor); increases expression of one or more markers of immune cell exhaustion by cells expressing a yc- containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor); increases expression of one or more markers of immune cell exhaustion by cells expressing IL- 7Ra; decreases multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra), decreases signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor), and / or decreases proliferation, survival and / or effector activity of cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL- 2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL- 7Ra receptor) independently of Fc-mediated function; decreases multimerization of yc and IL-7Ra, decreases signalling mediated by yc:IL-7Ra receptor, and / or decreases proliferation, survival and / or effector activity of cells expressing yc:IL- 7Ra receptor, independently of Fc-mediated function; increases cell killi ng / depletion of, and / or reduces the number / proportion of, cells comprising / expressing one or more of the target antigens of its constituent antigen-binding moieties ( / .e. yc, and / or a polypeptide of a yc-containing cytokine receptor other than yc (e.g. selected from IL-2R , IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra, and IL-7Ra)); increases cell killi ng / depletion of, and / or reduces the number / proportion of, cells comprising / expressing yc, and / or IL-7Ra; increased stability and / or half-life compared to one or more yc family cytokines (e.g. IL-2, IL-15, IL-4, IL-9, IL-21 and / or IL-7); increased stability and / or half-life compared to IL-7; increased upregulation of signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21Ra receptor and yc:IL-7Ra receptor) compared to a cytokine that binds to the yc-containing cytokine receptor; increased upregulation of signalling mediated by yc:IL-7Ra receptor compared to IL-7; decreased upregulation of signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21Ra receptor and yc:IL-7Ra receptor) compared to a cytokine that binds to the yc-containing cytokine receptor; decreased upregulation of signalling mediated by a yc:IL-7Ra receptor compared to IL-7; increased upregulation of proliferation, survival and / or effector activity of cells expressing a yc- containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor) compared to a cytokine that binds to the yc- containing cytokine receptor; increased upregulation of proliferation, survival and / or effector activity of cells expressing a yc:IL- 7Ra receptor compared to IL-7; decreased upregulation of proliferation, survival and / or effector activity of cells expressing a yc- containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor) compared to a cytokine that binds to the yc- containing cytokine receptor; decreased upregulation of proliferation, survival and / or effector activity of cells expressing a yc:IL- 7Ra receptor compared to IL-7; increased downregulation of expression of one or more markers of immune cell exhaustion by cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor) compared to a cytokine that binds to the yc-containing cytokine receptor; increased downregulation of expression of one or more markers of immune cell exhaustion by cells expressing a yc:IL-7Ra receptor compared to IL-7; decreased downregulation of expression of one or more markers of immune cell exhaustion by cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor) compared to a cytokine that binds to the yc-containing cytokine receptor; decreased downregulation of expression of one or more markers of immune cell exhaustion by cells expressing a yc:IL-7Ra receptor compared to IL-7; and / or enhances anticancer activity of cancer antigen-specific immune cells, e.g. in vivo.

[0887] It will be appreciated that a given antigen-binding molecule may display more than one of the properties recited in the preceding paragraph. A given antigen-binding molecule may be evaluated for the properties recited in the preceding paragraph using suitable assays. For example, the assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays. In some embodiments, the assays may be e.g. in vivo assays, i.e. performed in non-human animals. In some embodiments, the assays may be e.g. ex vivo assays, i.e. performed using cells / tissue / an organ obtained from a subject. Such assays may be utilised to screen for antigen-binding molecules with a desired functional property.

[0888] Relevant benchmark control molecules (e.g., benchmark control antibodies) can be used as controls for the assessment relative increases / decreases in properties mentioned above. Suitable benchmark control molecules are described in the Examples herein. The benchmark control antibody may be an anti-IL-7R antibody (e.g., OSE-127, or Bempikibart).

[0889] Where assays are cell-based assays, they may comprise treating cells with a given antigen-binding molecule in order to determine whether the antigen-binding molecule displays one or more of the recited properties. Assays may employ species labelled with detectable entities in order to facilitate their detection. Assays may comprise evaluating the recited properties following treatment of cells separately with a range of quantities / concentrations of a given antigen-binding molecule (e.g. a dilution series). It will be appreciated that the cells preferably express the target antigen for the antigen-binding molecule. Analysis of the results of such assays may comprise determining the concentration at which 50% of the maximal level of the relevant activity is attained. The concentration of a given agent at which 50% of the maximal level of the relevant activity is attained may be referred to as the ‘half-maximal effective concentration’ of the agent in relation to the relevant activity, which may also be referred to as the ‘EC50’. By way of illustration, the EC50 of a given antigen-binding molecule for binding to human yc may be the concentration of the antigen-binding molecule at which 50% of the maximal level of binding to human yc is achieved.

[0890] Depending on the property, the EC50 may also be referred to as the ‘half-maximal inhibitory concentration’ or ‘IC50’, this being the concentration of the agent at which 50% of the maximal level of inhibition of a given property is observed.

[0891] In some embodiments, the ICso of the antigen-binding molecule is the concentration of the agent at which 50% of the maximal level of inhibition of STAT5 signalling is observed.

[0892] In some embodiments, the ICso of the antigen-binding molecule is the concentration of the agent at which 50% of the maximal level of inhibition of STAT5 signalling is observed in a given cell type. In some embodiments, the ICso of the antigen-binding molecule is the concentration of the agent at which 50% of the maximal level of inhibition of STAT5 signalling in cells expressing yc and IL-7Ra (herein termed yc:IL- 7Ra-STAT5 IC50) is observed.

[0893] IC50 is determined in an appropriate assay. For example, yc-containing cytokine receptor-mediated signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by the relevant receptor-mediated signalling. Additionally, yc-containing cytokine receptor-mediated signalling can be investigated using a reporter cell line which express a secretable reporter that can be quantitatively detected from the supernatant and can be readily measured (e.g., Cytokine Reporter Cells described and utilised in Example 4 herein).

[0894] The yc:IL-7Ra-STAT5 IC50 is determined in an appropriate assay. In some embodiments, the yc:IL-7Ra- STAT5 IC50 is determined using reporter-based methods. In some embodiments, the yc:IL-7Ra-STAT5 IC50 is determined using reporter cells expressing yc and IL-7Ra. In some embodiments, the yc:IL-7Ra- STAT5 IC50 is determined using reporter HEK Blue cells expressing yc and IL-7Ra.ln some embodiments, the yc:IL-7Ra-STAT5 IC50 is determined through the method used in Example 4 herein.

[0895] In some embodiments, the ICso of the antigen-binding molecule is lower than a known anti-IL-7Ra antibody. In some embodiments, the ICso of the antigen-binding molecule is lower than 500nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 400nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 300nM. In some embodiments, the ICso of the antigenbinding molecule is lower than 200nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 100nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 90nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 80nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 70nM. In some embodiments, the ICsoof the antigen-binding molecule is lower than 60nM. In some embodiments, the ICso of the antigenbinding molecule is lower than 50nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 40nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 30nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 20nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 15nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 14nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 13nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 12nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 11 nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 10nM. In some embodiments, the ICsoof the antigen-binding molecule is lower than 9nM. In some embodiments, the ICsoofthe antigenbinding molecule is lower than 8nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 7nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 6nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 5nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 4nM. In some embodiments, the ICsoof the antigenbinding molecule is lower than 3nM. In some embodiments, the ICso of the antigen-binding molecule is lower than 2nM.

[0896] In some embodiments, the yc:IL-7Ra-STAT5 ICso of the antigen-binding molecule is lower than a known anti-IL-7Ra antibody. In some embodiments, the yc:IL-7Ra-STAT5 ICso of the antigen-binding molecule is lower than 500nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 400nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 300nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 200nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 100nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 90nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 80nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 70nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 60nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 50nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 40nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 30nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 20nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 15nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 14nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 13nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 12nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 11 nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 10nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoofthe antigen-binding molecule is lower than 9nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 8nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 7nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 6nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 5nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 4nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 3nM. In some embodiments, the yc:IL-7Ra-STAT5 ICsoof the antigen-binding molecule is lower than 2nM.

[0897] Where the functional properties of agents are compared (e.g. where the antigen binding molecules of the present disclosure are compared with other polypeptides), comparisons are performed at equivalent concentrations and / or quantity of the relevant agents.

[0898] The antigen-binding molecules and antigen-binding moieties described herein preferably display specific binding to yc and / or IL-7Ra. As used herein, ‘specific binding’ refers to binding which is selective for the antigen, and which can be discriminated from non-specific binding to non-target antigen. An antigenbinding molecule / moiety that specifically binds to a target molecule preferably binds the target with greater affinity, and / or with greater duration than it binds to other, non-target molecules.

[0899] The ability of a given polypeptide to bind specifically to a given molecule can be determined by analysis according to methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol. (2012) 907:411-442), Bio-Layer Interferometry (BLI; see e.g. Lad et al., J Biomol Screen (2015) 20(4):498-507), flow cytometry, or by a radiolabeled antigen-binding assay (RIA) enzyme-linked immunosorbent assay. Through such analysis, binding to a given molecule can be measured and quantified. In some embodiments, the binding may be the response detected in a given assay.

[0900] In some embodiments, the extent of binding of the antigen-binding molecule / moiety to a non-target molecule is less than about 10% of the binding of the antigen-binding molecule / moiety to the target molecule as measured, e.g. by ELISA, SPR, BLI or by RIA. Alternatively, binding specificity may be reflected in terms of binding affinity where the antigen-binding molecule / moiety binds with a dissociation constant (KD) that is at least 0.1 order of magnitude ( / .e. 0.1 x 10n, where n is an integer representing the order of magnitude) greater than the KD of the antigen-binding molecule towards a non-target molecule. This may optionally be one of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .5, or 2.0.

[0901] Binding affinity of an antigen-binding molecule / moiety for its target is often described in terms of its dissociation constant (KD). Binding affinity can be measured by methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol (2012) 907:411-442; or Rich etal., Anal Biochem. (2008) 373(1):112-20), Bio-Layer Interferometry (see e.g. Lad et al., J Biomol Screen (2015) 20(4):498-507; or Concepcion et al., Comb Chem High Throughput Screen. (2009) 12(8)791-800), MicroScale Thermophoresis (MST) analysis (see e.g. Jerabek-Willemsen et al., Assay Drug Dev Technol. (2011) 9(4):342-353), or by a radiolabelled antigen-binding assay (RIA). In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-7Ra with an affinity in the micromolar range, i.e. KD = 9.9 x 104to 1 x 106M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-7Ra with sub-micromolar affinity, i.e. KD < 1 x 10-6M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-7Ra with an affinity in the nanomolar range, i.e. KD = 9.9 x 10-7to 1 x 10-9M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-7Ra with sub- nanomolar affinity, i.e. KD < 1 x 10-9M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-7Ra with an affinity in the picomolar range, i.e. KD = 9.9 x 1010to 1 x 1012M. In some embodiments, an antigen-binding molecule / moiety described herein binds to yc and / or IL-7Ra with sub-picomolar affinity, i.e. KD < 1 x 1012M.

[0902] The antigen-binding molecules and antigen-binding moieties of the present disclosure may bind to a particular region of interest of their target antigen(s). For example, they may bind to a linear epitope of yc and / or IL-7Ra, consisting of a contiguous sequence of amino acids (i.e. an amino acid primary sequence). In some embodiments, they may bind to a conformational epitope of yc and / or IL-7Ra, consisting of a discontinuous sequence of amino acids of the amino acid sequence.

[0903] Different epitopes of IL-7Ra are described in WO2015 / 189302 A1 and Hixon et al. Leukemia. 2020 Jan; 34(1):35-49. which are hereby incorporated by reference in their entirety. Known anti-IL-7Ra antibodies, 2B8 and 4A10, have two distinct binding epitopes on IL-7Ra. The 4A10 Fab was found to bind IL-7Ra at an epitope distal to the membrane, interacting with IL-7Ra residues from p-strands C1 , C’1 , E1 , and the corresponding loop region of the D1 domain. In contrast, the 2B8 Fab was found to bind IL-7Ra at a membrane proximal epitope, interacting with IL-7Ra residues from p-strands A2, G2, and the loop region of the D2 domain.

[0904] In some embodiments, the IL-7Ra-binding moiety binds the D1 epitope of IL-7Ra. In some embodiments, the IL-7Ra-binding moiety binds the 2b epitope of IL-7Ra.

[0905] In some embodiments, the IL-7Ra-binding moiety binds an epitope comprising an amino acid sequence having at least 70%, e.g. one of >80%, >85%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%, amino acid sequence identity to SEQ ID NO:255.

[0906] In some embodiments, the IL-7Ra-binding moiety binds an epitope comprising an amino acid sequence having at least 70%, e.g. one of >80%, >85%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%, amino acid sequence identity to SEQ ID NO:256.

[0907] In some embodiments, the IL-7Ra-binding moiety does not bind an epitope comprising an amino acid sequence having at least 70%, e.g. one of >80%, >85%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%, amino acid sequence identity to SEQ ID NO:255. In some embodiments, the IL-7Ra-binding moiety does not bind an epitope comprising an amino acid sequence having at least 70%, e.g. one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%, amino acid sequence identity to SEQ ID NO:256

[0908] In some embodiments, the IL-7Ra-binding moiety does not bind the D1 epitope of IL-7Ra (SEQ ID NO:255). In some embodiments, the IL-7Ra-binding moiety does not bind the 2b epitope of IL-7Ra (SEQ ID NO:256). In some embodiments, the IL-7Ra-binding moiety does not bind the D1 epitope or the 2b epitope of IL-7Ra.

[0909] The region of a given target molecule to which an antigen-binding molecule binds can be determined by the skilled person using various methods well known in the art, including X-ray co-crystallography analysis of antibody-antigen complexes, peptide scanning, mutagenesis mapping, hydrogen-deuterium exchange analysis by mass spectrometry, phage display, competition ELISA and proteolysis-based ‘protection’ methods. Such methods are described, for example, in Gershoni et al., BioDrugs (2007) 21 (3):145-156, which is hereby incorporated by reference in its entirety.

[0910] Competition between different antigen-binding molecules for the binding of an antigen can be determined using a number of methods known in the art, such as competition ELISA, and the methodology of Example 7 herein.

[0911] The antigen-binding molecules and antigen-binding moieties preferably bind to their target antigen(s) in a region which is accessible to an antigen-binding molecule ( / .e. an extracellular antigen-binding molecule) when the target antigen(s) is / are expressed at the cell surface ( / .e. in or at the cell membrane). In some embodiments, the antigen-binding molecules and antigen-binding moieties are capable of binding to their target antigen(s) when they are expressed at the cell surface.

[0912] The antigen-binding molecules and antigen-binding moieties preferably bind to the extracellular domain(s) of target antigen(s). The extracellular domains of yc and IL-7Ra are described hereinabove.

[0913] The antigen-binding molecules and antigen-binding moieties of the present disclosure may sequester yc. In this context, sequester means that the antigen-binding molecules and antigen-binding moieties bind yc and prevent yc from forming a complex with another polypeptide (e.g. a polypeptide of the yc receptor family selected from IL-2R0, IL-2Ra, IL-15Ra, IL-4Ra, IL-9Ra, IL-21 Ra and IL-7Ra). Therefore, antigenbinding molecules and antigen-binding moieties of the present disclosure decrease the amount of unbound yc and / or decrease the availability of yc. The availability of unbound yc, or the amount of sequestered yc can be assessed by a dual reporter assay where differential signals are read for IL7 or other yc ligation (Figure 2).

[0914] The antigen-binding molecule may bind to yc and / or IL-7Ra-expressing cells.

[0915] The antigen-binding molecule may bind to yc and / or IL-7Ra-expressing cells. Such cells include immune cells, e.g. effector immune cells. The immune cell may be a cell of hematopoietic origin, e.g. a neutrophil, eosinophil, basophil, dendritic cell, lymphocyte, or monocyte. A lymphocyte may be e.g. a T cell, B cell, NK cell, NKT cell or innate lymphoid cell (ILC), or a precursor thereof (e.g. a thymocyte or pre-B cell). The immune cell may express a CD3 polypeptide (e.g. CD3y CD3e CD3 or CD36), a TCR polypeptide (TCRa or TCRp), CD27, CD28, CD4 or CD8. In some embodiments, the immune cell is a T cell, e.g. a CD3+ T cell. In some embodiments, the T cell is a CD3+, CD4+ T cell. In some embodiments, the T cell is a CD3+, CD8+ T cell. In some embodiments, the T cell is a T helper cell (TH cell). In some embodiments, the T cell is a cytotoxic T cell (e.g. a cytotoxic T lymphocyte (CTL)). In some embodiments, the immune cell is a T cell or an NK cell.

[0916] An ‘effector immune cell’ may be an immune cell displaying an effector function. An effector immune cell may be a CD8+ T cell, CD8+ cytotoxic T lymphocyte (CD8+ CTL), CD4+ T cell, CD4+ T helper cell, NK cell, IFNy-producing cell, memory T cell, central memory T cell, antigen-experienced T cell or CD45RO+ T cell. An effector immune cell may be characterised by one or more of the following properties: granzyme B expression, IFNy expression, CD107a expression, IL-2 expression, TNFa expression, perforin expression, granulysin expression, and / or FAS ligand (FASL) expression. In some embodiments, an effector immune cell according to the present disclosure is a granzyme B-expressing cell.

[0917] The ability of an antigen-binding molecule to bind to a given cell type (e.g. a cell expressing one or more specified molecules, e.g. selected from yc and / or IL-7Ra can be analysed by contacting cells with the antigen-binding molecule, and detecting antigen-binding molecule bound to the cells, e.g. after a washing step to remove unbound antigen-binding molecule. The ability of an antigen-binding molecule to bind to yc and / or I L-7Ra-ex pressing cells can be analysed by methods such as flow cytometry and immunofluorescence microscopy.

[0918] In some embodiments, the antigen-binding molecule increases multimerization of yc and IL-7Ra. In some embodiments, the antigen-binding molecule decreases multimerization of yc and IL-7Ra.

[0919] As used herein, ‘multimerization’ refers to the formation of a multimeric polypeptide complex ( / .e. formed by non-covalent, protein: protein interaction, as described hereinabove). Multimers comprise two or more polypeptides, and may e.g. be dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers or decamers. Accordingly, multimerization may be dimerization, trimerization, tetramerization, etc.

[0920] It will be appreciated that the multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc is heteromultimerization, as the constituent polypeptides of the multimer are non-identical. Thus, the multimers formed by multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc in accordance with the present disclosure are heteromultimers, rather than homomultimers.

[0921] The antigen-binding molecules of the present disclosure may promote multimerization of yc and IL-7Ra through binding to the respective polypeptides, via its constituent antigen-binding moieties. Binding to yc and IL-7Ra brings the polypeptides into close physical proximity (e.g. within 50 Angstroms, e.g. within 40, 30, 25, 20, 15, 10 or 5 Angstroms), thereby facilitating their association.

[0922] The antigen-binding molecules of the present disclosure may inhibit multimerization of yc and a polypeptide of a yc-containing cytokine receptor other than yc through binding to and sequestering yc. This sequestration of yc decreases or inhibits the association of yc and polypeptides of a yc-containing cytokine receptor other than yc.

[0923] Antigen-binding molecules can be analysed for their ability to increase / promote or decrease / inhibit association between two polypeptides using techniques known to the skilled person. For example, cells expressing the relevant polypeptides can be contacted in vitro with a given test antigen-binding molecule, and association of the relevant polypeptides can thereafter be analysed. Suitable techniques to be employed in the analysis include e.g. resonance energy transfer techniques such as fluorescence resonance energy transfer (FRET) and Bioluminescence Resonance Energy Transfer (BRET), using appropriate labelled interaction partners, e.g. as described in Ciruela, Curr Opin Biotechnol. (2008) 19(4):338-43. Other suitable technologies include protein-fragment complementation systems, e.g. NanoLuc and NanoBiT, which are described e.g. in Thirukkumaran et al., Front Chem. (2020) 7:938 and Dixon et al., ACS Chem Biol. (2016) 11 (2):400-408.

[0924] An antigen-binding molecule according to the present disclosure may increase or decrease the level of multimerization relative to the level observed in the absence of the antigen-binding molecule, or in the presence of an appropriate control antigen-binding molecule (e.g. an antigen-binding molecule known not to influence multimerization of the relevant polypeptides). In some embodiments, an ‘increased’ level of multimerization refers to a level of multimerization which is greater than 1 times, e.g. one of >1 .01 times, >1 .02 times, >1 .03 times, >1.04 times, >1 .05 times, >1.1 times, >1 .2 times, >1 .3 times, >1.4 times, >1 .5 times, >1.6 times, >1.7 times, >1 .8 times, >1 .9 times, >2 times, >3 times, >4 times, >5 times, >6 times, >7 times, >8 times, >9 times or >10 times the level observed in the absence of the antigen-binding molecule, or in the presence of an appropriate control antigen-binding molecule (e.g. an antigen-binding molecule known not to influence multimerization of the relevant polypeptides). In some embodiments, a ‘decreased’ level of multimerization refers to a level of multimerization which is less than 1 times, e.g. one of e.g.

[0925] <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level observed in the absence of the antigenbinding molecule, or in the presence of an appropriate control antigen-binding molecule (e.g. an antigenbinding molecule known not to influence multimerization of the relevant polypeptides).

[0926] In some embodiments, the antigen-binding molecule increases signalling mediated by a yc-containing cytokine receptor (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor). It will be appreciated that the antigen-binding molecule increases signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds. That is, the antigen-binding molecule increases signalling mediated by a yc-containing cytokine receptor comprising or consisting of a polypeptide complex comprising the polypeptides for which the antigen-binding molecule comprises binding moieties. By way of illustration, in embodiments wherein the antigen-binding molecule comprises (i) a yc-binding moiety and (ii) an IL-7Ra - binding moiety, the antigen-binding molecule may increase signalling through a yc-containing cytokine receptor comprising yc and IL-7Ra, e.g. the yc:IL-7Ra receptor.

[0927] Such antigen-binding molecules may variously be described as ‘upregulating’, ‘inducing’, ‘enhancing’ ‘promoting’, ‘stimulating’, ‘triggering’ or ‘potentiating’ signalling mediated by the relevant yc-containing cytokine receptor. They may also be referred to as ‘agonists’ of, or having ‘agonistic’ or ‘activating’ activity with respect to, the relevant yc-containing cytokine receptor.

[0928] In some embodiments, the antigen-binding molecule decreases signalling mediated by a yc-containing cytokine receptor (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor). It will be appreciated that the antigen-binding molecule decreases signalling mediated by a yc-containing cytokine receptor to which the antigen-binding molecule binds. That is, the antigen-binding molecule decreases signalling mediated by a yc-containing cytokine receptor comprising or consisting of a polypeptide complex comprising the polypeptides for which the antigen-binding molecule comprises binding moieties. By way of illustration, in embodiments wherein the antigen-binding molecule comprises (i) a yc-binding moiety and (ii) an IL-7Ra- binding moiety, the antigen-binding molecule may decrease signalling through a yc-containing cytokine receptor comprising yc and IL-7Ra, e.g. the yc:IL-7Ra receptor. Such antigen-binding molecules may variously be described as ‘downregulating’, ‘preventing’, ‘diminishing’ ‘inhibiting’, ‘decreasing’, ‘attenuating’ ‘blocking’ or ‘reducing’ signalling mediated by the relevant yc-containing cytokine receptor.

[0929] They may also be referred to as ‘antagonists’ of, or having ‘antagonistic’ or ‘inhibitory’ activity with respect to, the relevant yc-containing cytokine receptor.

[0930] When the antigen binding molecule binds and sequesters yc, this reduces the availability of yc to form a heteromeric complex with a polypeptide of the yc receptor family (e.g., IL-2Ra, IL-2Rp, IL-4Ra, IL-7Ra, IL- 9Ra, IL-15Ra, or IL-21 Ra). Therefore, the disclosed antigen binding molecules may affect the signalling of all yc-associated cytokine receptors, not just IL-7Ra. As a result, non-specific agonism is prevented. In some embodiments, the disclosed antigen-binding molecules inhibit signalling mediated by IL-2Ra, IL- 2Rp, IL-4Ra, IL-7Ra, IL-9Ra, IL-15Ra, and / or IL-21 Ra. In some embodiments, IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL21 signalling is inhibited.

[0931] In some embodiments, signalling mediated by IL-7Ra is inhibited. In some embodiments, signalling mediated by IL-2Ra is inhibited. In some embodiments, signalling mediated by IL-2R0 is inhibited. In some embodiments, signalling mediated by IL-4Ra is inhibited. In some embodiments, signalling mediated by IL-15Ra is inhibited. In some embodiments, signalling mediated by IL-9Ra is inhibited. In some embodiments, signalling mediated by IL-21 Ra is inhibited.

[0932] In some embodiments, signalling mediated by IL-7Ra is inhibited and signalling of one or more of IL-2Ra, IL-2R0, IL-15Ra, IL-4Ra, IL-9Ra, and / or IL-21 Ra is also inhibited. In some embodiments, signalling mediated by IL-7Ra and IL-2Ra is inhibited. In some embodiments, signalling mediated by IL-7Ra and IL- 2Rp is inhibited. In some embodiments, signalling mediated by IL-7Ra and IL-15Ra is inhibited. In some embodiments, signalling mediated by IL-7Ra and IL-4Ra is inhibited. In some embodiments, signalling mediated by IL-7Ra and IL-9Ra is inhibited. In some embodiments, signalling mediated by IL-7Ra and IL- 21 Rci is inhibited. In some embodiments, signalling mediated by IL-7Ra, IL-2Ra, and IL-2R0 is inhibited.

[0933] In some embodiments, the antigen-binding molecule inhibits signalling mediated by a yc-containing cytokine receptor (e.g. selected from yc:IL-2Rp receptor, yc:IL-2Rp:IL-2Ra, yc:IL-2Rp:IL-15Ra, yc:IL-4Ra receptor, yc:IL-9Ra receptor, yc:IL-21 Ra receptor and yc:IL-7Ra receptor).

[0934] In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-2Rp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-2Rp:IL-2Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-2Rp:IL-15Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-4Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-9Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-21 Ra.

[0935] In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra and yc:IL- 2Rp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra and yc:IL-2Rp:IL-2Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra and yc:IL-2Rp:IL-15Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra and yc:IL-4Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra and yc:IL-9Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by yc:IL-7Ra and yc:IL-21 Ra.

[0936] Signalling mediated by a yc-containing cytokine receptor can be analysed using cells expressing the relevant receptor, e.g. using an assay for detecting and / or quantifying receptor-mediated signalling. Suitable assays include e.g. assays for detecting the phosphorylation / activity / expression of factors which are phosphorylated / activated / expressed as a consequence of signalling through the yc-containing cytokine receptor.

[0937] Such assays may comprise contacting cells expressing a given yc-containing cytokine receptor with an antigen-binding molecule according to the present disclosure. By way of illustration, an assay for investigating the ability of an antigen-binding molecule to increase yc: IL-7Ra-mediated signalling may comprise contacting cells expressing the yc: IL-7Ra receptor with an antigen-binding molecule comprising a yc-binding moiety and an IL-7Ra-binding moiety.

[0938] For example, yc-containing cytokine receptor-mediated signalling can be investigated by evaluating phosphorylation of one or more signal transduction molecules of a signal transduction pathway triggered by signalling through the relevant yc-containing cytokine receptor (e.g. the JAK / STAT, MAPK / ERK or PI3K / Akt pathways). For example, the level of yc-containing cytokine receptor-mediated signalling can be analysed by detection and / or quantification of the level of phosphorylation of STATI , STAT3, STAT5 and / or ERK (e.g. STAT5 and / or ERK).

[0939] In some embodiments, the antigen-binding molecule increases JAK / STAT signalling mediated by a yc:IL- 7Ra receptor. In some embodiments, the antigen-binding molecule increases MAPK / ERK signalling mediated by a yc:IL-7Ra receptor. In some embodiments, the antigen-binding molecule increases PI3K / Akt signalling mediated by a yc:IL-7Ra receptor.

[0940] In some embodiments, the antigen-binding molecule increases the phosphorylation of STAT 1 , STAT3, STAT5 and / or ERK. In some embodiments, the antigen-binding molecule increases the activation of STAT1 , STAT3, STAT5 and / or ERK. In some embodiments, the antigen-binding molecule increases STAT1 , STAT3, STAT5 and / or ERK activity.

[0941] In some embodiments, the antigen-binding molecule increases the phosphorylation of STAT5. In some embodiments, the antigen-binding molecule increases the activation of STAT5. In some embodiments, the antigen-binding molecule increases STAT5 activity.

[0942] In some embodiments, the antigen-binding molecule decreases JAK / STAT signalling mediated by a yc:IL- 7Ra receptor. In some embodiments, the antigen-binding molecule decreases MAPK / ERK signalling mediated by a yc:IL-7Ra receptor. In some embodiments, the antigen-binding molecule decreases PI3K / Akt signalling mediated by a yc:IL-7Ra receptor.

[0943] In some embodiments, the antigen-binding molecule decreases the phosphorylation of STATI , STAT3, STAT5 and / or ERK. In some embodiments, the antigen-binding molecule decreases the activation of STAT1 , STAT3, STAT5 and / or ERK. In some embodiments, the antigen-binding molecule decreases STAT1 , STAT3, STAT5 and / or ERK activity.

[0944] In some embodiments, the antigen-binding molecule decreases the phosphorylation of STAT5. In some embodiments, the antigen-binding molecule decreases the activation of STAT5. In some embodiments, the antigen-binding molecule decreases STAT5 activity.

[0945] The level of signalling mediated by a given yc-containing cytokine receptor can also be evaluated by analysing one or more correlates of signalling through the relevant receptor. For example, yc-containing cytokine receptor-mediated signalling may be investigated by detecting and / or quantifying the expression or activity of a factor whose expression / activity is upregulated or downregulated as a consequence of signalling through the relevant receptor. In some embodiments, yc-containing cytokine receptor-mediated signalling may be investigated by detecting and / or quantifying the expression of a factor whose expression is upregulated as a consequence of yc-containing cytokine receptor-mediated signalling.

[0946] The level of signalling mediated by a given yc-containing cytokine receptor can also be analysed using re porter- based methods. For example, yc-containing cytokine receptor-mediated signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by signalling through the relevant receptor-mediated signalling. Additionally, yc-containing cytokine receptor-mediated signalling can be investigated using a reporter cell line which express a secretable reporter that can be quantitatively detected from the supernatant and can be readily measured (e.g., Cytokine Reporter Cells described and utilised in Example 4).

[0947] In some embodiments, the antigen-binding molecule increases proliferation, survival and / or effector activity of cells expressing a yc-containing cytokine receptor to which the antigen-binding molecule binds (e.g. yc:IL-7Ra receptor). In some embodiments, the antigen-binding molecule decreases proliferation, survival and / or effector activity of cells expressing a yc-containing cytokine receptor to which the antigenbinding molecule binds (e.g. yc:IL-7Ra receptor). It will be appreciated that the increase / decrease in proliferation, survival and / or effector activity is a cellular-level functional consequence of increased / decreased signalling through the relevant yc-containing cytokine receptor.

[0948] In some embodiments, the antigen-binding molecule inhibits IL-7 signalling. In some embodiments, the antigen-binding molecule inhibits IL-2 signalling. In some embodiments, the antigen-binding molecule inhibits IL-4 signalling. In some embodiments, the antigen-binding molecule inhibits IL-9 signalling. In some embodiments, the antigen-binding molecule inhibits IL-15 signalling. In some embodiments, the antigen-binding molecule inhibits IL-21 signalling.

[0949] In some embodiments, the antigen-binding molecule inhibits IL-7 signalling and IL-2 signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 signalling and IL-4 signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 signalling and IL-9 signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 signalling and IL-15 signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 signalling and IL-21 signalling.

[0950] In some embodiments, the antigen-binding molecule inhibits IL-7 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-2 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-4 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-9 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-15 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-21 mediated signalling.

[0951] In some embodiments, the antigen-binding molecule inhibits IL-7 mediated signalling and IL-2 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 mediated signalling and IL-4 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 mediated signalling and IL-9 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 mediated signalling and IL-15 mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-7 mediated signalling and IL-21 mediated signalling.

[0952] Cytokine signalling can be analysed using cells expressing the relevant cytokine receptor, for example the relevant cytokine receptor for assaying IL-7 signalling would be the yc:IL-7Ra receptor. Suitable assays include e.g. assays for detecting the phosphorylation / activity / expression of factors which are phosphorylated / activated / expressed as a consequence of signalling through the yc-containing cytokine receptor.

[0953] For example, cytokine signalling can be investigated by evaluating phosphorylation of one or more signal transduction molecules of a signal transduction pathway triggered by signalling through the relevant yc- containing cytokine receptor (e.g. the JAK / STAT, MAPK / ERK or PI3K / Akt pathways). For example, the level of yc-containing cytokine receptor-mediated signalling can be analysed by detection and / or quantification of the level of phosphorylation of STAT1 , STAT3, STAT5 and / or ERK (e.g. STAT5 and / or ERK).

[0954] The level of cytokine signalling can also be evaluated by analysing one or more correlates of signalling through the relevant receptor. For example, signalling may be investigated by detecting and / or quantifying the expression or activity of a factor whose expression / activity is upregulated or downregulated as a consequence of the specific cytokine signalling. In some embodiments, cytokine signalling may be investigated by detecting and / or quantifying the expression of a factor whose expression is upregulated as a consequence of cytokine signalling (e.g. IL-2, IL-4, IL-7, IL-9, IL-15, and / or IL-21 signalling).

[0955] The level of signalling can also be analysed using reporter-based methods. For example, cytokine signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by the relevant receptor-mediated signalling.

[0956] The ability of an antigen-binding molecule to increase / decrease proliferation of cells expressing a given yc-containing cytokine receptor can be analysed by contacting cells with the antigen-binding molecule, and subsequently evaluating proliferation of the cells ( / .e. after a period of time sufficient for an effect on cell proliferation / survival to be observed). Cell proliferation can be evaluated e.g. by detecting changes in number of cells over time, or by in vitro analysis of incorporation of3H-thymidine or by CFSE dilution assay, e.g. as described in Fulcher and Wong, Immunol Cell Biol. (1999) 77(6):559-564, hereby incorporated by reference in entirety. Proliferating cells may also be identified by analysis of incorporation of 5-ethynyl-2'-deoxyuridine (EdU) by an appropriate assay, as described e.g. in Buck et al., Biotechniques. (2008) 44(7):927-9, and Sali and Mitchison, PNAS USA. (2008) 105(7):2415-2420. Survival of cells may be evaluated e.g. by labelling cells, and monitoring cell number over time.

[0957] Effector activity can be evaluated by analysing correlates of such activity. For example, the ability of an antigen-binding molecule to increase / decrease effector activity of cells expressing a given yc-containing cytokine receptor can be analysed by contacting cells with the antigen-binding molecule, and subsequently evaluating gene and / or protein expression of one or more effector molecules by the cells ( / .e. after a period of time sufficient for an effect on gene and / or protein expression of such factor...

Claims

Claims:

1. An antigen-binding molecule, optionally isolated, comprising:(i) a yc-binding moiety, and(ii) an IL-7Ra-binding moiety.

2. An antigen-binding molecule, optionally isolated, comprising an IL-7Ra-binding moiety.

3. An antigen-binding molecule, optionally isolated, comprising a yc-binding moiety.

4. The antigen binding molecule according to any one of claims 1 to 3, wherein the yc-binding moiety and / or the IL-7Ra-binding moiety comprises a VHH.

5. The antigen-binding molecule according claim 1 , claim 2, or claim 4, wherein the IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs:(a) CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98,(b) CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266 CDR3 having the amino acid sequence of SEQ ID NO:271 ,(c) CDR1 having the amino acid sequence of SEQ ID NO:93 CDR2 having the amino acid sequence of SEQ ID NO:94 CDR3 having the amino acid sequence of SEQ ID NO:95,(d) CDR1 having the amino acid sequence of SEQ ID NO:99 CDR2 having the amino acid sequence of SEQ ID NQ:100 CDR3 having the amino acid sequence of SEQ ID NQ:101 ,(e) CDR1 having the amino acid sequence of SEQ ID NQ:102 CDR2 having the amino acid sequence of SEQ ID NQ:103 CDR3 having the amino acid sequence of SEQ ID NQ:104,(f) CDR1 having the amino acid sequence of SEQ ID NQ:105 CDR2 having the amino acid sequence of SEQ ID NQ:106 CDR3 having the amino acid sequence of SEQ ID NQ:107,(g) CDR1 having the amino acid sequence of SEQ ID NQ:108 CDR2 having the amino acid sequence of SEQ ID NQ:109CDR3 having the amino acid sequence of SEQ ID NO:110,(h) CDR1 having the amino acid sequence of SEQ ID NO:111 CDR2 having the amino acid sequence of SEQ ID NO:112 CDR3 having the amino acid sequence of SEQ ID NO:113,(i) CDR1 having the amino acid sequence of SEQ ID NO:111 CDR2 having the amino acid sequence of SEQ ID NO:114 CDR3 having the amino acid sequence of SEQ ID NO:115,(j) CDR1 having the amino acid sequence of SEQ ID NO:116 CDR2 having the amino acid sequence of SEQ ID NO:117 CDR3 having the amino acid sequence of SEQ ID NO:118, or(k) CDR1 having the amino acid sequence of SEQ ID NO:119 CDR2 having the amino acid sequence of SEQ ID NQ:120 CDR3 having the amino acid sequence of SEQ ID NO:118.

6. The antigen-binding molecule according to any one of claims 1 , 2, 4, or 5 wherein the IL-7Ra-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:254, SEQ ID NO:379, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NQ:30, SEQ ID NO:31 , SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

7. The antigen-binding molecule according to any one of claims 1 , 2, or 4 to 6, wherein the IL-7Ra-binding moiety comprises a VH sequence incorporating the following FRs:(a) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:126 FR3 having the amino acid sequence of SEQ ID NO:144 FR4 having the amino acid sequence of SEQ ID NO:145,(b) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:276 FR3 having the amino acid sequence of SEQ ID NO:378 FR4 having the amino acid sequence of SEQ ID NO:282,(c) FR1 having the amino acid sequence of SEQ ID NQ:209 FR2 having the amino acid sequence of SEQ ID NO:126 FR3 having the amino acid sequence of SEQ ID NO:134 FR4 having the amino acid sequence of SEQ ID NO:239,(d) FR1 having the amino acid sequence of SEQ ID NO:207 FR2 having the amino acid sequence of SEQ ID NO:125 FR3 having the amino acid sequence of SEQ ID NO:133 FR4 having the amino acid sequence of SEQ ID NO:238,(e) FR1 having the amino acid sequence of SEQ ID NO:121 FR2 having the amino acid sequence of SEQ ID NO:127 FR3 having the amino acid sequence of SEQ ID NO:135 FR4 having the amino acid sequence of SEQ ID NO:238,(f) FR1 having the amino acid sequence of SEQ ID NO:122 FR2 having the amino acid sequence of SEQ ID NO:128 FR3 having the amino acid sequence of SEQ ID NO:136 FR4 having the amino acid sequence of SEQ ID NO:143,(g) FR1 having the amino acid sequence of SEQ ID NO:123 FR2 having the amino acid sequence of SEQ ID NO:129 FR3 having the amino acid sequence of SEQ ID NO:137 FR4 having the amino acid sequence of SEQ ID NO:238,(h) FR1 having the amino acid sequence of SEQ ID NO:124 FR2 having the amino acid sequence of SEQ ID NO:130 FR3 having the amino acid sequence of SEQ ID NO:138 FR4 having the amino acid sequence of SEQ ID NO:143,(i) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:128 FR3 having the amino acid sequence of SEQ ID NO:139 FR4 having the amino acid sequence of SEQ ID NO:238,(j) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:131 FR3 having the amino acid sequence of SEQ ID NQ:140 FR4 having the amino acid sequence of SEQ ID NO:238,(k) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:132 FR3 having the amino acid sequence of SEQ ID NO:141 FR4 having the amino acid sequence of SEQ ID NO:238, or(l) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:132FR3 having the amino acid sequence of SEQ ID NO:142FR4 having the amino acid sequence of SEQ ID NO:238.

8. The antigen-binding molecule according to any one of claims 1 , or 3 to 7, wherein the yc-binding moiety comprises a VH sequence incorporating the following CDRs:(a) CDR1 having the amino acid sequence of SEQ ID NO:261 CDR2 having the amino acid sequence of SEQ ID NO:265 CDR3 having the amino acid sequence of SEQ ID NO:269,(b) CDR1 having the amino acid sequence of SEQ ID NO:182 CDR2 having the amino acid sequence of SEQ ID NO:183 CDR3 having the amino acid sequence of SEQ ID NO:184,(c) CDR1 having the amino acid sequence of SEQ ID NO:259 CDR2 having the amino acid sequence of SEQ ID NO:263 CDR3 having the amino acid sequence of SEQ ID NO:267,(d) CDR1 having the amino acid sequence of SEQ ID NQ:260 CDR2 having the amino acid sequence of SEQ ID NO:264 CDR3 having the amino acid sequence of SEQ ID NO:268,(e) CDR1 having the amino acid sequence of SEQ ID NO:161 CDR2 having the amino acid sequence of SEQ ID NO:162 CDR3 having the amino acid sequence of SEQ ID NO:163,(f) CDR1 having the amino acid sequence of SEQ ID NO:164 CDR2 having the amino acid sequence of SEQ ID NO:165 CDR3 having the amino acid sequence of SEQ ID NO:166,(g) CDR1 having the amino acid sequence of SEQ ID NO:179 CDR2 having the amino acid sequence of SEQ ID NQ:180 CDR3 having the amino acid sequence of SEQ ID NO:181 ,(h) CDR1 having the amino acid sequence of SEQ ID NO:185 CDR2 having the amino acid sequence of SEQ ID NO:186 CDR3 having the amino acid sequence of SEQ ID NO:187,(i) CDR1 having the amino acid sequence of SEQ ID NO:188 CDR2 having the amino acid sequence of SEQ ID NO:189 CDR3 having the amino acid sequence of SEQ ID NQ:190,216(j) CDR1 having the amino acid sequence of SEQ ID NO:191 CDR2 having the amino acid sequence of SEQ ID NO:192 CDR3 having the amino acid sequence of SEQ ID NO:193,(k) CDR1 having the amino acid sequence of SEQ ID NO:194 CDR2 having the amino acid sequence of SEQ ID NO:195 CDR3 having the amino acid sequence of SEQ ID NO:196,(l) CDR1 having the amino acid sequence of SEQ ID NO:197 CDR2 having the amino acid sequence of SEQ ID NO:198 CDR3 having the amino acid sequence of SEQ ID NO:199,(m) CDR1 having the amino acid sequence of SEQ ID NQ:200 CDR2 having the amino acid sequence of SEQ ID NQ:201 CDR3 having the amino acid sequence of SEQ ID NQ:202, or(n) CDR1 having the amino acid sequence of SEQ ID NQ:203 CDR2 having the amino acid sequence of SEQ ID NQ:204 CDR3 having the amino acid sequence of SEQ ID NQ:205.

9. The antigen-binding molecule according to any one of claims 1 , or 3 to 8, 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:287, SEQ ID NO:253, SEQ ID NO:286, SEQ ID NO:284, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:167, SEQ IDNO:168, SEQ ID NO:169, SEQ ID NQ:170, SEQ ID NO:171 , SEQ ID NO:172, SEQ ID NO:173, SEQ IDNO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, or SEQ ID NO:178.

10. The antigen-binding molecule according to any one of claims 1 , or 3 to 9, wherein the yc-binding moiety comprises a VH sequence incorporating the following FRs:(a) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:275 FR3 having the amino acid sequence of SEQ ID NQ:280 FR4 having the amino acid sequence of SEQ ID NO:282,(b) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NQ:220 FR3 having the amino acid sequence of SEQ ID NO:237 FR4 having the amino acid sequence of SEQ ID NO:145,(c) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:272217FR3 having the amino acid sequence of SEQ ID NO:278FR4 having the amino acid sequence of SEQ ID NO:282,(d) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:273 FR3 having the amino acid sequence of SEQ ID NO:277 FR4 having the amino acid sequence of SEQ ID NO:238,(e) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:217 FR3 having the amino acid sequence of SEQ ID NO:248 FR4 having the amino acid sequence of SEQ ID NQ:250,(f) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:217 FR3 having the amino acid sequence of SEQ ID NO:249 FR4 having the amino acid sequence of SEQ ID NQ:250,(g) FR1 having the amino acid sequence of SEQ ID NO:216 FR2 having the amino acid sequence of SEQ ID NO:218 FR3 having the amino acid sequence of SEQ ID NO:251 FR4 having the amino acid sequence of SEQ ID NO:252,(h) FR1 having the amino acid sequence of SEQ ID NQ:209 FR2 having the amino acid sequence of SEQ ID NQ:220 FR3 having the amino acid sequence of SEQ ID NO:229 FR4 having the amino acid sequence of SEQ ID NO:239,(i) FR1 having the amino acid sequence of SEQ ID NQ:206 FR2 having the amino acid sequence of SEQ ID NO:217 FR3 having the amino acid sequence of SEQ ID NO:226 FR4 having the amino acid sequence of SEQ ID NO:238,(j) FR1 having the amino acid sequence of SEQ ID NQ:207 FR2 having the amino acid sequence of SEQ ID NO:218 FR3 having the amino acid sequence of SEQ ID NO:227 FR4 having the amino acid sequence of SEQ ID NO:238,(k) FR1 having the amino acid sequence of SEQ ID NQ:208 FR2 having the amino acid sequence of SEQ ID NO:128 FR3 having the amino acid sequence of SEQ ID NO:228 FR4 having the amino acid sequence of SEQ ID NO:238,218(I) FR1 having the amino acid sequence of SEQ ID NO:209FR2 having the amino acid sequence of SEQ ID NO:211FR3 having the amino acid sequence of SEQ ID NQ:230FR4 having the amino acid sequence of SEQ ID NO:238,(m) FR1 having the amino acid sequence of SEQ ID NO:212FR2 having the amino acid sequence of SEQ ID NO:221FR3 having the amino acid sequence of SEQ ID NO:231FR4 having the amino acid sequence of SEQ ID NO:238,(n) FR1 having the amino acid sequence of SEQ ID NQ:210FR2 having the amino acid sequence of SEQ ID NO:222FR3 having the amino acid sequence of SEQ ID NO:232FR4 having the amino acid sequence of SEQ ID NO:241 ,(o) FR1 having the amino acid sequence of SEQ ID NO:213FR2 having the amino acid sequence of SEQ ID NO:223FR3 having the amino acid sequence of SEQ ID NO:233FR4 having the amino acid sequence of SEQ ID NO:238,(P) FR1 having the amino acid sequence of SEQ ID NQ:206FR2 having the amino acid sequence of SEQ ID NO:224FR3 having the amino acid sequence of SEQ ID NO:234FR4 having the amino acid sequence of SEQ ID NO:238,(q) FR1 having the amino acid sequence of SEQ ID NO:214FR2 having the amino acid sequence of SEQ ID N0:211FR3 having the amino acid sequence of SEQ ID NQ:230FR4 having the amino acid sequence of SEQ ID NO:238,( FR1 having the amino acid sequence of SEQ ID NO:215FR2 having the amino acid sequence of SEQ ID NO:225FR3 having the amino acid sequence of SEQ ID NO:235FR4 having the amino acid sequence of SEQ ID NO:238, orFR1 having the amino acid sequence of SEQ ID NQ:206FR2 having the amino acid sequence of SEQ ID NO:222FR3 having the amino acid sequence of SEQ ID NO:236FR4 having the amino acid sequence of SEQ ID NO:23821911 . The antigen-binding molecule according to any one of claims 1 to 10, wherein the antigen-binding molecule comprises:(a) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:182CDR2 having the amino acid sequence of SEQ ID NO:183CDR3 having the amino acid sequence of SEQ ID NO:184, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:96CDR2 having the amino acid sequence of SEQ ID NO:97CDR3 having the amino acid sequence of SEQ ID NO:98,(b) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:261CDR2 having the amino acid sequence of SEQ ID NO:265CDR3 having the amino acid sequence of SEQ ID NO:269, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:96CDR2 having the amino acid sequence of SEQ ID NO:97CDR3 having the amino acid sequence of SEQ ID NO:98,(c) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:182CDR2 having the amino acid sequence of SEQ ID NO:183CDR3 having the amino acid sequence of SEQ ID NO:184, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:262CDR2 having the amino acid sequence of SEQ ID NO:266CDR3 having the amino acid sequence of SEQ ID NO:271 , or(d) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:261CDR2 having the amino acid sequence of SEQ ID NO:265CDR3 having the amino acid sequence of SEQ ID NO:269, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:262CDR2 having the amino acid sequence of SEQ ID NO:266 CDR3 having the amino acid sequence of SEQ ID NO:271 .

12. The antigen-binding molecule according to any one of claims 1 to 11 , wherein the antigen-binding molecule comprises a further IL-7Ra-binding moiety.22013. The antigen-binding molecule according to any one of claims 1 to 12, wherein the further IL-7Ra- binding moiety comprises:(a) a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:262CDR2 having the amino acid sequence of SEQ ID NO:266CDR3 having the amino acid sequence of SEQ ID NO:271 , or(b) a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:261CDR2 having the amino acid sequence of SEQ ID NO:265CDR3 having the amino acid sequence of SEQ ID NO:269.

14. The antigen-binding molecule according to any one of claims 1 to 13, wherein the antigen-binding molecule comprises:(a) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:182CDR2 having the amino acid sequence of SEQ ID NO:183CDR3 having the amino acid sequence of SEQ ID NO:184, a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:96CDR2 having the amino acid sequence of SEQ ID NO:97CDR3 having the amino acid sequence of SEQ ID NO:98, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:262CDR2 having the amino acid sequence of SEQ ID NO:266CDR3 having the amino acid sequence of SEQ ID NO:271 , or(b) a yc-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:261CDR2 having the amino acid sequence of SEQ ID NO:265CDR3 having the amino acid sequence of SEQ ID NO:269, a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:96CDR2 having the amino acid sequence of SEQ ID NO:97CDR3 having the amino acid sequence of SEQ ID NO:98, and a IL-7Ra-binding moiety comprising a VH sequence incorporating the following CDRs:CDR1 having the amino acid sequence of SEQ ID NO:262CDR2 having the amino acid sequence of SEQ ID NO:266CDR3 having the amino acid sequence of SEQ ID NO:27115. The antigen-binding molecule according to any one of claims 1 to 14, wherein the antigen-binding molecule comprises or consists of, an amino acid sequence having at least 70% sequence identity to the221amino acid sequence of SEQ ID NO:377, SEQ ID NO:289, SEQ ID NO:290, SEQ ID NO:291 , SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:294, SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298, SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301 , SEQ ID NQ:302, SEQ ID NO:88, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NQ:40, SEQ ID NO:53, SEQ ID 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:89, SEQ ID NQ:90, SEQ ID NO:91 , or SEQ ID NO:92.

16. The antigen-binding molecule according to any one of claims 1 to 15, wherein the antigen-binding molecule comprises a polypeptide chain comprising, from N-terminus to C-terminus:(a) a first antigen-binding moiety,(b) a CH2-CH3 polypeptide, and(c) a second antigen-binding moiety.

17. The antigen-binding molecule according to any one of claims 1 to 16, wherein the antigen-binding molecule comprises:(i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:(a) a first antigen-binding moiety,(b) a CH2-CH3 polypeptide, and(c) a second antigen-binding moiety; and(ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

18. The antigen binding molecule according to claim 17, wherein the polypeptide chain B comprises an antigen-binding moiety.

19. The antigen-binding molecule according to claim 17 or claim 18, wherein the polypeptide chain B comprises, from N-terminus to C-terminus:(a) a first antigen-binding moiety,(b) a CH2-CH3 polypeptide, and(c) a second antigen-binding moiety.

20. The antigen-binding molecule according to any one of claims 16 to 19, wherein the first antigenbinding moiety or the second antigen-binding moiety comprises a yc-binding moiety.21 . The antigen-binding molecule according to any one of claims 16 to 20, wherein the first antigenbinding moiety or the second antigen-binding moiety binds to a polypeptide of a yc-containing cytokine receptor other than yc.22222. The antigen-binding molecule according to any one of claims 16 to 20, wherein the first antigenbinding moiety or the second antigen-binding moiety comprises an IL-7Ra-binding moiety.

23. The antigen-binding molecule according to any one of claims 16 to 22, wherein the first antigenbinding moiety of polypeptide chain A binds the same target antigen as first antigen-binding moiety of polypeptide chain B, and / or wherein the second antigen-binding moiety of polypeptide chain A binds the same target antigen as second antigen-binding moiety of polypeptide chain B.

24. The antigen-binding molecule according to any one of claims 1 to 23, wherein the antigen-binding molecule comprises: a polypeptide chain comprising, from N-terminus to C-terminus:(a) a yc-binding moiety,(b) a CH2-CH3 polypeptide, and(c) an IL-7Ra-binding moiety.

25. The antigen-binding molecule according to any one of claims 1 to 23, wherein the antigen-binding molecule comprises: a polypeptide chain comprising, from N-terminus to C-terminus:(a) an IL-7Ra-binding moiety,(b) a CH2-CH3 polypeptide, and(c) a yc-binding moiety.

26. The antigen-binding molecule according to any one of claims 1 to 24, wherein the antigen-binding molecule comprises:(i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:(a) a yc-binding moiety,(b) a CH2-CH3 polypeptide, and(c) an IL-7Ra-binding moiety; and(ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

27. The antigen-binding molecule according to any one of claims 1 to 23 or claim 25, wherein the antigen-binding molecule comprises:(i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:(a) an IL-7Ra-binding moiety,(b) a CH2-CH3 polypeptide, and(c) a yc-binding moiety; and(ii) a polypeptide chain (polypeptide chain B) comprising a CH2-CH3 polypeptide.

28. The antigen-binding molecule according to any one of claims 1 to 27, wherein the antigen-binding molecule comprises:(i) a polypeptide chain (polypeptide chain A) comprising, from N-terminus to C-terminus:(c) a yc-binding moiety,223(d) a CH2-CH3 polypeptide, and(c) a first IL-7Ra-binding moiety; and(ii) a polypeptide chain (polypeptide chain B) comprising, from N-terminus to C-terminus:(c) a yc-binding moiety,(d) a CH2-CH3 polypeptide, and(c) a second IL-7Ra-binding moiety, wherein the first IL-7Ra-binding moiety and the second IL-7Ra-binding moiety comprise different VH sequences.

29. The antigen-binding molecule according to any one of claim 28, wherein the first IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98, and the second IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266 CDR3 having the amino acid sequence of SEQ ID NO:271 , or the first IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:262 CDR2 having the amino acid sequence of SEQ ID NO:266CDR3 having the amino acid sequence of SEQ ID NO:271 , and the second IL-7Ra-binding moiety comprises a VH sequence incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:96 CDR2 having the amino acid sequence of SEQ ID NO:97 CDR3 having the amino acid sequence of SEQ ID NO:98.

30. A chimeric antigen receptor (CAR), comprising an antigen-binding molecule according to any one of claims 1 to 29.31 . A nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule according to any one of claims 1 to 29, or a CAR according to claim 30.

32. An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 31 .

33. A cell comprising an antigen-binding molecule according to any one of claims 1 to 29, a CAR according to claim 30, a nucleic acid or a plurality of nucleic acids according to claim 31 , or an expression vector or a plurality of expression vectors according to claim 32.22434. A method comprising culturing a cell according to claim 33 under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

35. A composition comprising an antigen-binding molecule according to any one of claims 1 to 29, a CAR according to claim 30, a nucleic acid or a plurality of nucleic acids according to claim 31 , or an expression vector or a plurality of expression vectors according to claim 32, or a cell according to claim 33, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

36. An antigen-binding molecule according to any one of claims 1 to 29, a CAR according to claim 30, a nucleic acid or a plurality of nucleic acids according to claim 31 , or an expression vector or a plurality of expression vectors according to claim 32, or a cell according to claim 33, or a composition according to claim 35, for use in a method of treatment or prophylaxis.

37. Use of an antigen-binding molecule according to any one of claims 1 to 29, a CAR according to claim 30, a nucleic acid or a plurality of nucleic acids according to claim 31 , or an expression vector or a plurality of expression vectors according to claim 32, or a cell according to claim 33, or a composition according to claim 35, in the manufacture of a medicament for use in a method of treatment or prophylaxis.

38. 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 29, a CAR according to claim 30, a nucleic acid or a plurality of nucleic acids according to claim 31 , or an expression vector or a plurality of expression vectors according to claim 32, or a cell according to claim 33, or a composition according to claim 35.

39. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to claim 36, the use according to claim 37 or the method according to claim 38, 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 autoimmune disease.

40. 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 39, wherein the autoimmune disease is selected from Crohn’s disease, Sjogren’s syndrome, lupus, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, alopecia areata, psoriasis, psoriatic arthritis, myasthenia gravis, sarcoidosis, type 1 diabetes, ulcerative colitis, Addison’s disease, Graves’ disease, Hashimoto’s thyroiditis, autoimmune vasculitis, pernicious anemia, or celiac disease.41 . The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to claim 36, the use according to claim 37 or the method according to claim 38, wherein the method of treatment or prophylaxis is a method of treating or preventing a disease / condition characterised by inflammation.22542. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to any one of claims 36 or 39-41 , the use according to any one of claims 37 or 39-41 , or the method according to any one of claims 38 or 39-41 , wherein yc is sequestered by the antigen binding molecule.

43. The antigen-binding molecule, nucleic acid or plurality thereof, expression vector or plurality thereof, cell, or composition for use according to any one of claims 36 or 39-42, the use according to any one of claims 37 or 39-42, or the method according to any one of claims 38 or 39-42, wherein the frequency of yc forming a complex with IL-2Ra, I L-2Rp , IL-4Ra, IL-9Ra, IL-15Ra, and / or IL-21 Ra is inhibited.

44. An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 29, or a CAR according to claim 30, bound to yc and a polypeptide of a yc-containing cytokine receptor other than yc.

45. A method for decreasing the proliferation, survival and / or effector activity of a cell expressing a yc-containing cytokine receptor, comprising contacting a cell expressing a yc-containing cytokine receptor in vitro, in vivo or ex vivo with an antigen-binding molecule according to any one of claims 1 to 29, or a CAR according to claim 30.

46. The method according to claim 45, wherein the cell is an effector immune cell.

47. A method for inhibiting signalling mediated by a yc-containing cytokine receptor, comprising contacting a cell expressing a polypeptide of 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 29, or a CAR according to claim 30.

48. The method according to any one of claims 45 to 47, wherein the yc-containing cytokine receptor is a yc:IL-7Ra receptor.

49. A method of sequestering yc, comprising contacting yc in vitro, in vivo or ex vivo with an antigenbinding molecule according to any one of claims 1 to 29, or a CAR according to claim 30.

50. A method of inhibiting the formation of a heteromeric complex of (i) yc and (ii) IL-2Ra, IL-2R0, IL- 4Ra, IL-9Ra, IL-15Ra, and / or IL-21 Ra, comprising contacting yc in vitro, in vivo or ex vivo with an antigen-binding molecule according to any one of claims 1 to 29, or a CAR according to claim 30.226

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