B7-h3 antigen-binding molecules

Abstract

Provided are antigen-binding molecules that specifically bind B7-H3 Also provided are articles comprising or encoding said antigen-binding molecules, and the use of such molecules / articles for treating or preventing disease, e.g. cancer.

Description

[0001] B7-H3 ANTIGEN-BINDING MOLECULES

[0002] Cross-Reference to Related Applications

[0003] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 697,022, filed September 20, 2024, and U.S. Provisional Patent Application No. 63 / 744,509, filed January 13, 2025, the disclosure of which are hereby incorporated herein by reference in their entirety.

[0004] Reference to an Electronic Sequence Listing

[0005] The content of the electronic sequence listing (366592001040seqlist.xml; Size: 294,760 bytes; and Date of Creation: September 2, 2025) is herein incorporated by reference in its entirety.

[0006] Technical Field

[0007] The present invention relates to molecular biology, more specifically antibody technology. The present disclosure also relates to methods of medical treatment and prophylaxis.

[0008] Background

[0009] Cancers remain the leading cause of deaths worldwide. Chemotherapies have good clinical benefits, but due to their low specificity they have very significant side effect and low therapeutic indices. More targeted therapies, such as monoclonal antibody therapies, show good specificity but response rates are smaller. Antibody-drug conjugates (ADCs) are a therapeutic modality that harness an antibody’s target specificity to selectively deliver cytotoxic payloads to tumours and are proving increasingly effective in the clinic.

[0010] B7-H3 (also known as e.g. CD276) is an immune checkpoint inhibitor that belongs to the B7 family of cellsurface protein ligands. Overexpression of B7-H3 is observed in many cancers and a meta-analysis of 24 observational studies consisting of 4,141 patients showed high B7-H3 expression was significantly correlated with poor overall survival and poor recurrence free survival (Malapelle et al., International Journal of Molecular Sciences 23(24):16077, 2022). In contrast, B7-H3 is generally not expressed, or only expressed at low levels, in normal tissue (Getu et al., Molecular Cancer 22: 43, 2023).

[0011] These findings have made B7-H3 a target for cancer therapy, including using antigen-binding molecules such as antibodies and ADCs. B7-H3-targeting chimeric antigen receptors (CAR) T cells have also demonstrated good anti-tumour activity against multiple tumour types in preclinical studies (Du et al., Cancer Cell 35: 221-237, 2019).

[0012] Anti-B7-H3 ADCs are described in Fabrizio et al., Translational Oncology (2024) 39:101801 , and include ifinatamab deruxtecan (also referred to as DS-7300a; DrugBank Acc. No. DB18212), HS-20093, and vobramitamab duocarmazine (also referred to as MGC018; DrugBank Acc. No. DB18871). Ifinatamab deruxtecan is currently the most advanced targeted anti-B7-H3 therapy. This ADC comprises a humanised B7-H3-specific monoclonal Ab (mAb) conjugated to a deruxtecan payload via an enzymatically cleavable tetra-peptide-based linker. A phase III clinical trial of ifinatamab deruxtecan for treating small cell lung cancer (SCLC) is currently ongoing (NCT06203210). HS-20093 comprises a B7-H3-targeted antibody linked to a topoisomerase inhibitor payload. Vobramitamab duocarmazine comprises a humanised anti-B7-H3 mAb conjugated to the cleavable linker-duocarmycin payload duocarmazine (valine-citrulline-seco duocarmycin hydroxybenzamide azaindole; vc-seco-DUBA). In clinical trials to date for ifinatamab deruxtecan and HS-20093, despite showing promising overall response rates in some indications, the majority of patients who responded progress within 6 months. There remains an unmet clinical need for the effective treatment of B7-H3-expressing cancers, including further therapeutic antibodies (which may target B7-H3 expressing cells for destruction by e g. antibodydependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC)) and ADCs.

[0013] Moreover, B7-H3 expression is also commonly expressed on immune cells within tumours, in which it down-regulates the immune response to cancers (Lee et al., Cell Research 2 . 1034-1045, 2017). Therefore B7-H3 checkpoint blockade using a non-cytotoxic immune cell engager is also a promising approach for cancer therapy.

[0014] Summary

[0015] The present invention relates to anti-B7-H3 antigen-binding molecules, articles comprising or encoding said antigen-binding molecules, and the use of such molecules / articles for treating or preventing disease, e.g. cancer.

[0016] In a first aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7-H3, comprising:

[0017] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0018] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3

[0019] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4

[0020] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and / or

[0021] (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

[0022] In some embodiments of the first aspect, the antigen-binding molecule comprises:

[0023] (i) a VH region incorporating the following CDRs:

[0024] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3

[0025] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4

[0026] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and

[0027] (ii) a VL region incorporating the following CDRs:

[0028] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

[0029] In some embodiments of the first aspect, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0030] HC-FR1 having the amino acid sequence of SEQ ID NO: 8

[0031] HC-FR2 having the amino acid sequence of SEQ ID NO: 9

[0032] HC-FR3 having the amino acid sequence of SEQ ID NO: 10

[0033] HC-FR4 having the amino acid sequence of SEQ ID NO: 11 .

[0034] In some embodiments of the first aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0035] LC-FR1 having the amino acid sequence of SEQ ID NO: 12

[0036] LC-FR2 having the amino acid sequence of SEQ ID NO: 13

[0037] LC-FR3 having the amino acid sequence of SEQ ID NO: 14

[0038] LC-FR4 having the amino acid sequence of SEQ ID NO: 15.

[0039] In some embodiments of the first aspect, the antigen-binding molecule comprises:

[0040] (i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or

[0041] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0042] In some embodiments of the first aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1 and a VL region comprising the amino acid sequence of SEQ ID NO: 2.

[0043] In a second aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7-H3, comprising:

[0044] (i) a VH region incorporating the following CDRs:

[0045] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and / or

[0046] (ii) a VL region incorporating the following CDRs:

[0047] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0048] LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182)

[0049] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0050] In some embodiments of the second aspect, the antigen-binding molecule comprises:

[0051] (i) a VH region incorporating the following CDRs:

[0052] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0053] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and

[0054] (ii) a VL region incorporating the following CDRs:

[0055] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0056] In some embodiments of the second aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0057] HC-FR1 having the amino acid sequence of SEQ ID NO: 23

[0058] HC-FR2 having the amino acid sequence of SEQ ID NO: 24

[0059] HC-FR3 having the amino acid sequence of SEQ ID NO: 25

[0060] HC-FR4 having the amino acid sequence of SEQ ID NO: 26.

[0061] In some embodiments of the second aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0062] LC-FR1 having the amino acid sequence of SEQ ID NO: 27

[0063] LC-FR2 having the amino acid sequence of SEQ ID NO: 28

[0064] LC-FR3 having the amino acid sequence of SEQ ID NO: 29

[0065] LC-FR4 having the amino acid sequence of SEQ ID NO: 30.

[0066] In some embodiments of the second aspect, the antigen-binding molecule comprises:

[0067] (i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 16; and / or

[0068] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 17.

[0069] In some embodiments of the second aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 16 and a VL region comprising the amino acid sequence of SEQ ID NO: 17.

[0070] In a third aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7-H3, comprising:

[0071] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0072] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and / or

[0073] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0074] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36

[0075] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0076] In some embodiments of the third aspect, the antigen-binding molecule comprises:

[0077] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0078] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and

[0079] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0080] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0081] In some embodiments of the third aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0082] HC-FR1 having the amino acid sequence of SEQ ID NO: 38

[0083] HC-FR2 having the amino acid sequence of SEQ ID NO: 39

[0084] HC-FR3 having the amino acid sequence of SEQ ID NO: 40

[0085] HC-FR4 having the amino acid sequence of SEQ ID NO: 41 .

[0086] In some embodiments of the third aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0087] LC-FR1 having the amino acid sequence of SEQ ID NO: 42

[0088] LC-FR2 having the amino acid sequence of SEQ ID NO: 43

[0089] LC-FR3 having the amino acid sequence of SEQ ID NO: 44

[0090] LC-FR4 having the amino acid sequence of SEQ ID NO: 45.

[0091] In some embodiments of the third aspect, the antigen-binding molecule comprises:

[0092] (i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 31 ; and / or

[0093] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 32.

[0094] In some embodiments of the third aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 31 and a VL region comprising the amino acid sequence of SEQ ID NO: 32.

[0095] In a fourth aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7H3, comprising:

[0096] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0097] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49

[0098] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and / or

[0099] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0100] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52.

[0101] In some embodiments of the fourth aspect, the antigen-binding molecule comprises:

[0102] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48

[0103] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49

[0104] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and

[0105] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0106] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52.

[0107] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0108] HC-FR1 having the amino acid sequence of SEQ ID NO: 53

[0109] HC-FR2 having the amino acid sequence of SEQ ID NO: 54

[0110] HC-FR3 having the amino acid sequence of SEQ ID NO: 55

[0111] HC-FR4 having the amino acid sequence of SEQ ID NO: 26.

[0112] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0113] LC-FR1 having the amino acid sequence of SEQ ID NO: 57

[0114] LC-FR2 having the amino acid sequence of SEQ ID NO: 58

[0115] LC-FR3 having the amino acid sequence of SEQ ID NO: 59

[0116] LC-FR4 having the amino acid sequence of SEQ ID NO: 45.

[0117] In some embodiments of the fourth aspect, the antigen-binding molecule comprises:

[0118] (i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 46; and / or

[0119] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 47.

[0120] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 46 and a VL region comprising the amino acid sequence of SEQ ID NO: 47. In a fifth aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7H3, comprising:

[0121] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0122] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63

[0123] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64

[0124] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65; and / or

[0125] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0126] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66

[0127] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183)

[0128] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0129] In some embodiments of the fifth aspect, the antigen-binding molecule comprises:

[0130] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0131] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63

[0132] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64

[0133] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65; and

[0134] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0135] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66

[0136] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183)

[0137] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0138] In some embodiments of the fifth aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0139] HC-FR1 having the amino acid sequence of SEQ ID NO: 68

[0140] HC-FR2 having the amino acid sequence of SEQ ID NO: 69

[0141] HC-FR3 having the amino acid sequence of SEQ ID NO: 70

[0142] HC-FR4 having the amino acid sequence of SEQ ID NO: 71 .

[0143] In some embodiments of the fifth aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0144] LC-FR1 having the amino acid sequence of SEQ ID NO: 72

[0145] LC-FR2 having the amino acid sequence of SEQ ID NO: 73

[0146] LC-FR3 having the amino acid sequence of SEQ ID NO: 74

[0147] LC-FR4 having the amino acid sequence of SEQ ID NO: 75.

[0148] In some embodiments of the fifth aspect, the antigen-binding molecule comprises:

[0149] (I) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 61 ; and / or

[0150] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 62. In some embodiments of the fifth aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 61 and a VL region comprising the amino acid sequence of SEQ ID NO: 62.

[0151] In a sixth aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7H3, comprising:

[0152] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0153] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and / or

[0154] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0155] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0156] In some embodiments of the sixth aspect, the antigen-binding molecule comprises:

[0157] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0158] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and

[0159] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0160] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0161] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0162] HC-FR1 having the amino acid sequence of SEQ ID NO: 83

[0163] HC-FR2 having the amino acid sequence of SEQ ID NO: 84

[0164] HC-FR3 having the amino acid sequence of SEQ ID NO: 85

[0165] HC-FR4 having the amino acid sequence of SEQ ID NO: 71 .

[0166] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0167] LC-FR1 having the amino acid sequence of SEQ ID NO: 87

[0168] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0169] LC-FR3 having the amino acid sequence of SEQ ID NO: 89

[0170] LC-FR4 having the amino acid sequence of SEQ ID NO: 30. In some embodiments of the sixth aspect, the antigen-binding molecule comprises:

[0171] (I) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 76; and / or

[0172] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 77.

[0173] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 76 and a VL region comprising the amino acid sequence of SEQ ID NO: 77.

[0174] In a seventh aspect, provided herein is an antigen-binding molecule, optionally isolated, that specifically binds B7H3, comprising:

[0175] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0176] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 95; and / or

[0177] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0178] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96 LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

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

[0180] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0181] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93

[0182] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94

[0183] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 95; and

[0184] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0185] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96 LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0186] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0187] HC-FR1 having the amino acid sequence of SEQ ID NO: 98

[0188] HC-FR2 having the amino acid sequence of SEQ ID NO: 99

[0189] HC-FR3 having the amino acid sequence of SEQ ID NO: 100

[0190] HC-FR4 having the amino acid sequence of SEQ ID NO: 71 .

[0191] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs: LC-FR1 having the amino acid sequence of SEQ ID NO: 102

[0192] LC-FR2 having the amino acid sequence of SEQ ID NO: 103

[0193] LC-FR3 having the amino acid sequence of SEQ ID NO: 104

[0194] LC-FR4 having the amino acid sequence of SEQ ID NO: 15.

[0195] In some embodiments of the seventh aspect, the antigen-binding molecule comprises:

[0196] (i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 91 ; and / or

[0197] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 92.

[0198] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 91 and a VL region comprising the amino acid sequence of SEQ ID NO: 92.

[0199] In another aspect, provided herein is an antigen-binding molecule that specifically binds B7-H3, comprising:

[0200] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0201] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227; and / or

[0202] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0203] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0204] In some embodiments, the antigen-binding molecule comprises:

[0205] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0206] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227; and

[0207] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0208] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0209] In another aspect, provided herein is an antigen-binding molecule that specifically binds B7-H3, comprising:

[0210] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0211] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0212] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 190; and / or

[0213] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0214] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81

[0215] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191

[0216] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0217] In some embodiments, the antigen-binding molecule comprises:

[0218] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0219] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78

[0220] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0221] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 190; and

[0222] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0223] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81

[0224] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191

[0225] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0226] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0227] HC-FR1 having the amino acid sequence of SEQ ID NO: 231

[0228] HC-FR2 having the amino acid sequence of SEQ ID NO: 232

[0229] HC-FR3 having the amino acid sequence of SEQ ID NO: 233

[0230] HC-FR4 having the amino acid sequence of SEQ ID NO: 234.

[0231] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following framework regions:

[0232] LC-FR1 having the amino acid sequence of SEQ ID NO: 235

[0233] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0234] LC-FR3 having the amino acid sequence of SEQ ID NO: 236

[0235] LC-FR4 having the amino acid sequence of SEQ ID NO: 237.

[0236] In some embodiments, the antigen-binding molecule comprises:

[0237] (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 229; and / or

[0238] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 230.

[0239] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 229 and a VL region comprising the amino acid sequence of SEQ ID NO: 230. In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0240] HC-FR1 having the amino acid sequence of SEQ ID NO: 192

[0241] HC-FR2 having the amino acid sequence of SEQ ID NO: 193

[0242] HC-FR3 having the amino acid sequence of SEQ ID NO: 194

[0243] HC-FR4 having the amino acid sequence of SEQ ID NO: 195.

[0244] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following framework regions:

[0245] LC-FR1 having the amino acid sequence of SEQ ID NO: 196

[0246] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0247] LC-FR3 having the amino acid sequence of SEQ ID NO: 197

[0248] LC-FR4 having the amino acid sequence of SEQ ID NO: 198.

[0249] In some embodiments, the antigen-binding molecule comprises:

[0250] (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 188; and / or

[0251] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 189.

[0252] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 188 and a VL region comprising the amino acid sequence of SEQ ID NO: 189.

[0253] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0254] HC-FR1 having the amino acid sequence of SEQ ID NO: 201

[0255] HC-FR2 having the amino acid sequence of SEQ ID NO: 202

[0256] HC-FR3 having the amino acid sequence of SEQ ID NO: 203

[0257] HC-FR4 having the amino acid sequence of SEQ ID NO: 204.

[0258] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following framework regions:

[0259] LC-FR1 having the amino acid sequence of SEQ ID NO: 205

[0260] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0261] LC-FR3 having the amino acid sequence of SEQ ID NO: 206

[0262] LC-FR4 having the amino acid sequence of SEQ ID NO: 207.

[0263] In some embodiments, the antigen-binding molecule comprises:

[0264] (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 199; and / or (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 200.

[0265] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 199 and a VL region comprising the amino acid sequence of SEQ ID NO: 200.

[0266] In another aspect, provided herein is an antigen-binding molecule that specifically binds B7-H3, comprising:

[0267] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0268] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238

[0269] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0270] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239; and / or

[0271] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0272] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0273] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182

[0274] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0275] In some embodiments, the antigen-binding molecule comprises:

[0276] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0277] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238

[0278] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0279] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239; and

[0280] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0281] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0282] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182

[0283] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0284] In another aspect, provided herein is an antigen-binding molecule that specifically binds B7-H3, comprising:

[0285] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0286] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238

[0287] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0288] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or

[0289] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0290] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0291] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182

[0292] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0293] In some embodiments, the antigen-binding molecule comprises:

[0294] (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238

[0295] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0296] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and

[0297] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0298] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0299] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182

[0300] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0301] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0302] HC-FR1 having the amino acid sequence of SEQ ID NO: 242

[0303] HC-FR2 having the amino acid sequence of SEQ ID NO: 243

[0304] HC-FR3 having the amino acid sequence of SEQ ID NO: 244

[0305] HC-FR4 having the amino acid sequence of SEQ ID NO: 245.

[0306] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following framework regions:

[0307] LC-FR1 having the amino acid sequence of SEQ ID NO: 246

[0308] LC-FR2 having the amino acid sequence of SEQ ID NO: 247

[0309] LC-FR3 having the amino acid sequence of SEQ ID NO: 248

[0310] LC-FR4 having the amino acid sequence of SEQ ID NO: 249.

[0311] In some embodiments, the antigen-binding molecule comprises:

[0312] (I) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 240; and / or

[0313] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 241 .

[0314] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 240 and a VL region comprising the amino acid sequence of SEQ ID NO: 241 .

[0315] In another aspect, provided herein is an antigen-binding molecule that specifically binds B7-H3, comprising:

[0316] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0317] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18

[0318] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0319] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or

[0320] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0321] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0322] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0323] In some embodiments, the antigen-binding molecule comprises:

[0324] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0325] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18

[0326] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0327] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and

[0328] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0329] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0330] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182

[0331] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0332] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0333] HC-FR1 having the amino acid sequence of SEQ ID NO: 211

[0334] HC-FR2 having the amino acid sequence of SEQ ID NO: 212

[0335] HC-FR3 having the amino acid sequence of SEQ ID NO: 213

[0336] HC-FR4 having the amino acid sequence of SEQ ID NO: 204.

[0337] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following framework regions:

[0338] LC-FR1 having the amino acid sequence of SEQ ID NO: 214

[0339] LC-FR2 having the amino acid sequence of SEQ ID NO: 215

[0340] LC-FR3 having the amino acid sequence of SEQ ID NO: 216

[0341] LC-FR4 having the amino acid sequence of SEQ ID NO: 217.

[0342] In some embodiments, the antigen-binding molecule comprises:

[0343] (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 208; and / or

[0344] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 209.

[0345] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 208 and a VL region comprising the amino acid sequence of SEQ ID NO: 209.

[0346] In another aspect, provided herein is an antigen-binding molecule that specifically binds B7-H3, comprising:

[0347] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0348] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220

[0349] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or

[0350] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0351] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0352] In some embodiments, the antigen-binding molecule comprises:

[0353] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0354] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220

[0355] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0356] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and

[0357] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0358] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0359] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0360] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):

[0361] HC-FR1 having the amino acid sequence of SEQ ID NO: 221

[0362] HC-FR2 having the amino acid sequence of SEQ ID NO: 222

[0363] HC-FR3 having the amino acid sequence of SEQ ID NO: 223

[0364] HC-FR4 having the amino acid sequence of SEQ ID NO: 195.

[0365] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following framework regions:

[0366] LC-FR1 having the amino acid sequence of SEQ ID NO: 224

[0367] LC-FR2 having the amino acid sequence of SEQ ID NO: 225

[0368] LC-FR3 having the amino acid sequence of SEQ ID NO: 226

[0369] LC-FR4 having the amino acid sequence of SEQ ID NO: 30.

[0370] In some embodiments, the antigen-binding molecule comprises:

[0371] (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 218; and / or

[0372] (ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 219.

[0373] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 218 and a VL region comprising the amino acid sequence of SEQ ID NO: 219.

[0374] In some embodiments of the above aspects, the antigen-binding molecule is humanised. In some embodiments of the above aspects, the antigen-binding molecule of the invention comprises a heavy chain comprising a constant region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 110 and comprising an alanine residue at the position corresponding to position 180 of SEQ ID NO: 110.

[0375] In some embodiments of the first aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 113; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 114 or 115.

[0376] In some embodiments of the second aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 116; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 117 or 118.

[0377] In some embodiments of the third aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 119; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 120 or 121 .

[0378] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 122; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 123 or 124.

[0379] In some embodiments of the fifth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 125; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 126 or 127.

[0380] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 128; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 129 or 130.

[0381] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 131 ; and / or a light chain comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 132 or 133.

[0382] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 250; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 251 or 252.

[0383] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 253; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 254 or 255.

[0384] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 256; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 257 or 258.

[0385] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 259; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 260 or 261 .

[0386] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 262; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 263 or 264.

[0387] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 265; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 266 or 267. In an eighth aspect, provided herein is an antibody-drug conjugate (ADC) comprising an antigen-binding molecule as provided herein.

[0388] In a ninth aspect, provided herein is a nucleic acid, or a plurality of nucleic acids (e.g. a pair of nucleic acids), optionally isolated, encoding an antigen-binding molecule as provided herein.

[0389] In a tenth aspect, provided herein is an expression vector, or a plurality of expression vectors (e.g. a pair of expression vectors), comprising the nucleic acid or plurality (e.g. pair) of nucleic acids of the seventh aspect.

[0390] In an eleventh aspect, provided herein is a cell comprising an antigen-binding molecule, nucleic acid or plurality of nucleic acids or expression vector or plurality of expression vectors of the invention.

[0391] In a twelfth aspect, provided herein is a composition comprising an antigen-binding molecule, ADC, nucleic acid or plurality of nucleic acids, an expression vector or plurality of expression vectors or a cell of the invention. In some embodiments, the composition also comprises a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0392] In a thirteenth aspect, provided herein is an antigen-binding molecule, ADC, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, composition or cell of the invention for use in a method of medical treatment or prophylaxis, or in a method of diagnosis or prognosis.

[0393] In a fourteenth aspect, provided herein is an antigen-binding molecule, ADC, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, composition or cell of the invention for use in a method of treating or preventing cancer.

[0394] In a related aspect, provided herein is the use of an antigen-binding molecule, ADC, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, composition or cell of the invention in the manufacture of a medicament for treating or preventing a cancer.

[0395] In a related aspect, provided herein is a method of treating or preventing cancer, comprising administering to a subject a therapeutically- or prophylactically-effective amount of an antigen-binding molecule, ADC, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, composition or cell of the invention.

[0396] In some embodiments, the cancer treated or prevented according to these related aspects comprises cells expressing or overexpressing B7-H3.

[0397] In a fifteenth aspect, provided herein is an in vitro complex comprising an antigen-binding molecule of the invention bound to B7-H3. In a sixteenth aspect, provided herein is a method comprising contacting a sample containing, or suspected to contain, B7-H3 with an antigen-binding molecule of the invention, and detecting the formation of a complex of the antigen-binding molecule with B7-H3.

[0398] In a seventeenth aspect, provided herein is the use of an antigen-binding molecule of the invention as an in vitro or in vivo diagnostic or prognostic agent.

[0399] Description

[0400] The present invention relates to novel B7-H3-binding molecules having novel and / or improved properties as compared to known anti-B7-H3 antibodies, and ADCs comprising the binding molecules.

[0401] B7-H3

[0402] Human B7-H3 (B7 Homologue 3) has the UniProt accession number Q5ZPR3. B7-H3 is also known as CD276. The canonical isoform of human B7-H3 (sometimes known as 4lg-B7-H3) has the amino acid sequence of Q5ZPR3-1 (v1 , 2004-11-23; SEQ ID NO: 134). Alternative splicing of mRNA encoded by the human B7H3 gene yields four main isoforms: isoform 1 (4lg-B7-H3, SEQ ID NO: 134), isoform 2 (2lg-B7-H3, SEQ ID NO: 135), isoform 3 (SEQ ID NO: 136), and isoform 4 (SEQ ID NO: 137). Isoform 2 differs from isoform 1 in that positions 159 to 376 are absent. Isoform 3 differs in that positions 465 to 493 of SEQ ID NO: 134 are replaced with a different sequence of amino acids, and positions 494 to 534 are absent. Isoform 4 differs in that positions 528-534 of SEQ ID NO: 134 are replaced with a shorter 6 amino acid sequence.

[0403] The canonical isoform of human B7-H3 comprises a 28 amino acid N-terminal signal peptide (SEQ ID NO: 139), followed by an extracellular domain (SEQ ID NO: 140), a transmembrane domain (SEQ ID NO: 141), and a cytoplasmic domain (SEQ ID NO: 142) at the C-terminus. The mature form of human B7-H3 isoform 1 is shown in SEQ ID NO: 138.

[0404] In the canonical (4lg) isoform of human B7-H3, the extracellular domain comprises two pairs of immunoglobulin variable (Ig V)-like and immunoglobulin constant (IgC)-like domains: IgV-like type 1 (SEQ ID NO: 143) and IgC-like type 1 (SEQ ID NO: 144); and IgV-like type 2 (SEQ ID NO: 145) and IgC-like type 2 (SEQ ID NO: 146). The IgV-like type 1 domain and IgC-like type 1 domain are connected by a linker having the amino acid sequence shown in SEQ ID NO: 147. The IgC-like type 1 domain and IgV- like type 2 domain are connected by a linker having the amino acid sequence shown in SEQ ID NO: 148. The IgV-like type 2 domain and IgC-like type 2 domain are connected by a linker having the amino acid sequence shown in SEQ ID NO: 147. The IgC-like type 2 domain is connected to the transmembrane domain by a linker having the amino acid sequence shown in SEQ ID NO: 150. The cytoplasmic domain of the canonical isoform of human B7-H3 is short without any known signaling motif (SEQ ID NO: 142). The structure and function of B7-H3 is described in e.g. Getu et al. (supra), which is hereby incorporated by reference in its entirety.

[0405] The B7 family proteins are a type of integral membrane proteins found on activated antigen-presenting cells and consists of structurally related cell-surface protein ligands that bind to receptors on lymphocytes. B7.1 (CD80) and B7.2 (CD86) are the two major types of B7 proteins. Other proteins in the B7 family include B7-H3, inducible co-stimulator ligand (ICOS-L) and co-inhibitory programmed death ligand-1 (PD-L1), programmed death ligand-2 (PD-L2), and B7-H4. B7 family proteins produce a costimulatory or coinhibitory signal to enhance or decrease the activity of the MHC-TCR signal between antigen presenting cells (APCs) and T cells. Interaction of B7 family members with costimulatory receptors augments immune responses while interaction with coinhibitory receptors attenuates immune responses. B7-H3 shares 20-27 % amino acid identity with other B7 family members.

[0406] B7-H3 is involved in non-immune-mediated signalling pathways: PI3K / AKT / mTOR, Ras / Raf / MEK / MAPK, HIF-a and VEGF signalling pathways. The PI3K / AKT / mTOR and Ras / Raf / MEK / MAPK signaling pathways are involved in promoting the migration, invasion and epithelial-mesenchymal transition (ETM) of cancer cells. The HIF-a pathway is involved in glucose metabolic reprogramming and enhancing neoplastic tumour growth. The VEGF signaling pathway is involved in promoting neo-angiogenesis and metastasis. B7-H3 is also involved in immune-mediated signaling pathways. B7-H3 can act as an immune co-stimulatory molecule, increasing IFN-y and IL-12 levels and promoting CD4+ and CD8+ T cell proliferation and enhancing cytotoxic T cell activity. B7-H3 can also play an immune co-inhibitory role, reducing cytokines (IL-2, IL-10, IL-13, and IFN-y) and inhibiting T cell proliferation and NK cell activity.

[0407] Reference herein to ‘B7-H3’ generally refers to the canonical isoform of the human B7H3 (i.e. isoform 1 of SEQ ID NO: 134) or the mature version thereof (SEQ ID NO: 138), but also contemplates isoforms, fragments, variants (including mutants) and orthologues thereof (i.e. from other species, e g. non-human mammalian species (e.g. a non-human primate, such as rhesus or cynomolgous; or e.g. a rodent, such as rat or mouse). Murine B7-H3 has the UniProt accession number Q8VE98 and the amino acid sequence set forth in SEQ ID NO: 151 . Cynomolgus (macaque) B7-H3 has the UniProt accession number A0A7N9CYV2 and the amino acid sequence set forth in SEQ ID NO: 152.

[0408] As used herein, a ‘fragment’ or ‘variant’ (or ‘homologue’) of a protein may be characterised as having at least 60 % (but less than 100 %) amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 % or >99 % amino acid sequence identity to the amino acid sequence of the reference protein (e.g. the canonical isoform of human B7-H3). In some embodiments fragments / variants / isoforms / homologues may be characterised by ability to perform a function performed by the reference protein.

[0409] 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 (e.g. human B7-H3 isoforms 1 to 4 are all isoforms of one another).

[0410] An ‘orthologue’ generally refers to a variant of the reference protein which has the same function as the reference protein but is produced by a different species as compared to the species of the reference protein. For example, human B7-H3 and mouse B7-H3 are orthologues of one another. An orthologue may be characterised by having the same degree of sequence identity to a reference protein as set out above in respect of variants.

[0411] A ‘fragment’ may be of any length (by number of amino acids), although may optionally be at least 20 % of the length of the reference protein (that is, the protein from which the fragment is derived) and may have a maximum length of 50 %, 75 %, 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 % of the length of the reference protein. A fragment of B7H3 may have a minimum length of e.g. 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 amino acids, and may have a maximum length of e.g. 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 amino acids.

[0412] The antigen-binding molecules provided herein bind human B7-H3 of SEQ ID NO: 134. As set out further below, the antigen-binding molecules may bind B7-H3 from other mammalian species, e.g. non-human primates (such as rhesus or cynomolgus) and / or rodents (such as rat or mouse).

[0413] The antigen-binding molecules provided herein may also bind isoforms, fragments, variants or homologues of human B7-H3 of SEQ ID NO: 134, which may optionally be characterized as having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 % or >99 % amino acid sequence identity to SEQ ID NO: 134.

[0414] B7-H3-binding antigen-binding molecules

[0415] An ‘antigen-binding molecule’ refers to a molecule that binds to a given target antigen. Antigen-binding molecules comprise one or more antigen-binding moieties through which the antigen-binding molecule binds to its target antigen(s). The antigen-binding molecules provided herein comprise or consist of an antigen-binding moiety that binds to B7-H3 (i.e. a B7-H3-binding moiety). In some embodiments, the antigen-binding molecules comprise an antigen-binding polypeptide complex comprising an antigenbinding moiety that binds to B7-H3.

[0416] The antigen-binding molecules provided herein may be, may comprise or may be derived from an antibody. As used herein, the term ‘antibodies’ includes full-length antibodies (both monoclonal and polyclonal antibodies), monospecific and multispecific (e.g. bispecific, trispecific, etc.) antibodies, and antibody-derived 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.

[0417] In some embodiments, an antigen-binding moiety according to the present disclosure comprises, or consists of, the antigen-binding region of an antibody (e g. an antigen-binding fragment of an antibody). In some embodiments, an antigen-binding moiety may be or comprise the Fv (e.g. provided as an scFv) or the Fab region of an antibody that binds to B7-H3, or the whole antibody. Thus the antigen-binding molecule provided herein may be a full-length antibody (particularly a monoclonal antibody). In other embodiments, the antigen-binding molecule provided herein is an antigen-binding fragment of an antibody.

[0418] The antigen-binding moieties of the present disclosure may be designed and prepared using the sequences of monoclonal antibodies (mAbs) capable of binding to B7-H3. Antigen-binding regions of antibodies, such as variable fragment (Fv), Fab and F(ab’)2 fragments may also be used. An ‘antigenbinding region’ is any fragment of an antibody that binds to the target for which the given antibody is specific.

[0419] In some embodiments, an antigen-binding moiety comprises the antibody heavy chain variable region (VH) and the antibody light chain variable region (VL) of an antibody capable of specific binding to the target antigen. In some embodiments, the antigen-binding moiety is or comprises the Fv (e.g. provided as an scFv) of an antibody. In some embodiments, the antigen-binding moiety is or comprises the Fab region of an antibody. In some embodiments, the antigen-binding moiety is or comprises the whole antibody (i.e. a full-length antibody comprising variable and constant regions).

[0420] An antigen-binding moiety may be, or may comprise, an antigen-binding polypeptide, or an antigenbinding polypeptide complex. An antigen-binding moiety may comprise more than one polypeptide which together form an antigen-binding moiety. The polypeptides may associate covalently or non-covalently. In some embodiments, the polypeptides form part of a larger polypeptide comprising the polypeptides (e g. in the case of an scFv comprising VH and VL, or in the case of an scFab comprising VH-CH1 and VL-CL).

[0421] In some embodiments, an antigen-binding moiety according to the present disclosure comprises, or consists of, a polypeptide complex formed by protein: protein interactions between constituent peptides / polypeptides of the antigen-binding moiety. An antigen-binding moiety 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 moiety comprising two heavy chain polypeptides and two light chain polypeptides. Antibodies generally comprise six complementarity-determining regions (CDRs): three in the heavy chain variable region (VH): HC-CDR1 , HC-CDR2 and HC-CDR3, and three in the light chain variable region (VL): 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.

[0422] 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.

[0423] 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, 5thEd. 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.

[0424] In some embodiments, an antigen-binding moiety according to the present disclosure comprises, or consists of, an Fv region that binds to B7-H3. In some embodiments, the VH and VL regions of the Fv are provided as a single polypeptide joined by a linker sequence, i.e. a single chain Fv (scFv).

[0425] 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 moiety 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 CH1 (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 a single polypeptide joined by linker regions, i.e. as a single chain Fab (scFab) or a single chain CrossFab (scCrossFab).

[0426] In some embodiments, an antigen-binding molecule provided herein comprises, or consists of, a whole (i.e. full-length) antibody which binds to B7-H3. 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.

[0427] 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. lgG1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM. The light chain may be kappa (K) or lambda (A).

[0428] In some embodiments, the antigen-binding molecule comprises, or consists of, an IgG (e.g. lgG1 , lgG2, lgG3, lgG4), IgA (e.g. Ig A1 , lgA2), IgD, IgE, or IgM which binds to B7-H3.

[0429] In some embodiments, an antigen-binding molecule of the present disclosure comprises one or more regions (e.g. CH1 , hinge, 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. h IgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. h Ig A1 , hlgA2), hlgD, h IgE 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 ml , G1 m2, G1 m3 or G1 ml 7).

[0430] In some embodiments, an antigen-binding molecule comprises one or more polypeptides (e.g. heavy chain(s)) comprising an amino acid sequence having at least 60% amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 153 (human lgG1 CH1 domain) or SEQ ID NO: 176 (human lgG1 G1 m3 allotype CH1 domain). In some embodiments, an antigen-binding molecule comprises one or more polypeptides (e.g. heavy chain(s)) comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 154 (human lgG1 hinge). In some embodiments, an antigen-binding molecule comprises one or more polypeptides (e.g. heavy chain(s)) comprising an amino acid sequence having at least 60% amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 155 or 156 (human lgG1 CH2 domain and modified version thereof comprising N297A mutation, described further below, respectively). In some embodiments, an antigen-binding molecule comprises one or more polypeptides (e.g. heavy chain(s)) comprising an amino acid sequence having at least 60% amino acid sequence identity, e g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 157 (human lgG1 CH3 domain) or SEQ ID NO: 177 (human lgG1 G1 m3 allotype CH3 domain). In some embodiments, an antigen-binding moiety comprises one or more polypeptides (e.g. heavy chain(s)) comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 158, 159 or 178 (human lgG1 CH2-CH3 region and modified version thereof comprising N297A mutation, described further below, and human lgG1 G1 m3 allotype CH2-CH3 region, respectively). In some embodiments, an antigen-binding moiety comprises one or more polypeptides (e.g. heavy chain(s)) comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 160, 110 or 179 (human IgG 1 constant region and modified version thereof comprising N297A mutation, described further below, and human lgG1 G1 m3 allotype constant region, respectively).

[0431] In some embodiments, an antigen-binding moiety of the present disclosure comprises one or more regions of an immunoglobulin light chain constant sequence. In some embodiments, the immunoglobulin light chain constant sequence is human immunoglobulin kappa constant (IGKC; CK, SEQ ID NO: 111). In some embodiments, the immunoglobulin light chain constant sequence is a human immunoglobulin lambda constant (IGLC; CA), e.g. IGLC1 (SEQ ID NO: 161), IGLC2 (SEQ ID NO: 112), IGLC3 (SEQ ID NO: 162), IGLC6 (SEQ ID NO: 163) or IGLC7 (SEQ ID NO: 164).

[0432] In some embodiments, an antigen-binding moiety comprises one or more polypeptides comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 11 1 , 112, 161 , 162, 163 or 164.

[0433] In some embodiments described herein, one or more amino acids of an amino acid sequence referred to herein {e g. an amino acid sequence of an antigen-binding moiety, e.g. an amino acid sequence of a VH / VL region) are substituted with another (non-identical) amino acid (the “replacement” amino acid). A replacement amino acid residue of a substitution according to the present disclosure may be a naturally- occurring amino acid residue (i.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 a!., Meth. Enzym. 202 (1991) 301-336.

[0434] 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:

[0435] 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.

[0436] 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:

[0437] That is, in some embodiments, a nonpolar amino acid is substituted with another, non-identical nonpolar amino acid. In some embodiments, a polar amino acid is substituted with another, non-identical polar amino acid. In some embodiments, an acidic polar amino acid is substituted with another, non-identical acidic polar amino acid. In some embodiments, a basic polar amino acid is substituted with another, non- identical basic polar amino acid. In some embodiments, a neutral amino acid is substituted with another, non-identical neutral amino acid. In some embodiments, a positive amino acid is substituted with another, non-identical positive amino acid. In some embodiments, a negative amino acid is substituted with another, non-identical negative amino acid.

[0438] 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 moiety comprising the substitution as compared to the equivalent unsubstituted molecule.

[0439] It will be appreciated that the antigen-binding molecules of the present disclosure could be formulated as multispecific antigen-binding molecules. By ‘multispecific’ it is meant that the antigen-binding molecule binds to more than one target antigen (e.g. one of 2, 3, 4, 5, 6 or more target antigens). 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 moieties. In some embodiments, the antigen-binding molecule comprises at least two antigen-binding moieties, wherein each antigen-binding moiety binds to a different target antigen.

[0440] The antigen-binding molecules of the present disclosure display at least monovalent binding with respect to B7-H3. Binding valency refers to the number of binding sites in an antigen-binding molecule for a given antigenic determinant. Accordingly, the antigen-binding molecules provided herein comprise at least one binding site for B7-H3.

[0441] Multispecific antigen-binding molecules may be provided in any suitable format, such as those formats described in Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212, which is hereby incorporated by reference in its entirety. Multispecific antigen-binding molecule formats include those shown in Figure 2 of Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212: antibody conjugates, e.g. lgG2, F(ab’)z 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 dAb / VHH, tetravalent dAb.VHH; Non-lg fusion proteins, e.g. scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fabz-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, scFv -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.

[0442] In some embodiments, the antigen-binding molecule provided herein is an isolated antigen-binding molecule. An “isolated” antigen-binding molecule as used herein means an antigen-binding molecule that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody or antigen-binding fragment thereof that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody exists or is produced, is defined herein as an “isolated antibody” or an “isolated antigen-binding fragment of an antibody”. Isolated antigen-binding molecules are antigen-binding molecules that have been subjected to at least one purification or isolation step. An isolated antigen-binding molecule may be substantially free of other cellular material and / or chemicals.

[0443] The present disclosure also provides chimeric antigen receptors (CARs) comprising the antigen-binding molecules / polypeptides / polypeptide complexes of the present disclosure.

[0444] 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 moiety 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.

[0445] The CAR of the present disclosure comprises an antigen-binding moiety which comprises or consists of an antigen-binding polypeptide or an antigen-binding polypeptides / polypeptide complex of the present disclosure. Thus, in some aspects and embodiments, an antigen-binding molecule according to the present disclosure is a CAR.

[0446] 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-C, 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 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the reference sequence.

[0447] 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 co-stimulation preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway, whereas the 4-1 BB-mediated signalling is through TNF receptor associated factor (TRAF) adaptor proteins. Signalling regions of CARs therefore sometimes contain co-stimulatory sequences derived from signalling regions of more than one co-stimulatory molecule. In some embodiments, the CAR of the present disclosure comprises one or more co-stimulatory sequences comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the intracellular domain of one or more of CD28, 0X40, 4-1 BB, ICOS and CD27.

[0448] 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 lgG1. 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 lgG1 (SEQ ID NO: 154).

[0449] The antigen-binding moiety of the CAR of the present disclosure may be provided with any suitable format, e.g. scFv, scFab, etc.

[0450] B7-H3-binding moieties

[0451] The antigen-binding molecules of the present disclosure comprise an antigen-binding moiety that binds to B7-H3, in particular human B7-H3 as discussed above. Thus, the antigen-binding molecules provided herein bind to human B7-H3. Generally, the antigen-binding molecules provided herein specifically bind to human B7-H3. As defined herein, an antigen-binding molecule which specifically binds to human B7-H3 is an antigen-binding molecule which binds to human B7-H3 with a greater affinity than that with which it binds to other human members of the B7 family. In some embodiments, an antigen-binding molecule which specifically binds to human B7-H3 binds human B7-H3 with a greater affinity than it binds any other human protein. An antigen-binding molecule which specifically binds human B7-H3 may crossreact with B7-H3 proteins from other species (e.g. the antibodies exemplified below are shown to bind murine and cynomolgus B7-H3 as well as human B7-H3, see Table 1). In such cases the antigen-binding molecule may bind human B7-H3 more strongly than B7-H3 from any other species, but may equally bind B7-H3 from one or more other species more strongly than human B7-H3.

[0452] Thus the antigen-binding molecule provided herein is capable of binding to a polypeptide comprising, or consisting of, the amino acid sequence of one of SEQ ID NOs: 134-137 (isoforms 1-4 of human B7-H3). The ability of an antigen-binding moiety to bind to a given peptide / polypeptide can be analysed by methods well known to the skilled person, including analysis by ELISA, immunoblot (e.g. western blot), immunoprecipitation, Surface Plasmon Resonance (SPR; see e g. Hearty et al., Methods Mol Biol (2012) 907:411-442) or Bio-Layer Interferometry (see e.g. Lad et al., (2015) J Biomol Screen 20(4): 498-507).

[0453] In some embodiments, the antigen-binding moiety comprises the CDRs of an antigen-binding moiety which is capable of binding to B7-H3. In some embodiments, the antigen-binding moiety comprises the FRs of an antigen-binding moiety which is capable of binding to B7-H3. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antibody that is capable of binding to B7-H3. That is, in some embodiments the antigen-binding moiety comprises the VH region and the VL region of an antibody that is capable of binding to B7-H3.

[0454] In some embodiments, the antigen-binding moiety comprises the heavy chain CDRs and the light chain CDRs of a B7-H3-binding antibody described herein. In some embodiments, the antigen-binding moiety comprises the VH and VL of a B7-H3-binding antibody described herein. In some embodiments, the antigen-binding moiety comprises the heavy chain polypeptide (i.e. comprising VH, CH1 , CH2 and CH3 region sequences) and light chain polypeptide (i.e. comprising VL and CL region sequences) of a B7-H3- binding antibody described herein. In a first aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 1001 . In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0455] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3

[0456] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4

[0457] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, 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.

[0458] According to this first aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0459] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6

[0460] LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181)

[0461] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0462] In some embodiments, the antigen-binding molecule comprises:

[0463] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0464] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and / or

[0465] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0466] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

[0467] Generally, the antigen-binding molecule comprises:

[0468] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0469] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and

[0470] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0471] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6

[0472] LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181)

[0473] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments of this first aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0474] HC-FR1 having the amino acid sequence of SEQ ID NO: 8

[0475] HC-FR2 having the amino acid sequence of SEQ ID NO: 9

[0476] HC-FR3 having the amino acid sequence of SEQ ID NO: 10

[0477] HC-FR4 having the amino acid sequence of SEQ ID NO: 11 , or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0478] In some embodiments of this first aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0479] LC-FR1 having the amino acid sequence of SEQ ID NO: 12

[0480] LC-FR2 having the amino acid sequence of SEQ ID NO: 13

[0481] LC-FR3 having the amino acid sequence of SEQ ID NO: 14

[0482] LC-FR4 having the amino acid sequence of SEQ ID NO: 15, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0483] In some embodiments of this first aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 1 .

[0484] In some embodiments of this first aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0485] In some embodiments of this first aspect, the antigen-binding molecule comprises:

[0486] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and

[0487] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 2; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 1 , it comprises an HC-CDR1 of SEQ ID NO: 3, an HC-CDR2 of SEQ ID NO: 4 and an HC-CDR3 of SEQ ID NO: 5; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 2, it comprises an LC-CDR1 of SEQ ID NO: 6, an LC-CDR2 of WAS (SEQ ID NO: 181) and an LC-CDR3 of SEQ ID NO: 7.

[0488] In some embodiments of the first aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1 and a VL region comprising the amino acid sequence of SEQ ID NO: 2.

[0489] In a second aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 1047. In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0490] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18

[0491] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0492] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20 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] According to this second aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0494] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21

[0495] LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182)

[0496] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22 or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0497] In some embodiments, the antigen-binding molecule comprises:

[0498] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0499] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and / or

[0500] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0501] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0502] Generally, the antigen-binding molecule comprises:

[0503] (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18

[0504] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0505] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and

[0506] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0507] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0508] In some embodiments of this second aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0509] HC-FR1 having the amino acid sequence of SEQ ID NO: 23

[0510] HC-FR2 having the amino acid sequence of SEQ ID NO: 24

[0511] HC-FR3 having the amino acid sequence of SEQ ID NO: 25

[0512] HC-FR4 having the amino acid sequence of SEQ ID NO: 26 or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0513] In some embodiments of this second aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0514] LC-FR1 having the amino acid sequence of SEQ ID NO: 27

[0515] LC-FR2 having the amino acid sequence of SEQ ID NO: 28

[0516] LC-FR3 having the amino acid sequence of SEQ ID NO: 29

[0517] LC-FR4 having the amino acid sequence of SEQ ID NO: 30 or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0518] In some embodiments of this second aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 16.

[0519] In some embodiments of this second aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 17.

[0520] In some embodiments of this second aspect, the antigen-binding molecule comprises: (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 16; and

[0521] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 17; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 16, it comprises an HC-CDR1 of SEQ ID NO: 18, an HC-CDR2 of SEQ ID NO: 19 and an HC-CDR3 of SEQ ID NO: 20; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 17, it comprises an LC-CDR1 of SEQ ID NO: 21 , an LC-CDR2 of NAR (SEQ ID NO: 182) and an LC-CDR3 of SEQ ID NO: 22.

[0522] In some embodiments of the second aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 16 and a VL region comprising the amino acid sequence of SEQ ID NO: 17.

[0523] In a third aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 1074. In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0524] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33

[0525] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34

[0526] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35, 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.

[0527] According to this third aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0528] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36

[0529] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183)

[0530] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0531] In some embodiments, the antigen-binding molecule comprises:

[0532] (I) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33

[0533] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34

[0534] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and / or

[0535] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0536] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36

[0537] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183)

[0538] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0539] Generally, the antigen-binding molecule comprises:

[0540] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0541] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33

[0542] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34

[0543] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and

[0544] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0545] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36

[0546] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183)

[0547] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0548] In some embodiments of this third aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0549] HC-FR1 having the amino acid sequence of SEQ ID NO: 38

[0550] HC-FR2 having the amino acid sequence of SEQ ID NO: 39

[0551] HC-FR3 having the amino acid sequence of SEQ ID NO: 40

[0552] HC-FR4 having the amino acid sequence of SEQ ID NO: 41 , or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0553] In some embodiments of this third aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0554] LC-FR1 having the amino acid sequence of SEQ ID NO: 42

[0555] LC-FR2 having the amino acid sequence of SEQ ID NO: 43

[0556] LC-FR3 having the amino acid sequence of SEQ ID NO: 44

[0557] LC-FR4 having the amino acid sequence of SEQ ID NO: 45, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0558] In some embodiments of this third aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 31.

[0559] In some embodiments of this third aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 32.

[0560] In some embodiments of th is third aspect, the antigen-binding molecule comprises:

[0561] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 31 ; and

[0562] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 32; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 31 , it comprises an HC-CDR1 of SEQ ID NO: 33, an HC-CDR2 of SEQ ID NO: 34 and an HC-CDR3 of SEQ ID NO: 35; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 32, it comprises an LC-CDR1 of SEQ ID NO: 36, an LC-CDR2 of ATS (SEQ ID NO: 183) and an LC-CDR3 of SEQ ID NO: 37.

[0563] In some embodiments of the third aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 31 and a VL region comprising the amino acid sequence of SEQ ID NO: 32.

[0564] In a fourth aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 1083. In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0565] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50, 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. According to this fourth aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0566] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36

[0567] LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184)

[0568] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0569] In some embodiments, the antigen-binding molecule comprises:

[0570] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0571] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and / or

[0572] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0573] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52.

[0574] Generally, the antigen-binding molecule comprises:

[0575] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0576] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and

[0577] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0578] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52.

[0579] In some embodiments of this fourth aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0580] HC-FR1 having the amino acid sequence of SEQ ID NO: 53

[0581] HC-FR2 having the amino acid sequence of SEQ ID NO: 54

[0582] HC-FR3 having the amino acid sequence of SEQ ID NO: 55

[0583] HC-FR4 having the amino acid sequence of SEQ ID NO: 26, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0584] In some embodiments of this fourth aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0585] LC-FR1 having the amino acid sequence of SEQ ID NO: 57 LC-FR2 having the amino acid sequence of SEQ ID NO: 58

[0586] LC-FR3 having the amino acid sequence of SEQ ID NO: 59

[0587] LC-FR4 having the amino acid sequence of SEQ ID NO: 45, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0588] In some embodiments of this fourth aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 46.

[0589] In some embodiments of this fourth aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 47.

[0590] In some embodiments of this fourth aspect, the antigen-binding molecule comprises:

[0591] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 46; and

[0592] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 47; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 46, it comprises an HC-CDR1 of SEQ ID NO: 48, an HC-CDR2 of SEQ ID NO: 49 and an HC-CDR3 of SEQ ID NO: 50; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 47, it comprises an LC-CDR1 of SEQ ID NO: 36, an LC-CDR2 of GTS (SEQ ID NO: 184) and an LC-CDR3 of SEQ ID NO: 52.

[0593] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 46 and a VL region comprising the amino acid sequence of SEQ ID NO: 47.

[0594] In a fifth aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 1094. In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63

[0595] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64

[0596] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65, 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.

[0597] According to this fifth aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0598] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66

[0599] LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183)

[0600] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0601] In some embodiments, the antigen-binding molecule comprises:

[0602] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0603] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65; and / or

[0604] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0605] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0606] Generally, the antigen-binding molecule comprises:

[0607] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0608] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65; and

[0609] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0610] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0611] In some embodiments of this fifth aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0612] HC-FR1 having the amino acid sequence of SEQ ID NO: 68

[0613] HC-FR2 having the amino acid sequence of SEQ ID NO: 69

[0614] HC-FR3 having the amino acid sequence of SEQ ID NO: 70 HC-FR4 having the amino acid sequence of SEQ ID NO: 71 , or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0615] In some embodiments of this fifth aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0616] LC-FR1 having the amino acid sequence of SEQ ID NO: 72

[0617] LC-FR2 having the amino acid sequence of SEQ ID NO: 73

[0618] LC-FR3 having the amino acid sequence of SEQ ID NO: 74

[0619] LC-FR4 having the amino acid sequence of SEQ ID NO: 75, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0620] In some embodiments of this fifth aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 61.

[0621] In some embodiments of this fifth aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 62.

[0622] In some embodiments of this fifth aspect, the antigen-binding molecule comprises:

[0623] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 61 ; and

[0624] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 62; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 61 , it comprises an HC-CDR1 of SEQ ID NO: 63, an HC-CDR2 of SEQ ID NO: 64 and an HC-CDR3 of SEQ ID NO: 65; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 62, it comprises an LC-CDR1 of SEQ ID NO: 66, an LC-CDR2 of ATS (SEQ ID NO: 183) and an LC-CDR3 of SEQ ID NO: 67. In some embodiments of the fifth aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 61 and a VL region comprising the amino acid sequence of SEQ ID NO: 62.

[0625] In a sixth aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 2007. In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0626] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80, 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.

[0627] According to this sixth aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0628] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81

[0629] LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186)

[0630] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0631] In some embodiments, the antigen-binding molecule comprises:

[0632] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0633] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and / or

[0634] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0635] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0636] Generally, the antigen-binding molecule comprises:

[0637] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0638] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and

[0639] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0640] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0641] In some embodiments of this sixth aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0642] HC-FR1 having the amino acid sequence of SEQ ID NO: 83

[0643] HC-FR2 having the amino acid sequence of SEQ ID NO: 84

[0644] HC-FR3 having the amino acid sequence of SEQ ID NO: 85

[0645] HC-FR4 having the amino acid sequence of SEQ ID NO: 71 , or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0646] In some embodiments of this sixth aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0647] LC-FR1 having the amino acid sequence of SEQ ID NO: 87

[0648] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0649] LC-FR3 having the amino acid sequence of SEQ ID NO: 89

[0650] LC-FR4 having the amino acid sequence of SEQ ID NO: 30, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0651] In some embodiments of this sixth aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 76.

[0652] In some embodiments of this sixth aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 77.

[0653] In some embodiments of this sixth aspect, the antigen-binding molecule comprises:

[0654] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 76; and

[0655] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 77; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 76, it comprises an HC-CDR1 of SEQ ID NO: 78, an HC-CDR2 of SEQ ID NO: 79 and an HC-CDR3 of SEQ ID NO: 80; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 77, it comprises an LC-CDR1 of SEQ ID NO: 81 , an LC-CDR2 of QMS (SEQ ID NO: 186) and an LC-CDR3 of SEQ ID NO: 82.

[0656] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 76 and a VL region comprising the amino acid sequence of SEQ ID NO: 77.

[0657] In a seventh aspect, the antigen-binding molecule is or is based on the anti-B7-H3 antibody 2009. In this aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0658] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93

[0659] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94

[0660] HC-CDR3 comprising 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.

[0661] According to this seventh aspect, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0662] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96

[0663] LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187)

[0664] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0665] In some embodiments, the antigen-binding molecule comprises:

[0666] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0667] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93

[0668] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94

[0669] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 95; and / or

[0670] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0671] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96

[0672] LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0673] Generally, the antigen-binding molecule comprises:

[0674] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0675] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93

[0676] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94

[0677] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 95; and

[0678] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0679] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96 LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0680] In some embodiments of this seventh aspect, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0681] HC-FR1 having the amino acid sequence of SEQ ID NO: 98

[0682] HC-FR2 having the amino acid sequence of SEQ ID NO: 99

[0683] HC-FR3 having the amino acid sequence of SEQ ID NO: 100

[0684] HC-FR4 having the amino acid sequence of SEQ ID NO: 71 , or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0685] In some embodiments of this seventh aspect, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0686] LC-FR1 having the amino acid sequence of SEQ ID NO: 102

[0687] LC-FR2 having the amino acid sequence of SEQ ID NO: 103

[0688] LC-FR3 having the amino acid sequence of SEQ ID NO: 104

[0689] LC-FR4 having the amino acid sequence of SEQ ID NO: 15, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0690] In some embodiments of this seventh aspect, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 91.

[0691] In some embodiments of this seventh aspect, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 92.

[0692] In some embodiments of this seventh aspect, the antigen-binding molecule comprises:

[0693] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 91 ; and

[0694] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 92; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 91 , it comprises an HC-CDR1 of SEQ ID NO: 93, an HC-CDR2 of SEQ ID NO: 94 and an HC-CDR3 of SEQ ID NO: 95; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 92, it comprises an LC-CDR1 of SEQ ID NO: 96, an LC-CDR2 of NAK (SEQ ID NO: 187) and an LC-CDR3 of SEQ ID NO: 97.

[0695] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 91 and a VL region comprising the amino acid sequence of SEQ ID NO: 92.

[0696] In another aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0697] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78

[0698] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0699] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227, 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.

[0700] In some embodiments, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0701] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81

[0702] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228

[0703] LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid. In some embodiments, the antigen-binding molecule comprises:

[0704] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0705] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78

[0706] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0707] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227; and / or

[0708] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0709] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0710] In some embodiments, the antigen-binding molecule comprises:

[0711] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0712] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78

[0713] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0714] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227; and

[0715] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0716] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0717] In some embodiments, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0718] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78

[0719] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0720] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 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.

[0721] In some embodiments, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0722] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0723] In some embodiments, the antigen-binding molecule comprises: (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0724] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 190; and / or

[0725] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0726] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0727] In some embodiments, the antigen-binding molecule comprises:

[0728] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0729] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78

[0730] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79

[0731] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 190; and

[0732] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0733] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81

[0734] LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0735] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0736] HC-FR1 having the amino acid sequence of SEQ ID NO: 231

[0737] HC-FR2 having the amino acid sequence of SEQ ID NO: 232

[0738] HC-FR3 having the amino acid sequence of SEQ ID NO: 233

[0739] HC-FR4 having the amino acid sequence of SEQ ID NO: 234, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0740] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0741] LC-FR1 having the amino acid sequence of SEQ ID NO: 235

[0742] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0743] LC-FR3 having the amino acid sequence of SEQ ID NO: 236

[0744] LC-FR4 having the amino acid sequence of SEQ ID NO: 237, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0745] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 229.

[0746] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 230.

[0747] In some embodiments, the antigen-binding molecule comprises:

[0748] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 229; and

[0749] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 230; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 229, it comprises an HC-CDR1 of SEQ ID NO: 78, an HC-CDR2 of SEQ ID NO: 79 and an HC-CDR3 of SEQ ID NO: 227; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 230, it comprises an LC-CDR1 of SEQ ID NO: 81 , an LC-CDR2 of SEQ ID NO: 228 and an LC-CDR3 of SEQ ID NO: 82.

[0750] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 229 and a VL region comprising the amino acid sequence of SEQ ID NO: 230.

[0751] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0752] HC-FR1 having the amino acid sequence of SEQ ID NO: 192

[0753] HC-FR2 having the amino acid sequence of SEQ ID NO: 193

[0754] HC-FR3 having the amino acid sequence of SEQ ID NO: 194

[0755] HC-FR4 having the amino acid sequence of SEQ ID NO: 195, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0756] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0757] LC-FR1 having the amino acid sequence of SEQ ID NO: 196

[0758] LC-FR2 having the amino acid sequence of SEQ ID NO: 88 LC-FR3 having the amino acid sequence of SEQ ID NO: 197

[0759] LC-FR4 having the amino acid sequence of SEQ ID NO: 198, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0760] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 188.

[0761] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 189.

[0762] In some embodiments, the antigen-binding molecule comprises:

[0763] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 188; and

[0764] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 189; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 188, it comprises an HC-CDR1 of SEQ ID NO: 78, an HC-CDR2 of SEQ ID NO: 79 and an HC-CDR3 of SEQ ID NO: 190; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 189, it comprises an LC-CDR1 of SEQ ID NO: 81 , an LC-CDR2 of SEQ ID NO: 191 and an LC-CDR3 of SEQ ID NO: 82.

[0765] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 188 and a VL region comprising the amino acid sequence of SEQ ID NO: 189.

[0766] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0767] HC-FR1 having the amino acid sequence of SEQ ID NO: 201

[0768] HC-FR2 having the amino acid sequence of SEQ ID NO: 202

[0769] HC-FR3 having the amino acid sequence of SEQ ID NO: 203

[0770] HC-FR4 having the amino acid sequence of SEQ ID NO: 204, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0771] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0772] LC-FR1 having the amino acid sequence of SEQ ID NO: 205

[0773] LC-FR2 having the amino acid sequence of SEQ ID NO: 88

[0774] LC-FR3 having the amino acid sequence of SEQ ID NO: 206

[0775] LC-FR4 having the amino acid sequence of SEQ ID NO: 207, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0776] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 199.

[0777] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 200.

[0778] In some embodiments, the antigen-binding molecule comprises:

[0779] (I) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 199; and

[0780] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 200; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 199, it comprises an HC-CDR1 of SEQ ID NO: 78, an HC-CDR2 of SEQ ID NO: 79 and an HC-CDR3 of SEQ ID NO: 190; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 200, it comprises an LC-CDR1 of SEQ ID NO: 81 , an LC-CDR2 of SEQ ID NO: 191 and an LC-CDR3 of SEQ ID NO: 82.

[0781] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 199 and a VL region comprising the amino acid sequence of SEQ ID NO: 200. In another aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0782] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239, 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.

[0783] In some embodiments, the antigen-binding molecule may comprise a light chain variable (VL) region incorporating the following CDRs:

[0784] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0785] In some embodiments, the antigen-binding molecule comprises:

[0786] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0787] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239; and / or

[0788] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0789] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0790] In some embodiments, the antigen-binding molecule comprises:

[0791] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0792] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239; and

[0793] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0794] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0795] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210, 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.

[0796] In some embodiments, the antigen-binding molecule comprises:

[0797] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0798] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or

[0799] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0800] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0801] In some embodiments, the antigen-binding molecule comprises:

[0802] (I) a heavy chain variable (VH) region incorporating the following CDRs:

[0803] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and

[0804] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0805] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0806] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0807] HC-FR1 having the amino acid sequence of SEQ ID NO: 242

[0808] HC-FR2 having the amino acid sequence of SEQ ID NO: 243

[0809] HC-FR3 having the amino acid sequence of SEQ ID NO: 244

[0810] HC-FR4 having the amino acid sequence of SEQ ID NO: 245, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0811] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following FRs: LC-FR1 having the amino acid sequence of SEQ ID NO: 246

[0812] LC-FR2 having the amino acid sequence of SEQ ID NO: 247

[0813] LC-FR3 having the amino acid sequence of SEQ ID NO: 248

[0814] LC-FR4 having the amino acid sequence of SEQ ID NO: 249, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0815] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 240.

[0816] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 241 .

[0817] In some embodiments, the antigen-binding molecule comprises:

[0818] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 240; and

[0819] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 241 ; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 240, it comprises an HC-CDR1 of SEQ ID NO: 238, an HC-CDR2 of SEQ ID NO: 19 and an HC-CDR3 of SEQ ID NO: 239; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 241 , it comprises an LC-CDR1 of SEQ ID NO: 21 , an LC-CDR2 of SEQ ID NO: 182 and an LC-CDR3 of SEQ ID NO: 22.

[0820] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 240 and a VL region comprising the amino acid sequence of SEQ ID NO: 241.

[0821] In another aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0822] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210, 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.

[0823] In some embodiments, the antigen-binding molecule comprises:

[0824] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0825] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18

[0826] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0827] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or

[0828] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0829] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0830] In some embodiments, the antigen-binding molecule comprises:

[0831] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0832] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18

[0833] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0834] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and

[0835] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0836] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0837] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following FRs:

[0838] HC-FR1 having the amino acid sequence of SEQ ID NO: 211

[0839] HC-FR2 having the amino acid sequence of SEQ ID NO: 212

[0840] HC-FR3 having the amino acid sequence of SEQ ID NO: 213

[0841] HC-FR4 having the amino acid sequence of SEQ ID NO: 204, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0842] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0843] LC-FR1 having the amino acid sequence of SEQ ID NO: 214

[0844] LC-FR2 having the amino acid sequence of SEQ ID NO: 215

[0845] LC-FR3 having the amino acid sequence of SEQ ID NO: 216

[0846] LC-FR4 having the amino acid sequence of SEQ ID NO: 217, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid.

[0847] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 208.

[0848] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 209.

[0849] In some embodiments, the antigen-binding molecule comprises:

[0850] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 208; and

[0851] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 209; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 208, it comprises an HC-CDR1 of SEQ ID NO: 18, an HC-CDR2 of SEQ ID NO: 19 and an HC-CDR3 of SEQ ID NO: 210; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 209, it comprises an LC-CDR1 of SEQ ID NO: 21 , an LC-CDR2 of SEQ ID NO: 182 and an LC-CDR3 of SEQ ID NO: 22.

[0852] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 208 and a VL region comprising the amino acid sequence of SEQ ID NO: 209.

[0853] In another aspect, the antigen-binding molecule may comprise a heavy chain variable (VH) region incorporating the following CDRs:

[0854] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220

[0855] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0856] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210, 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. In some embodiments, the antigen-binding molecule comprises:

[0857] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0858] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220

[0859] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0860] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or

[0861] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0862] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0863] In some embodiments, the antigen-binding molecule comprises:

[0864] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0865] HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220

[0866] HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19

[0867] HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and

[0868] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0869] LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0870] In some embodiments, the antigen-binding molecule comprises a VH region incorporating the following

[0871] FRs:

[0872] HC-FR1 having the amino acid sequence of SEQ ID NO: 221

[0873] HC-FR2 having the amino acid sequence of SEQ ID NO: 222

[0874] HC-FR3 having the amino acid sequence of SEQ ID NO: 223

[0875] HC-FR4 having the amino acid sequence of SEQ ID NO: 195, or a variant thereof in which one or two or three amino acids in one or more of HC-FR1 , HC-FR2, HC-FR3, or HC-FR4 are substituted with another amino acid.

[0876] In some embodiments, the antigen-binding molecule comprises a VL region incorporating the following FRs:

[0877] LC-FR1 having the amino acid sequence of SEQ ID NO: 224

[0878] LC-FR2 having the amino acid sequence of SEQ ID NO: 225

[0879] LC-FR3 having the amino acid sequence of SEQ ID NO: 226

[0880] LC-FR4 having the amino acid sequence of SEQ ID NO: 30, or a variant thereof in which one or two or three amino acids in one or more of LC-FR1 , LC-FR2, LC-FR3, or LC-FR4 are substituted with another amino acid. In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 218.

[0881] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 219.

[0882] In some embodiments, the antigen-binding molecule comprises:

[0883] (i) a VH region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 218; and

[0884] (ii) a VL region comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 219; wherein, when the VH region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 218, it comprises an HC-CDR1 of SEQ ID NO: 220, an HC-CDR2 of SEQ ID NO: 19 and an HC-CDR3 of SEQ ID NO: 210; and when the VL region comprises an amino acid sequence with less than 100 % identity to SEQ ID NO: 219, it comprises an LC-CDR1 of SEQ ID NO: 21 , an LC-CDR2 of SEQ ID NO: 182 and an LC-CDR3 of SEQ ID NO: 22.

[0885] In some embodiments, the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 218 and a VL region comprising the amino acid sequence of SEQ ID NO: 219.

[0886] The antigen-binding molecule of any of the aspects provided herein may be humanised. A “humanised” antibody is an antibody derived from non-human germline immunoglobulin sequences, but which has been modified to replace non-human sequences with human ones. A humanised antibody may be derived, for instance, from mouse, rat, rabbit, etc., germline immunoglobulin sequences. Indeed, a humanised antibody may be derived from the germline immunoglobulin sequences of any non-human animal. In the present case, the antibodies described in the Examples and on which the antigen-binding molecules described above are based were originally derived from mice, and so may be humanised relative to their original murine sequences. As defined herein, an antibody is considered humanised if at least one of the VH and VL domains is humanised. In particular, a humanised antibody may comprise a humanised VH sequence and a humanised VL sequence. In a humanised variable domain, a non-human variable domain sequence is modified to replace the nonhuman (e.g. murine) framework sequences with human framework sequences, such that, generally, the only non-human sequences in the antibody are the CDR sequences (though the CDR sequences may also be modified during the humanisation process). Antibody humanisation is generally performed by a process known as CDR grafting, though any other technique in the art may be used. CDR grafting is well described in Williams, D.G. et al., Antibody Engineering Vol. 1 , edited by R. Kontermann and S. Dubel, Chapter 21 , pp. 319-339, 2010. In this process, humanisation of non-human variable domains involves intercalating the non-human CDRs from each immunoglobulin chain within the framework regions of the most appropriate human variable region. This is done by aligning the non-human variable domains with databases of known human variable domains (e.g. IMGT or Kabat). Appropriate human framework regions are identified from the best aligned variable domains, e.g. domains with high sequence identity between the human and non-human framework regions, domains containing CDRs of the same length, domains having the most similar structures (based on homology modelling), etc. The non-human CDR sequences are then grafted into the lead human framework sequences at the appropriate locations using recombinant DNA technology, and the humanised antibodies then produced and tested for binding to the target antigen. The process of antibody humanisation is known and understood by the skilled individual, who can perform the technique without further instruction. Antibody humanisation services are also offered by a number of commercial companies, e.g. GenScript (USA / China) and LifeArc (UK).

[0887] Fc regions

[0888] In some embodiments, the antigen-binding molecules of the present disclosure comprise an Fc region. 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. Generally, when an antigen-binding molecule provided herein comprises an Fc region, it also comprises a CH1 domain of an Ig heavy chain constant sequence, i.e. it generally comprises the CH1-CH2-CH3 region of an Ig heavy chain constant sequence.

[0889] 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 a / ., 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 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 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 described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85. In some embodiments, a CH2 domain, CH3 domain and / or a CH2-CH3 region according to the present disclosure corresponds to the CH2 domain / CH3 domain / CH2-CH3 region of an IgG (e.g. lgG1 , lgG2, lgG3, lgG4), IgA (e g. Ig A1 , lgA2), IgD, IgE or IgM. In some embodiments, the CH2 domain, CH3 domain and / or a CH2-CH3 region corresponds to the CH2 domain / CH3 domain / CH2-CH3 region of a human IgG (e.g. h IgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), h Ig D , h IgE or hlgM. In some embodiments, the CH2 domain, CH3 domain and / or a CH2-CH3 region corresponds to the CH2 domain / CH3 domain / CH2-CH3 region of a human lgG1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17).

[0890] 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.

[0891] In some embodiments, an antigen-binding molecule according to the present disclosure comprises one or more (e.g. two) polypeptides (e.g. heavy chains) comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 158 (the human Ig G 1 CH2-CH3 sequence) or SEQ ID NO: 178 (the human lgG1 g1 m3 allotype CH2-CH3 sequence). In some embodiments, the antigen-binding molecule comprises an Fc region comprising one or more (e.g. two) polypeptides comprising an amino acid sequence having at least 60 % amino acid sequence identity, e.g. >70 %, >75 %, >80 %, >85 %, >86 %, >87 %, >88 %, >89 %, >90 %, >91 %, >92 %, >93 %, >94 %, >95 %, >96 %, >97 %, >98 %, >99 % or 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 158 or 178.

[0892] Modifications to antibody Fc regions that influence Fc-mediated functions are known in the art, such as those described 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 antigenbinding 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. Where an Fc region / CH2 / CH3 is described as comprising mod ification(s) ‘corresponding to’ reference substitution(s), equivalent substitution(s) in the homologous Fc / CH2 / CH3 are contemplated.

[0893] Moreover, recombinant co-expression of constituent polypeptides of antigen-binding molecules and their subsequent association leads to several possible combinations. To improve the yield of the desired combinations of polypeptides in recombinant production, it is advantageous to introduce Fc region modification(s) promoting association of the desired combinations of polypeptides. Modifications may promote e.g. hydrophobic and / or electrostatic interaction between CH2 and / or CH3 regions of different polypeptide chains. Such modifications are described e.g. in Ha et al., Front Immunol. (2016) 7:394, which is hereby incorporated by reference in its entirety.

[0894] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising one or more modifications relative to the native sequence(s). 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.

[0895] In some embodiments, an 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-RVT5.S, SEED or A107.

[0896] In some embodiments, an Fc region according to the present disclosure comprises the ‘knob-into-hole’ or ‘KiH’ modification which is described e.g. in US 7,695,936, Atwell et al., J Mol Biol. (1997) 270(1):26-35 and Carter, J Immunol Meth. (2001) 248(1-2):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 an Fc region of the present disclosure comprises the substitution T366W, and the other CH3 region of the Fc region comprises the substitution Y407V (numbering of positions / substitutions in the Fc, CH2 and CH3 regions herein is according to the EU numbering system as described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85). In some embodiments, one of the CH3 regions of the Fc region comprises the substitution T366W, and the other CH3 region comprises the substitutions T366S and L368A. In some embodiments, one of the CH3 regions of the Fc region comprises the substitution T366W, and the other CH3 region comprises the substitutions Y407V, T366S and L368A. In some embodiments, the Fc region comprises modification to promote hexamerisation of the antigenbinding molecule. In some embodiments, the Fc region comprises modification to increase antigenbinding molecule half-life.

[0897] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions F243L / R292P / Y300L / V305I / P396L as described in Stavenhagen et a / . 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.

[0898] 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.

[0899] 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. 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.

[0900] 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.

[0901] In some embodiments, the Fc region comprises modification to reduce / prevent an Fc-mediated function (e g. ADCC, ADCP, CDC). In some embodiments, the Fc region comprises modification to reduce / prevent ADCC. In some embodiments, the Fc region comprises modification to reduce / prevent CDC. In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fc receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fey receptor. In some embodiments the Fc region comprises modification to reduce / prevent binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments the Fc region comprises modification to reduce / prevent binding to FcyRllla. In some embodiments the Fc region comprises modification to reduce / prevent binding to FcyRlla. In some embodiments the Fc region comprises modification to reduce / prevent binding to FcyRllb. In some embodiments the Fc region comprises modification to reduce / prevent binding to a complement protein. In some embodiments the Fc region comprises modification to reduce / prevent binding to C1q. In some embodiments, the Fc region comprises modification to reduce / prevent glycosylation of the amino acid residue corresponding to N297.

[0902] In some embodiments, the Fc region comprises modification at the amino acid residue corresponding to N297. In some embodiments, the Fc region comprises modification corresponding to N297A or N297Q or N297G as described in Leabman et al., Mabs. (2013) 5:896-903. Glycosylation of N297 is required for interactions between the Fc region of an antibody and Fey receptors or C1q. 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 also reducing CDC and ADCC. In some embodiments, the Fc region comprises modification corresponding to N297A.

[0903] By “the amino acid corresponding to N297” is meant the amino acid which is at the position corresponding to position 297 of the immunoglobulin according to the EU numbering system described above. A modified version of the human lgG1 CH2-CH3 region comprising the N297A mutation is set out in SEQ ID NO: 159. In some embodiments, the antigen-binding molecule provided herein comprises an Fc region comprising one or more (e.g. two) polypeptides comprising the amino acid sequence of SEQ ID NO: 159. Discussion of amino acids corresponding to other positions in other sequences has the equivalent meaning.

[0904] In some embodiments the Fc region comprises modification corresponding to L235E as described in Alegre et al., J Immunol. (1992) 148:3461-3468. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A or F234A / L235A as described in Xu et al., Cell Immunol. (2000) 200:16-26. In some embodiments the Fc region comprises modification corresponding to P329A or P329G as described in Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G as described in Lo et al. J. Biol. Chem (2017) 292(9):3900-3908. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions described in Rother et al., Nat Biotechnol. (2007) 25:1256-1264. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions S228P / L235E as described in Newman et al., Clin. Immunol. (2001) 98:164- 174. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions H268Q / V309L / A330S / P331 S as described in An et al., MAbs. (2009) 1 :572-579. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions V234A / G237A / P238S / H268A / V309L / A330S / P331S as described in Vafa et al., Methods. (2014) 65:1 14- 126. In some embodiments the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331 S as described in US 2015 / 0044231 A1 .

[0905] 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). In some embodiments the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G (LALA-PG) (positions 234, 235 and 329 correspond to residues 117, 118 and 212 in SEQ ID NO: 160, the full-length human lgG1 constant region).

[0906] In some embodiments the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329A (LALA-PA). This combination of substitutions is set out in SEQ ID NO: 180 (human lgG1 constant region L234A / L235A / P329A). These substitutions are equivalent to positions 117, 118 and 212, respectively, in SEQ ID NO: 159. In some embodiments, an antigen binding molecule described herein comprises a heavy chain comprising 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: 159, and comprising alanine residues at the positions corresponding to positions 117, 118 and 329 of SEQ ID NO: 159.

[0907] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G.

[0908] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G / N297A.

[0909] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331 S.

[0910] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P.

[0911] In some embodiments, the antigen-binding molecule described herein comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % amino acid sequence identity to SEQ ID NO: 160 (the human lgG1 constant region). In some embodiments, the antigen-binding molecule described herein comprises a heavy chain comprising a modified version of the human lgG1 constant domain comprising the N297A mutation. The sequence of human lgG1 constant region N297A is set out in SEQ ID NO: 110. IgG position 297 corresponds to position 180 of SEQ ID NOs: 110 and 160. In some embodiments, the antigen-binding molecule provided herein comprises a variant of the human lgG1 N297A constant region (i.e. a version of the human lgG1 constant region comprising the N297A mutation, and also other modifications relative to the native sequence). Thus in some embodiments, the antigen-binding molecule provided herein comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 110 and comprising an alanine residue at the position corresponding to position 180 of SEQ ID NO: 110.

[0912] Corresponding amino acid positions can be identified by sequence alignment, i.e. the position in an IgG constant sequence of interest corresponding to position 180 of SEQ ID NO: 110 is the position which corresponds to (or aligns to) position 180 of SEQ ID NO: 110 when the constant region sequence of interest is aligned to SEQ ID NO: 110.

[0913] In some embodiments of the first aspect of the invention, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 113; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % amino acid sequence identity to the amino acid sequence of sequence identity to the amino acid sequence of SEQ ID NO: 114 or 1 15.

[0914] In some embodiments of the first aspect of the invention, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % amino acid sequence identity to the amino acid sequence of SEQ ID NO: 113; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % amino acid sequence identity to the amino acid sequence of sequence identity to the amino acid sequence of SEQ ID NO: 114 or 1 15.

[0915] In some embodiments of the first aspect of the invention, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 113 and a light chain comprising the amino acid sequence of SEQ ID NO: 114 or 115.

[0916] In some embodiments of the second aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 116; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 117 or 118.

[0917] In some embodiments of the second aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 116; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 1 17 or 118.

[0918] In some embodiments of the second aspect, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 16, and a light chain comprising the amino acid sequence of SEQ ID NO: 1 17 or 118.

[0919] In some embodiments of the third aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 119; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 120 or 121.

[0920] In some embodiments of the third aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 119; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 120 or 121.

[0921] In some embodiments of the third aspect, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 120 or 121.

[0922] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 122; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 123 or 124. In some embodiments of the fourth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 122; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 123 or 114.

[0923] In some embodiments of the fourth aspect, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 122 and a light chain comprising the amino acid sequence of SEQ ID NO: 123 or 124.

[0924] In some embodiments of the fifth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 125; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 126 or 127.

[0925] In some embodiments of the fifth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 125; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 126 or 127.

[0926] In some embodiments of the fifth aspect, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 125 and a light chain comprising the amino acid sequence of SEQ ID NO: 126 or 127.

[0927] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 128; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 129 or 130.

[0928] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 128; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 129 or 130.

[0929] In some embodiments of the sixth aspect, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 128 and a light chain comprising the amino acid sequence of SEQ ID NO: 129 or 130.

[0930] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 131 ; and / or a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 132 or 133.

[0931] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 131 ; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 132 or 133.

[0932] In some embodiments of the seventh aspect, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 131 and a light chain comprising the amino acid sequence of SEQ ID NO: 132 or 133.

[0933] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 250; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 251 or 252.

[0934] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 250 and a light chain comprising the amino acid sequence of SEQ ID NO: 251 or 252.

[0935] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 253; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 254 or 255.

[0936] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 253 and a light chain comprising the amino acid sequence of SEQ ID NO: 254 or 255.

[0937] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 256; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 257 or 258.

[0938] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 256 and a light chain comprising the amino acid sequence of SEQ ID NO: 257 or 258.

[0939] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 259; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 260 or 261 .

[0940] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 259 and a light chain comprising the amino acid sequence of SEQ ID NO: 260 or 261.

[0941] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 262; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 263 or 264.

[0942] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 262 and a light chain comprising the amino acid sequence of SEQ ID NO: 263 or 264. In some embodiments, the antigen-binding molecule comprises a heavy chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 265; and a light chain comprising an amino acid sequence having at least 70 %, preferably at least 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 % or 99 %, or having 100 % sequence identity to the amino acid sequence of SEQ ID NO: 266 or 267.

[0943] In some embodiments, the antigen-binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 265 and a light chain comprising the amino acid sequence of SEQ ID NO: 266 or 267.

[0944] In the above embodiments relating to the sequences of full-length heavy and light chains of antigenbinding molecules provided herein, where a variant of the specified heavy and / or light chain is included (i.e. a heavy or light chain having less than 100 % sequence identity to the amino acid sequences specified), the variant sequence preferably has the six CDR sequences specified above for the relevant aspect (i.e. the variation is not in the CDR sequences). The variants may also comprise a constant region comprising the N297A substitution described above.

[0945] Linker-payload moieties

[0946] The antigen-binding molecules described herein may be used as portions of antibody-drug conjugates (ADCs). That is, the present disclosure provides antibody-drug conjugates (ADCs) that comprise the antigen-binding molecules described herein. The ADCs described herein may comprise an antigenbinding molecule joined to a linker-payload moiety. As used herein, a linker-payload moiety refers to a moiety comprising a payload moiety, and a linker moiety for linking the payload moiety to the antigenbinding molecule of the present disclosure.

[0947] A payload moiety according to the present disclosure may comprise or consist of a cytotoxic agent. Payload moieties are described e.g. in Parslow et al., Biomedicines. 2016 Sep; 4(3): 14, Goundry and Parker, Org. Process Res. Dev. (2022) 26, 8, 2121-2123, Fu et al., Signal Transduction and Targeted Therapy (2022) 7:93, Wang et al., Acta Pharmaceutica Sinica B (2023) 13 (10): 4025-4059 and Conilh et al., J. Hematol. & Oncol. (2023) 16:3, all of which are hereby incorporated by reference in their entirety.

[0948] Suitable payload moieties include DNA damage response (DDR) inhibitors (e g. a PARP inhibitor such as olaparib), DNA topoisomerase I (TOP1) inhibitors (e.g. exetecan), mitotic inhibitors (e.g. monomethyl aureostatin E (MMAE) or monomethyl aureostatin F (MMAF)), tubulin inhibitors (e.g. maytansinoids), minor groove-binding DNA-alkylating agents (MGBAs, e.g. duocarmycins), calicheamicins, toxins (e.g. Diphtheria toxin) or any other chemotherapeutic, antineoplastic or cytotoxic agent (e.g. gemcitabine or doxorubicin). A linker moiety according to the present disclosure may be any moiety suitable for linking the payload moiety to the antigen-binding region of the antigen-binding molecule of the present disclosure. Accordingly, they generally comprise a group enabling connection to the payload moiety, a group connecting conjugation to the antigen-binding region of the antigen-binding molecule, and a linker core.

[0949] Linker moieties are described e g. in Su et al., Acta Pharmaceutica Sinica B (2021) 11 (12): 3889-3907, Fu et al., Signal Transduction and Targeted Therapy (2022) 7:93.

[0950] A linker moiety according to the present disclosure may be a cleavable linker moiety or a non-cleavable moiety.

[0951] Cleavable linkers typically utilise differences between the environment of systemic circulation and that in cancer cells / the tumour microenvironment to release the payload moiety in a targeted manner. Cleavable linkers include chemical cleavage linkers (e.g. acid-cleavable linkers, GSH-cleavable linkers, Fe(ll)- cleavable linkers) and enzyme cleavage linkers (e.g. cathepsin-cleavable linkers, glycosidase-cleavable linkers, phosphatase-cleavable linkers, sulfatase-cleavable linkers).

[0952] Non-cleavable linkers remain inert in common chemical and enzymatic environments in the body, with the payload moiety being released following processing of the ADC by cellular lysosomal proteases. Non- cleavable linkers include linkers comprising thioether or maleimidocaproyl groups.

[0953] In some embodiments, a linker moiety further comprises a spacer moiety. Spacer moieties are sometimes required due to the bulky nature of payload moieties. Commonly employed spacer moieties include para-aminobenzyl carbamate (PABC), hemiaminal groups, PEG groups, polar acyl sulfamide groups, a polar carbamoyl sulfamide groups and HydraSpace (described e.g. in Verkade et al., Antibodies (Basel) (2018) 7(1 ):12 and WO 2016 / 053107 A1 , both of which are hereby incorporated by reference in their entirety). PABC is commonly employed as a spacer moiety in cathepsin-cleavable dipeptide linkers, p-glucuronidase-cleavable linkers, p-galactosidase-cleavable linkers and phosphatase cleavable linkers.

[0954] Functional properties of the antigen-binding molecules

[0955] The 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 cells expressing B7-H3; inhibits B7-H3-mediated signalling; inhibits proliferation of B7-H3-expressing cells; increases killing of cells expressing B7-H3; inhibits tumour growth and / or reduces tumour size / volume (e.g. of a B7H3-expressing cancer); increases survival of subjects having a cancer (e.g. a B7H3-expressing cancer); increases immune cell (e.g. T cell and / or NK cell) activity (e.g. in a subject with cancer); increases tumour-infiltrating lymphocyte (TIL) activity (e.g. in a subject with cancer); increases immune cell-mediated killing of tumour cells (e.g. in a subject with cancer).

[0956] 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 in vitro assays or in vivo assays, i.e. performed in non-human animals. Alternatively, the assays may be ex vivo assays, i.e. performed using cells / tissue / an organ obtained from a subject.

[0957] Where cell-based assays are used, they may comprise treating cells with an 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).

[0958] 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 ‘ECso’. Depending on the property, the ECso 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.

[0959] The antigen-binding molecules of the present disclosure bind to B7-H3 in regions which are accessible to an antigen-binding molecule when B7-H3 is expressed at the cell surface (i.e. in or at the cell membrane), i.e. they bind the extracellular domain of B7-H3. Example 2 below shows that certain of the provided antibodies bind a B7-H3 V-domain and the others bind a B7-H3 C-domain. Thus the antigenbinding molecules provided bind to B7-H3 expressed at the cell surface of a cell expressing B7-H3. Thus the antigen-binding molecules bind to B7-H3-expressing cells.

[0960] In some embodiments, the antigen-binding molecule inhibits proliferation of B7-H3-expressing cells (e.g. B7-H3-expressing cancer cells). The ability of an antigen-binding molecule to inhibit proliferation of a given cell type can be analysed by contacting cells with the antigen-binding molecule, and subsequently evaluating proliferation of the cells (i.e. after a period of time sufficient for an effect on cell proliferation 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. In some embodiments, the antigen-binding molecule of the present invention is capable of inhibiting proliferation of B7-H3-expressing cells to less than 1 times, e.g. <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 of proliferation of B7-H3-expressing cells observed in the absence of the antigenbinding molecule (or in the presence of an appropriate control antigen-binding molecule known not to influence proliferation of B7H3-expressing cells), in a given assay.

[0961] In some embodiments, the antigen-binding molecule described herein inhibits proliferation of cells expressing human B7-H3 with an ICso of 100 nM or less, preferably one of <50 nM, <40 nM, <30 nM, <20 nM, <10 nM, <5 nM, <4 nM, <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM or <500 pM.

[0962] In some embodiments, the antigen-binding molecule according to the present disclosure potentiates ( / .e. upregulates, enhances) killing of cells comprising / expressing B7-H3.

[0963] In some embodiments, an antigen-binding molecule according to the present disclosure may inhibit growth or reduce metastasis of a cancer comprising cells comprising / expressing B7-H3. In some embodiments, an antigen-binding molecule may potentiate (f.e. upregulate, enhance) killing of cells comprising / expressing B7-H3. In some embodiments, an antigen-binding molecule may inhibit growth of cells of a cancer, or may inhibit growth of a tumour, comprising cells comprising / expressing B7-H3. In some embodiments, an antigen-binding molecule may inhibit metastasis of a cancer / tumour comprising cells comprising / expressing B7-H3.

[0964] Cell killing can be investigated, for example, using any of the methods reviewed in Zaritskaya et al., Expert Rev Vaccines (2011), 9(6):601-616, hereby incorporated by reference in its entirety. Examples of in vitro assays of cytotoxicity / cell killing assays include release assays such as the51Cr release assay, the lactate dehydrogenase (LDH) release assay, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) release assay, ATP release assay using Cell Titre Gio, and the calcein-acetoxymethyl (calcein-AM) release assay. These assays measure cell killing based on the detection of factors released from lysed cells.

[0965] In some embodiments an antigen-binding molecule according to the present disclosure is capable of reducing the number / proportion of cells expressing B7-H3. In some embodiments, an antigen-binding molecule according to the present disclosure is capable of depleting / enhancing depletion of such cells.

[0966] In some embodiments, an antigen-binding molecule of the present disclosure displays anti-cancer activity. In some embodiments, the antigen-binding molecule increases killing of cancer cells. In some embodiments, the antigen-binding molecule causes a reduction in the number of cancer cells in vivo, e.g. as compared to an appropriate control condition. The cancer may be a cancer as described herein, e.g. a cancer expressing / overexpressing B7-H3.

[0967] In some embodiments, an antigen-binding molecule according to the present disclosure reduces / inhibits growth of a cancer and / or of a tumour of a cancer. In some embodiments, an antigen-binding molecule reduces tissue invasion by cells of a cancer. In some embodiments, an antigen-binding molecule reduces metastasis of a cancer. In some embodiments, an antigen-binding molecule displays anticancer activity. In some embodiments, an antigen-binding molecule reduces the growth / proliferation of cancer cells. In some embodiments, an antigen-binding molecule reduces the survival of cancer cells. In some embodiments, an antigen-binding molecule increases the killing of cancer cells. In some embodiments, an antigen-binding molecule of the present disclosure causes a reduction in the number of cancer cells e.g. in vivo. The cancer may be a cancer comprising cells expressing B7H3.

[0968] An antigen-binding molecule of the present disclosure may be analysed for the properties described in the preceding paragraph in appropriate assays. Such assays include e.g. in vivo models.

[0969] In some embodiments, administration of an antigen-binding molecule according to the present disclosure may cause one or more of: inhibition of the development / progression of the cancer, a delay to / prevention of onset of the cancer, a reduction in / delay to / prevention of tumour growth, a reduction in / delay to / prevention of tissue invasion, a reduction in / delay to / prevention of metastasis, a reduction in the severity of one or more symptoms of the cancer, a reduction in the number of cancer cells, a reduction in the cancer burden, a reduction in tumour size / volume, and / or an increase in survival of subjects having the cancer (e.g. progression free survival or overall survival), e.g. as determined in an appropriate model.

[0970] In some embodiments, the antigen-binding molecule provided herein may be used as immune cell engagers. I.e. the antigen-binding molecules may be used to bind B7-H3 on immune cells (such as T cells or NK cells) and thereby block its interaction with its receptor, preventing B7-H3-mediated suppression of immune cell activity.

[0971] The antigen-binding molecule provided herein may thus increase immune cell (e.g. T cell or NK cell) activity. Immune cell activity, as referred to herein, includes immune cell-mediated killing of target cells (e.g. cancer cells), immune cell proliferation and pro-inflammatory cytokine (e.g. IFNy) release. The effect of the antigen-binding molecules on immune cell activity can be measured by e.g. applying the antigenbinding molecule to T cells and stimulating the T cells with antigenic peptides, and measuring T cell activity in respect of e.g. T cell proliferation or cytokine (e.g. IFNy) release. The effect of the antigenbinding molecules on immune cell-mediated cell killing can be measured by e.g. applying the antigenbinding molecule to immune cells which express B7-H3 (e.g. T cells or NK cells) and incubating the immune cells with target cells, particularly cancer cells. An anti-B7-H3 antigen-binding molecule of the invention which increases immune cell activity may cause an e.g. 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or greater increase in immune cell activity (e.g. proliferation, cytokine release or target cell killing) than a suitable control (e.g. an isotype control). It will be appreciated that effects recited in the preceding paragraphs are evaluated after a period of time sufficient for an effect associated with treatment using the antigen-binding molecule to be observed. Tumour growth may be monitored by investigating tumour volume over time. Tumour growth may be evaluated by measuring tumour volume (e.g. in mm3) over time.

[0972] In some embodiments, an antigen-binding molecule of the present disclosure is capable of reducing tumour size / volume (e.g. the mean tumour size / volume for the treatment group in an in vivo model) to less than 1 times, e.g. <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 tumour size / volume observed at the same timepoint in the absence of treatment with the antigen-binding molecule (or following treatment with an appropriate control antigen-binding molecule known not to influence tumour growth), in a given assay. In some embodiments, evaluation of tumour size / volume for the purposes of such comparison is performed after more than 5 days, e.g. >10 days, >15 days, >20 days, >25 days, >30 days, >35 days, >40 days, >45 days, >50 days, >55 days, >60 days, >65 days, >70 days, >75 days, >80 days, >85 days, >90 days, >95 days or >100 days following administration of the first dose of the antigen-binding molecule, in the relevant model.

[0973] In some embodiments, an antigen-binding molecule of the present disclosure achieves a level of tumour growth inhibition (e.g. expressed as % tumour growth inhibition, e.g. calculated relative to tumour growth observed on treatment with an appropriate control antigen-binding molecule) which is at least 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 % or 90 %.

[0974] In some embodiments, an antigen-binding molecule of the present disclosure is capable of increasing median survival of subjects having a cancer to greater than 1 times, e.g. >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 median survival observed in the absence of treatment with the antigen-binding molecule (or following treatment with an appropriate control antigen-binding molecule known not to influence survival of subjects having the cancer), in a given assay. Median survival may be expressed in days from the start of the experiment, for subjects in the relevant treatment groups.

[0975] Additional sequences

[0976] The antigen-binding molecules of the present disclosure and their constituent polypeptides may additionally comprise further amino acids or sequences of amino acids.

[0977] The polypeptides of the present disclosure may comprise one or more linker sequences between sequences of amino acids. Linker sequences are known to the skilled person, and are described, for example in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369, which is hereby incorporated by reference in its entirety. In some embodiments, a linker sequence may be a flexible linker sequence. Flexible linker sequences allow for relative movement of the amino acid sequences which are linked by the linker sequence. Flexible linkers are known to the skilled person, and several are identified in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369. Flexible linker sequences often comprise high proportions of glycine and / or serine residues.

[0978] In some embodiments, the linker sequence comprises at least one glycine residue and / or at least one serine residue. In some embodiments, the linker sequence comprises or consists of glycine and serine residues. 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 linker sequence comprises one or more (e.g. 1 , 2, 3, 4, 5 or 6) copies (e.g. in tandem) of the sequence motif G4S. In some embodiments, the linker sequence comprises or consists of (G4S)4 or (G4S)B. In some embodiments, the linker sequence has a length of 1 -2, 1-3, 1-4, 1-5, 1-10, 1-15, 1-20, 1-25, or 1-30 amino acids.

[0979] The antigen-binding molecules of the present disclosure and their constituent polypeptides may comprise amino acid sequence(s) to facilitate expression, folding, trafficking, processing, purification or detection of the antigen-binding molecule / polypeptide. For example, antigen-binding molecules and polypeptides of the present disclosure may additionally comprise a sequence of amino acids forming a detectable moiety, e g. as described hereinbelow.

[0980] The antigen-binding molecules of the present disclosure and their constituent polypeptides may additionally comprise a signal peptide (also known as a leader sequence or signal sequence). Signal peptides normally consist of a sequence of 5-30 hydrophobic amino acids, which form a single alpha helix. Secreted proteins and proteins expressed at the cell surface often comprise signal peptides. Signal peptides are known for many proteins, and are recorded in databases such as GenBank, UniProt and Ensembl, and / or can be identified / predicted e.g. using amino acid sequence analysis tools such as SignalP (Petersen et al., 2011 Nature Methods 8: 785-786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: 2172-2176).

[0981] The signal peptide may be present at the N-terminus of the polypeptide, and may be present in the newly synthesised polypeptide. The signal peptide provides for efficient trafficking of the polypeptide. Signal peptides are often removed by cleavage, and thus are not comprised in the mature polypeptide.

[0982] Signal peptides are known for many proteins, and are recorded in databases such as GenBank, UniProt, Swiss-Prot, TrEMBL, Protein Information Resource, Protein Data Bank, Ensembl, and InterPro, and / or can be identified / predicted e.g. using amino acid sequence analysis tools such as SignalP (Petersen et al., 2011 Nature Methods 8: 785-786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: 2172- Labels and conjugates

[0983] In some embodiments, the antigen-binding molecules of the present disclosure and their constituent polypeptides comprise a detectable moiety.

[0984] In some embodiments, a detectable moiety is a fluorescent label, phosphorescent label, luminescent label, immuno-detectable label (e.g. an epitope tag), radiolabel or a chemical, nucleic acid or enzymatic label. An antigen-binding molecule or a constituent polypeptide thereof may be covalently or non- covalently labelled with the detectable moiety.

[0985] Fluorescent labels include e.g. fluorescein, rhodamine, allophycocyanin, eosin, nitrobenzoxadiazole (NBD), green fluorescent protein (GFP), chelates of rare earths such as europium (Eu), terbium (Tb) and samarium (Sm), tetramethyl rhodamine, Texas Red, 4-methyl umbelliferone, 7-amino-4-methyl coumarin, Cy3, and Cy5. Radiolabels include radioisotopes such as Hydrogen3, Sulfur35, Carbon14, Phosphorus32, Iodine123, Iodine125, Iodine126, Iodine131, Iodine133, Bromine77, Technetium99"1, Indium111, Indium113"1, Gallium67, Gallium68, Ruthenium95, Ruthenium97, Ruthenium103, Ruthenium105, Mercury203, Mercury207, Rhenium99"1, Rhenium101, Rhenium105, Scandium47, Tellurium121"1, Tellurium122"1, Tellurium125"1, Thulium165, Thulium167, Thulium168, Copper67, Fluorine18, Yttrium90, Palladium100, Bismuth217and Antimony211. Luminescent labels include radioluminescent, chemiluminescent (e.g. acridinium ester, luminol, isoluminol) and bioluminescent labels. Immuno-detectable labels include haptens, peptides / polypeptides, antibodies, receptors and ligands such as biotin, avidin, streptavidin or digoxigenin. Nucleic acid labels include aptamers.

[0986] In some embodiments, an antigen-binding molecule or a constituent polypeptide thereof comprises a radionuclide. Such conjugates may be called radionuclide drug conjugates (RDCs) or radioimmunoconjugates (RICs). In some embodiments, an antigen-binding molecule or a constituent polypeptide thereof comprises a chelator group that is capable of chelating a radionuclide. Radionuclides include radioisotopes such as those listed above, or others such as Lutetium177, Actinium225and Strontium90.

[0987] In some embodiments, an antigen-binding molecule or a constituent polypeptide thereof comprises an epitope tag, e.g. a His (e.g. 6XHis) tag, FLAG tag, c-Myc, Strep tag, HA tag, calmodulin-binding protein (CBP), glutathione-s-transferase (GST), maltose-binding protein (MBP), thioredoxin, S-peptide, T7 peptide, SH2 domain, avidin, streptavidin and haptens (e.g. biotin, digoxigenin, dinitrophenol), optionally at the N- or C-terminus of the antigen-binding molecule / polypeptide.

[0988] In some embodiments, an antigen-binding molecule or a constituent polypeptide thereof comprises a moiety having a detectable activity, e.g. an enzymatic moiety. Enzymatic moieties include e.g. luciferases, glucose oxidases, galactosidases (e g. beta-galactosidase), glucorinidases, phosphatases (e.g. alkaline phosphatase), peroxidases (e.g. horseradish peroxidase) and cholinesterases. Nucleic acids and vectors

[0989] The present disclosure provides a nucleic acid, or a plurality of nucleic acids (particularly a pair of nucleic acids, i.e. two nucleic acids), encoding an antigen-binding molecule / antigen-binding polypeptide complex or a constituent polypeptide thereof according to the present disclosure. In some embodiments, the nucleic acid(s) comprise or consist of DNA and / or RNA.

[0990] In some embodiments, the antigen-binding molecule comprises a heavy chain and a light chain and both are encoded on a single nucleic acid molecule. In some embodiments, the antigen-binding molecule comprises a heavy chain and a light chain and each chain is encoded on a different nucleic acid molecule, i.e. the heavy chain is encoded on a first nucleic acid molecule and the light chain is encoded on a second nucleic acid molecule.

[0991] An antigen-binding molecule / antigen-binding polypeptide complex or a constituent polypeptide thereof according to the present disclosure may be produced within a cell by translation of RNA encoding the polypeptide(s). An antigen-binding molecule / antigen-binding polypeptide complex or a constituent polypeptide thereof may be produced within a cell by transcription from nucleic acid(s) encoding the polypeptide(s), and subsequent translation of the transcribed RNA.

[0992] In some embodiments, the nucleic acid(s) may be, or may be comprised / contained in, a vector, or a plurality of (particularly a pair of) vectors. A ‘vector’ as used herein is a nucleic acid molecule used as a vehicle to transfer exogenous nucleic acid into a cell.

[0993] Accordingly, the present disclosure also provides a vector, or plurality of vectors, comprising the nucleic acid or plurality of nucleic acids according to the present disclosure. The vector may facilitate delivery of the nucleic acid(s) encoding a polypeptide according to the present disclosure to a cell. The vector may be an expression vector comprising elements required for expressing a polypeptide according to the present disclosure. The vector may comprise elements facilitating integration of the nucleic acid(s) into the genomic DNA of cell into which the vector is introduced.

[0994] Nucleic acids and vectors according to the present disclosure may be provided in purified or isolated form, i.e. from other nucleic acid, or naturally-occurring biological material.

[0995] A vector may be a vector for expression of the nucleic acid in the cell (i.e. an expression vector). Such vectors may include a promoter sequence operably linked to a nucleotide sequence encoding an antigenbinding molecule or polypeptide according to the present disclosure. A vector may also include a termination codon (i.e. 3’ in the nucleotide sequence of the vector to the nucleotide sequence encoding the polypeptide(s)) and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used to express a peptide or polypeptide from a vector according to the present disclosure. The term ‘operably linked’ may include the situation where nucleic acid encoding a polypeptide according to the present disclosure and regulatory nucleic acid sequence(s) (e.g. a promoter and / or enhancers) are covalently linked in such a way as to place the expression of the nucleic acid encoding a polypeptide under the influence or control of the regulatory nucleic acid sequence(s) (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to the selected nucleic acid sequence if the regulatory sequence is capable of effecting transcription of the nucleic acid sequence. The resulting transcript(s) may then be translated into the desired polypeptide(s).

[0996] Vectors contemplated in connection with the present disclosure include DNA vectors, RNA vectors, plasmids (e g. conjugative plasmids (e.g. F plasmids), non-conjugative plasmids, R plasmids, col plasmids, episomes), viral vectors (e.g. retroviral vectors, e.g. gammaretroviral vectors (e.g. murine Leukemia virus (MLV)-derived vectors, e.g. SFG vector), lentiviral vectors, adenovirus vectors, adeno- associated virus vectors, vaccinia virus vectors and herpesvirus vectors), transposon-based vectors, and artificial chromosomes (e.g. yeast artificial chromosomes), e.g. as described in Maus et al., Annu Rev Immunol (2014) 32:189-225 and Morgan and Boyerinas, Biomedicines (2016) 4:9, which are both hereby incorporated by reference in their entirety. In some embodiments, a vector according to the present disclosure is a lentiviral vector.

[0997] In some embodiments, the vector may be a eukaryotic vector, i.e. a vector comprising the elements necessary for expression of protein from the vector in a eukaryotic cell. In some embodiments, the vector may be a mammalian vector, e.g. comprising a cytomegalovirus (CMV) or SV40 promoter to drive protein expression.

[0998] Constituent polypeptides of an antigen-binding molecule / antigen-binding polypeptide complex according to the present disclosure may be encoded by different nucleic acids of the plurality of nucleic acids, or by different vectors of the plurality of vectors. In some embodiments, the antigen-binding molecule comprises a heavy chain and a light chain and both are encoded by a single vector (in which case the two chains may be encoded by the same open reading frame or by separate open reading frames). In some embodiments, the antigen-binding molecule comprises a heavy chain and a light chain and each chain is encoded by a separate vector, i.e. a first vector encodes the heavy chain and second vector encodes the light chain.

[0999] Producing the antigen-binding molecules

[1000] Antigen-binding molecules according to the present disclosure may be prepared according to methods for the production of polypeptides known to the skilled person.

[1001] Polypeptides may be prepared by chemical synthesis, e.g. liquid or solid phase synthesis. For example, peptides / polypeptides can by synthesized using the methods described in, for example, Chandrudu et al., Molecules (2013), 18: 4373-4388, which is hereby incorporated by reference in its entirety. Alternatively, antigen-binding molecules and polypeptides may be produced by recombinant expression. Molecular biology techniques suitable for recombinant production of polypeptides are well known in the art, such as those set out in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th Edition), Cold Spring Harbor Press, 2012, and in Nat Methods. (2008); 5(2): 135-146 both of which are hereby incorporated by reference in their entirety. Methods for the recombinant production of antigen-binding molecules are also described in Frenzel et al., Front Immunol. (2013); 4: 217 and Kunert and Reinhart, Appl Microbiol Biotechnol. (2016) 100: 3451-3461 , both of which are hereby incorporated by reference in their entirety.

[1002] In some cases the antigen-binding molecule of the present disclosure are comprised of more than one polypeptide chain. In such cases, production of the antigen-binding molecules may comprise transcription and translation of more than one polypeptide, and subsequent association of the polypeptide chains to form a polypeptide complex.

[1003] The skilled person is able to design and prepare antigen-binding polypeptides / polypeptide complexes. Methods for producing antigen-binding polypeptides / polypeptide complexes include chemically crosslinking antigen-binding molecules or antibody fragments, e.g. with reducible disulphide or nonreducible thioether bonds, for example as described in Segal and Bast, 2001 . Production of Bispecific Antigen-binding molecules. Current Protocols in Immunology. 14: IV:2.13:2.13.1 - 2.13.16, which is hereby incorporated by reference in its entirety. For example, / V-succinimidyl-3-(-2-pyridyldithio)-propionate (SPDP) can be used to chemically crosslink e.g. Fab fragments via hinge region SH- groups, to create disulfide-linked bispecific F(ab)2 heterodimers. Other methods for producing bispecific antigen-binding polypeptides / polypeptide complexes include fusing antibody-producing hybridomas e.g. with polyethylene glycol, to produce a quadroma cell capable of secreting bispecific antibody, for example as described in D. M. and Bast, B. J. 2001. Production of Bispecific Antigen-binding molecules. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16.

[1004] For recombinant production according to the present disclosure, any cell suitable for the expression of polypeptides may be used. The cell may be a prokaryote or eukaryote. In some embodiments, the cell is a prokaryotic cell, such as a cell of archaea or bacteria. In some embodiments, the bacteria may be Gram-negative bacteria such as bacteria of the family Enterobacteriaceae, for example Escherichia coli. In some embodiments, the cell is a eukaryotic cell such as a yeast cell, a plant cell, insect cell or a mammalian cell, e.g. a cell described hereinabove. In some cases, the cell is not a prokaryotic cell because some prokaryotic cells do not allow for the same folding or post-translational modifications as eukaryotic cells. In addition, very high expression levels are possible in eukaryotes and proteins can be easier to purify from eukaryotes using appropriate tags. Specific plasmids may also be utilised which enhance secretion of the protein into the media. In some embodiments polypeptides may be prepared by cell-free-protein synthesis (CFPS), e.g. according to a system described in Zemella et al. Chembiochem (2015) 16(17): 2420-2431 , which is hereby incorporated by reference in its entirety.

[1005] Production of antigen-binding polypeptides / polypeptide complexes may involve culture or fermentation of a eukaryotic cell modified to express the polypeptide(s) of interest. The culture or fermentation may be performed in a bioreactor provided with an appropriate supply of nutrients, air / oxygen and / or growth factors. Secreted proteins can be collected by partitioning culture media / fermentation broth from the cells, extracting the protein content, and separating individual proteins to isolate secreted polypeptide(s). Culture, fermentation and separation techniques are well known to those of skill in the art, and are described, for example, in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4thEdition; incorporated by reference herein above). Bioreactors include one or more vessels in which cells may be cultured. Culture in the bioreactor may occur continuously, with a continuous flow of reactants into, and a continuous flow of cultured cells from, the reactor. Alternatively, the culture may occur in batches. The bioreactor monitors and controls environmental conditions such as pH, oxygen, flow rates into and out of, and agitation within the vessel such that optimum conditions are provided for the cells being cultured.

[1006] Following culturing of the cells that express the polypeptide(s), the polypeptide(s) of interest may be isolated. Any suitable method for separating proteins from cells known in the art may be used. In order to isolate the polypeptide, it may be necessary to separate the cells from nutrient medium. If the polypeptide(s) are secreted from the cells, the cells may be separated by centrifugation from the culture media that contains the secreted polypeptide(s) of interest. If the polypeptide(s) of interest collect within the cell, protein isolation may comprise centrifugation to separate cells from cell culture medium, treatment of the cell pellet with a lysis buffer, and cell disruption e.g. by Bonification, rapid freeze-thaw or osmotic lysis.

[1007] It may then be desirable to isolate the polypeptide(s) of interest from the supernatant or culture medium, which may contain other protein and non-protein components. A common approach to separating protein components from a supernatant or culture medium is by precipitation. Proteins of different solubilities are precipitated at different concentrations of precipitating agent such as ammonium sulfate. For example, at low concentrations of precipitating agent, water soluble proteins are extracted. Thus, by adding different increasing concentrations of precipitating agent, proteins of different solubilities may be distinguished. Dialysis may be subsequently used to remove ammonium sulfate from the separated proteins. Other methods for distinguishing different proteins are known in the art, for example ion exchange chromatography and size chromatography. These may be used as an alternative to precipitation or may be performed subsequently to precipitation.

[1008] Once the polypeptide(s) of interest have been isolated from culture it may be desired or necessary to concentrate the polypeptide(s). A number of methods for concentrating proteins are known in the art, such as ultrafiltration or lyophilisation. The present disclosure also provides an antigen-binding molecule obtained or obtainable by the methods of the present disclosure.

[1009] Linker-Payload Conjugation

[1010] To produce ADCs, antigen-binding polypeptides / polypeptide complexes according to the present disclosure may be conjugated to linker-payload moieties according to the present disclosure by any suitable techniques, which are well known to the skilled person and routinely employed in the art.

[1011] General methods for the conjugation of antigen-binding polypeptides / polypeptide complexes to linkerpayload moieties are described e.g. in Chudasama et al., Nature Chemistry, (2016), 8:114-119, Baah et al., Molecules. (2021) 26(10): 2943, and Walsh et al., Chem. Soc. Rev. (2021) 50:1305-1353, all of which are hereby incorporated by reference in their entirety. Conjugation of antigen-binding moieties and linkerpayload moieties and purification of antigen-binding molecules produced by such conjugation is described e.g. in Beck et al., (2017) Nat Rev Drug Discov 16: 315-337; Peters and Brown Biosci Rep (2015) 35: art:e00225; McCombs and Owen, The AAPS Journal (2015) 17: 339-351 ; Jackson, Org Process Res Dev (2016) 20: 852-866; and Olivier and Hurvitz, Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcome to Target Cancer (2016) Wiley. Other relevant disclosures relating to conjugation and linkers are: Tsuchikama and An, Protein Cell. (2018) 9(1): 33-46, Khongorzul et al., Mol Cancer Res (2020) 18 (1): 3-19 and Drago et al., Nature Reviews Clinical Oncology (2021) 18: 327-344, all of which are hereby incorporated by reference in their entirety.

[1012] Lysine amide coupling

[1013] Lysine-based conjugation is one of the most widely used non-specific conjugation strategies. Such conjugation occurs on reactive amine side chains of lysine residues due to their good nucleophilicity. Immunoglobulin scaffolds contain over 80 lysine residues, most of which are exposed on the surface of the molecule. Among the surface lysine residues, more than 20 have been shown as highly solvent- accessible and can serve as potential ADC conjugation sites. Lysine conjugation follows two main strategies that result in the formation of a stable amide or amidine bond between the protein and the drug-linker complex. Generally speaking, activated esters on the drug-linker complexes, often O-succinimide reagents such as N-hydroxysuccinimidyl (NHS) or sulfo-NHS esters, react with the antibody lysine residues and achieve the conjugation via amide bonds. On the other hand, stable amidine bonds can be generated on an antibody by the reaction of imido ester compounds, such as Traut’s reagent, with antibody lysine residues.

[1014] A one-step conjugation of a drug-linker moiety containing an amine-reactive group to the antibody via amide bonds is known, as well as two-step conjugation, where in the first step, a small bi-functional reagent containing both an amine- and a thiol-reactive functional groups is reacted with the available lysine s-amino groups to serve as a chemical adaptor, leaving free thiol-reactive groups on the antibody. In the second step, the payload drugs or drug-linker complexes are attached to the thiol-reactive groups introduced previously to form the ADC. The two-step approach is often used when the drug / drug-linker complex contains a thiol-reactive module or as an alternative route when introducing an amine-reactive module into the drug or drug-linker complex is proven to be difficult. Four small adaptors commonly used in the two-step conjugation: SPDB disulfide, MCC (maleimidomethyl cyclohexane-1 -carboxylate), sulfo- SPDB, and Hydrazine.

[1015] Cysteine coupling

[1016] Cysteine modification occurs most commonly by 1 ,4-conjugate addition to N-substituted maleimides. Maleimides are particularly attractive reagents due to their synthetic accessibility and rapid reaction rates with cysteine under mild conditions. The resulting thiosuccinimide conjugates are inherently unstable, due to their propensity towards retro-Michael addition. This instability can be mitigated by forcing postconjugation hydrolysis of the thiosuccinimide, creating a stable chemical linkage. Accordingly, a number of “self-hydrolysing” maleimides have now been developed, with ring-opening catalysed by adjacent functional groups such as primary amine, polyethylene glycol (PEG) and N-ary I amongst the most promising. Other reagents including a-halocarbonyls, palladium oxidative-addition complexes, ethynylphosphonamidates, vinylphosphonites and ethynylbenziodoxolones.

[1017] Some non-maleimide cysteine conjugations are summarised in Kang, et al., Chem Sci (2021) 12, 13613- 13647, and include the use of:

[1018] (i) alkynyl carboxylic acid derivatives;

[1019] (ii) 5-methylene pyrrolone (5MP);

[1020] (iii) 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB);

[1021] (iv) phenyloxadiazole sulfone (PODS);

[1022] (v) aza-dibenzocyclooctyne (DBCO);

[1023] (vi) phosphonamidite;

[1024] (vii) 3-arylpropionitrile (APN);

[1025] (viii) perfluoroarene;

[1026] (ix) ethynylbenziodoxolone (EBX);

[1027] (x) bicyclo[1.1.0]butane (BOB) carboxylic amide; and

[1028] (xi) allenamide.

[1029] Another possible approach is described in Cheng, et al., Front. Oncol. 12:951589 where 2- methylsulfonyl pyrimidine is used instead of a maleimide.

[1030] Genetic modification of the number of accessible cysteine residues on an antibody surface is a method to achieve site-selective and homogeneous modification. For example, in THIOMABs, the engineered cysteine is installed on an anti-MUC16 antibody by mutation of heavy chain alanine 114 (HC-A114).

[1031] Other approaches have engineered antibodies to contain cysteine mutations at D265C, S239C, E269C, K326C or A327C, or to insert additional cysteines before and after positions HC-S239, HC-A114, and LC-V205. Non-natural amino acid incorporation by genetic engineering

[1032] Site-specific incorporation of non-canonical amino acids (ncAAs) into antibodies results in an efficient approach to the site-specific modification of antibodies, and therefore homogeneous ADCs.

[1033] NcAAs bearing unique functionalities, such as ketones, azides, cyclopropenes or diene functional groups, have been developed and incorporated into antibodies. Such ncAAs include p-acetylphenylalanine (pAcF), which has a ketone side chain which can participate in oxime ligation reactions;

[1034] N£-(1-methylcycloprop-2-enecarboxamido)-lysine (CpK), which has a cyclopropene side chain which can participate in IEDDA reactions; para-azidomethyl phenylalanine (pAMF), which has a an azide side chain which can undergo click reactions; spiro[2.4]hepta-4,6-diene-lysine (SCpHK), which has a spiro[2.4]hepta-4,6-diene side chain which can participate in Diels-Alder reactions; and N6-(2-azidoethoxy)-carbonyl-L-lysine (AzK), which has a an azide side chain which can undergo click reactions.

[1035] Azide-containing ncAAs can undergo rapid CuAAC or SPAAC reactions under physiological conditions, para-azidophenylalanine (pAzF) can undergo reactions with, for example, cyclooctyne-functionalised linkers and dibenzylcyclooctyne (DBCO)-functionalised linkers. A cyclopropene derivative of lysine (N e-[((2-methylcycloprop-2-en-1 -yl)methoxy)carbonyl]-l-lysine; CypK) can undergo a rapid and efficient inverse-electron demand Diels-Alder (IEDDA) reaction with a tetrazine-functionalised linker.

[1036] Cyclopentadiene-containing ncAAs, spiro[2.4]hepta-4,6-diene-lysine (SCpHK) and cyclopentadienelysine (CpHK), can undergo irreversible Diels-Alder cycloadditions with maleimide-modified drugs.

[1037] Enzymatic conjugation

[1038] Enzymes can be used to achieve site-selective antibody modification due to their high specificity and mild reaction conditions. Enzymes can either directly attach a payload to a specific amino acid sequence or introduce a reactive functionality on the antibody that can be further functionalised with the desired pay load.

[1039] Transpeptidation using sortase

[1040] Sortase-mediated antibody conjugation (SMAC) technology is an additional enzymatic ligation approach. SMAC-technology uses Staphylococcus aureus sortase A, which is a transpeptidase that cleaves the amide bond between threonine and glycine residues in the LPXTG (X = any amino acid) pentapeptide motif, and subsequently catalyses the attachment of glycine-functionalised payloads to the newly generated C-terminus. The sortase recognition motif and a Strep II tag, which is used to aid removal of unreacted antibody, can be fused to the light and heavy chain C-terminus of different antibodies. Sortase- mediated conjugation can then be used to attach a series of penta-glycine tagged payloads. Transpeptidation using microbial transglutaminase

[1041] The use of bacterial transglutaminases is a powerful approach for site-specific incorporation of a payload onto an antibody. A transglutaminase derived from Streptomyces mobaraensis catalyzes transpeptidation where a primary amine-containing linker is covalently attached to the primary amide side chain of a specific glutamine (Q295) within deglycosylated antibodies, resulting in ADCs with a defined drug to antibody ratio (DAR) arising from the conjugation of 2 linker-payloads (one conjugation site per heavy chain). An N297Q mutation prior to this conjugation provides two more reaction sites (resulting in the conjugation of 4-linker-payloads). An alternative version uses a peptide sequence-specific transglutaminase. This enzyme recognizes and utilizes an LLQG motif that is genetically incorporated, resulting in site-specific antibody-drug conjugation. Another advantage of this LLQG-specific bacterial transglutaminase is that conjugation sites can be flexibly laid by inserting this short peptide motif within the antibody structure. Further alternative approaches allow for the use of transglutaminase without deglycosylation.

[1042] N-Glycan engineering

[1043] Asn297 (N297) within the Fc domain and the N-glycan on this residue are conserved in all IgG classes, making these components attractive reaction sites for broadly applicable ADC conjugation. Incorporation of an aldehyde group on the N-glycan terminus using p-1 ,4-galactosyltransferase (GalT) and a-2,6-sialyltransferase (SialT) introduce a sialic acid on each N-glycan terminus, which is subsequently converted into an aldehyde group using NaIC under mild oxidation conditions. The aldehyde groups generated can then be used to conjugate aminooxy-functionalized payloads.

[1044] Another approach is to incorporate non-natural saccharides possessing orthogonal reaction handles into the antibody. A technology based on this strategy is GlycoConnect in which the glycan chain at Asn297 is trimmed using the endoglycosidase Endo S2 and then azide groups are introduced using a mutant galactosyl transferase GalT(Y289L) and N-azidoacetylgalactosamine (GalNAz). The azide handles can be used for a strain-promoted click reaction with payloads.

[1045] In some embodiments, the linker-payload terminates in an amino group which is conjugated to the antigen-binding molecule using transglutaminase.

[1046] The present disclosure also provides an ADC obtained or obtainable by the methods of the present disclosure.

[1047] Cells comprisinq / expressinq the antigen-binding polypeptides and their constituent polypeptides The present disclosure also provides a cell comprising or expressing an antigen-binding molecule / antigen-binding polypeptide complex or a constituent polypeptide thereof according to the present disclosure. Also provided is a cell comprising or expressing a nucleic acid, a plurality of nucleic acids, a vector or a plurality of vectors according to the present disclosure. It will be appreciated that where cells are referred to herein in the singular ( / .e. ‘a / the cell’), pluralities / populations of such cells are also contemplated.

[1048] The cell may be a eukaryotic cell, e.g. a mammalian cell. The mammal may be a primate (rhesus, cynomolgus, non-human primate or human) or a non-human mammal (e.g. rabbit, guinea pig, rat, mouse or other rodent (including any animal in the order Rodentia), cat, dog, pig, sheep, goat, cattle (including cows, e.g. dairy cows, or any animal in the order Bos), horse (including any animal in the order Equidae), donkey, and non-human primate).

[1049] In some embodiments, the cell is, or is derived from, a cell type commonly used for the expression of polypeptides for use in therapy in humans. Exemplary cells are described e.g. in Kunert and Reinhart, Appl Microbiol Biotechnol. (2016) 100:3451-3461 (hereby incorporated by reference in its entirety), and include e.g. CHO, HEK 293, PER.C6, NSO and BHK cells. In preferred embodiments, the cell is, or is derived from, a CHO cell.

[1050] The present disclosure also provides a method for producing a cell comprising a nucleic acid(s) or vector(s) according to the present disclosure, comprising introducing a nucleic acid, a plurality of nucleic acids, a vector or a plurality of vectors according to the present disclosure into a cell. In some embodiments, introducing an isolated nucleic acid(s) or vector(s) according to the present disclosure into a cell comprises transformation, transfection, electroporation or transduction (e.g. retroviral transduction).

[1051] The present disclosure also provides a method for producing a cell expressing / comprising an antigenbinding polypeptide complex or a constituent polypeptide thereof according to the present disclosure, comprising introducing a nucleic acid, a plurality of nucleic acids, a vector or a plurality of vectors according to the present disclosure in a cell. In some embodiments, the methods additionally comprise culturing the cell under conditions suitable for expression of the nucleic acid(s) or vector(s) by the cell. In some embodiments, the methods are performed in vitro.

[1052] The present disclosure also provides cells obtained or obtainable by the methods according to the present disclosure.

[1053] 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. In such embodiments, the immune cell (e.g. T cell or NK cell) is generally a human cell.

[1054] Compositions

[1055] The present disclosure provides a composition comprising an antigen-binding molecule / polypeptide / polypeptide complex according to the present disclosure, an ADC according to the present disclosure a nucleic acid or plurality of nucleic acids according to the present disclosure, an expression vector or plurality of expression vectors according to the present disclosure, or a cell according to the present disclosure.

[1056] In particular, the composition may comprise an antigen-binding molecule according to the present disclosure, and ADC according to the present disclosure or an immune cell expressing a CAR according to the present disclosure.

[1057] The antigen-binding molecules, ADCs and immune cells expressing a CAR as described herein may be formulated as pharmaceutical compositions or medicaments for clinical use and may comprise a pharmaceutically-acceptable carrier, diluent, excipient or adjuvant. Thus, the present disclosure provides a pharmaceutical composition / medicament comprising an antigen-binding molecule described herein, an ADC as described herein or an immune cell expressing a CAR as described herein.

[1058] The pharmaceutical compositions / medicaments of the present disclosure may comprise one or more pharmaceutically-acceptable carriers (e.g. liposomes, micelles, microspheres, nanoparticles), diluents / excipients (e.g. starch, cellulose, a cellulose derivative, a polyol, dextrose, maltodextrin, magnesium stearate), adjuvants, fillers, buffers, preservatives (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben), anti-oxidants (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium), lubricants (e.g. magnesium stearate, talc, silica, stearic acid, vegetable stearin), binders (e g. sucrose, lactose, starch, cellulose, gelatin, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), xylitol, sorbitol, mannitol), stabilisers, solubilisers, surfactants (e.g, wetting agents), masking agents or colouring agents (e.g. titanium oxide).

[1059] The term pharmaceutically-acceptable’ as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent of a composition according to the present disclosure must also be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, binders, stabilisers, solubilisers, surfactants, masking agents, colouring agents, flavouring agents or sweetening agents can be found in standard pharmaceutical texts, for example, Remington’s ‘The Science and Practice of Pharmacy’ (Ed. A. Adejare), 23rdEdition (2020), Academic Press.

[1060] Pharmaceutical compositions and medicaments of the present disclosure may be formulated for topical, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, intrathecal, oral or transdermal routes of administration. In some embodiments, a pharmaceutical composition / medicament may be formulated for administration by injection or infusion, or administration by ingestion.

[1061] Suitable formulations may comprise the antigen-binding molecule provided in a sterile or isotonic medium. Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form. Fluid formulations may be formulated for administration by injection or infusion (e.g. via catheter) to a selected region of the human or animal body.

[1062] In some embodiments, the pharmaceutical compositions / medicament is formulated for injection or infusion, e.g. into a blood vessel, tissue / organ of interest, or a tumour.

[1063] The present disclosure also provides methods for the production of pharmaceutically useful compositions, such methods of production may comprise one or more steps selected from: producing an antigen-binding molecule, ADC or immune cell expressing a CAR as described herein; isolating / purifying an antigen-binding molecule, ADC or immune cell expressing a CAR as described herein; and / or mixing an antigen-binding molecule, ADC or immune cell expressing a CAR as described herein with a pharmaceutically-acceptable carrier, adjuvant, excipient or diluent.

[1064] For example, a further aspect of the present disclosure relates to a method of formulating or producing a medicament or pharmaceutical composition for use in the treatment of a disease / condition (e.g. a disease / condition described herein), the method comprising formulating a pharmaceutical composition or medicament by mixing an antigen-binding molecule, ADC or immune cell expressing a CAR as described herein with a pharmaceutically-acceptable carrier, adjuvant, excipient or diluent.

[1065] Therapeutic and prophylactic applications

[1066] The antigen-binding molecules / polypeptides, ADCs, nucleic acids, expression vectors, cells (expressing a CAR) and compositions described herein find use in therapeutic and prophylactic intervention for disease, e.g. cancers.

[1067] It will be appreciated that the antigen-binding molecules, ADCs and compositions, etc., of the present disclosure may be used for the treatment / prevention of any disease / condition that would derive therapeutic or prophylactic benefit from a reduction in the level of expression or activity of B7-H3, or a reduction in the number or activity of cells comprising / expressing B7-H3.

[1068] For example, the disease / condition may be a disease / condition in which B7-H3, or cells expressing / overexpressing B7-H3 are pathologically-implicated, e.g. a disease / condition in which an increased level / activity of B7-H3, or an increase in the number / proportion of cells comprising / expressing B7-H3 is positively associated with the onset, development or progression of the disease / condition, and / or severity of one or more symptoms of the disease / condition. In some embodiments, an increased level / activity of B7-H3, or an increase in the number / proportion of cells comprising / expressing B7-H3 may be a risk factor for the onset, development or progression of the disease / condition.

[1069] Additionally, as noted above, B7-H3 expressed on immune cells within tumours acts as an immune checkpoint, down-regulating immune cell activity. The antigen-binding molecules provided herein may be used to block B7-H3 expressed on immune cells, thereby releasing the cells from B7-H3-mediated suppression. When used in this way, the antigen-binding molecules provided herein may be used to treat cancers in general (i.e. regardless of the degree of B7-H3 expression on the cancer itself).

[1070] The present disclosure provides an antigen-binding molecule, ADC, immune cell expressing a CAR or composition, etc., described herein for use in a method of medical treatment or prophylaxis. Also provided is an antigen-binding molecule or composition described herein for use in a method of treating or preventing a cancer (e.g. a cancer described herein). Also provided is the use of an antigen-binding molecule or composition described herein in the manufacture of a medicament for treating or preventing a cancer (e.g. a cancer described herein). Also provided is a method of treating or preventing a cancer (e.g. a cancer described herein) in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of an antigen-binding molecule or composition described herein.

[1071] The methods may be effective to reduce the development or progression of a cancer, alleviate the symptoms of a cancer or reduce the pathology of a cancer. The methods may be effective to prevent progression of the cancer, e.g. to prevent worsening of, or to slow the rate of development of, the cancer. In some embodiments, the methods may lead to an improvement in the cancer, e.g. a reduction in the symptoms of the cancer or reduction in some other correlate of the severity / activity of the cancer. In some embodiments, the methods may prevent development of the cancer to a later stage (e.g. a chronic stage or metastasis).

[1072] As used herein, a cancer’ may be or comprise any unwanted cell proliferation (or any disease manifesting itself by unwanted cell proliferation), neoplasm or tumour. The cancer may be benign or malignant. The cancer may be primary or secondary (metastatic). A neoplasm or tumour may be any abnormal growth or proliferation of cells and may be located in any tissue. For example, the cancer may be of tissues / cells derived from e.g. the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain) cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g. renal epithelia), gallbladder, biliary tract, oesophagus, glial cells, heart, ileum, jejunum, kidney, lacrimal glad, larynx, liver, lung, lymph, lymph node, lymphoblast, maxilla, mediastinum, mesentery, myometrium, nasopharynx, omentum, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissues, spleen, stomach, testis, thymus, thyroid gland, tongue, tonsil, trachea, uterus, vulva or white blood cells. Tumours to be treated may be nervous or non-nervous system tumours. Nervous system tumours may originate either in the central or peripheral nervous system, e.g. glioma, medulloblastoma, meningioma, neurofibroma, ependymoma, Schwannoma, neurofibrosarcoma, astrocytoma and oligodendroglioma. Non-nervous system cancers / tumours may originate in any other non-nervous tissue. Examples include melanoma, mesothelioma, lymphoma, myeloma, leukaemia, non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, chronic myelogenous leukaemia (CML), acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukaemia (CLL), hepatoma, epidermoid carcinoma, prostate carcinoma, breast cancer, lung cancer (including non-small cell lung cancer, NSCLC), colon cancer, ovarian cancer, pancreatic cancer, thymic carcinoma, hematologic cancer and sarcoma.

[1073] In some embodiments the cancer is a cancer in which B7-H3 is pathologically implicated. That is, in some embodiments the cancer is a cancer which is caused or exacerbated by the expression of B7-H3, a cancer for which expression of B7-H3 is a risk factor and / or a cancer for which expression of B7-H3 is positively associated with onset, development, progression, severity or metastasis of the cancer. The cancer may be characterised by expression of B7-H3, e.g. the cancer may comprise cells (e g. cells of tumour tissue, i.e. cancerous cells) expressing B7-H3. Such cancers may be referred to as being positive for B7-H3. A cancer which is ‘positive’ for B7-H3 may be a cancer comprising cells expressing B7-H3 (e.g. at the cell surface). A cancer which is ‘positive’ for B7H3 may overexpress B7-H3.

[1074] Expression may be determined by any suitable means. Expression may be gene expression or protein expression. Gene expression can be determined e.g. by detection of mRNA encoding B7-H3, for example by quantitative real-time PCR (qRT-PCR). Protein expression can be determined e.g. by antibody-based methods, for example by western blot, immunohistochemistry, immunocytochemistry, flow cytometry or ELISA.

[1075] In some embodiments, the cancer to be treated / prevented comprises cells harbouring a genetic variant (e.g. a mutation) which causes increased (gene and / or protein) expression and / or activity of B7-H3, relative to comparable cells harbouring a reference allele not comprising the genetic variant (e.g. a nonmutated, or ‘wild type’ allele). The genetic variant may be or comprise insertion, deletion, substitution, or larger-scale translocation / rearrangement of, the nucleotide sequence relative to the reference allele.

[1076] A mutation ‘resulting in’ increased expression of B7-H3 may be known or predicted to cause, or may be associated with, increased gene / protein expression of B7-H3. A mutation ‘resulting in’ increased activity of B7-H3 may be known or predicted to cause, or may be associated with, increased B7-H3-mediated signaling. Mutations resulting in increased expression and / or activity of B7-H3 may be referred to as ‘activating’ mutations.

[1077] A mutation which causes increased expression of B7-H3 may result in gene or protein expression of B7-H3 which is not expressed by, and / or not encoded by, the genomic nucleic acid of an equivalent cell not harbouring the mutation. That is, the expression of B7-H3 may be a result of the mutation, and thus ‘increased expression’ may be relative to no expression.

[1078] A mutation which causes increased expression of B7-H3 may result in increased gene or protein expression of B7-H3 which is expressed by, and / or which is encoded by, genomic nucleic acid of an equivalent cell not comprising the mutation. By way of illustration, a cell may comprise a mutation resulting in an increase in the level of transcription of nucleic acid encoding B7-H3 relative to the level of transcription of nucleic acid encoding B7-H3 by an equivalent cell not comprising the mutation.

[1079] In some embodiments, a mutation which causes increased expression of B7-H3 may cause an increase in gene expression of B7-H3 relative to an equivalent cell not comprising the mutation. In some embodiments, a mutation which causes increased expression of B7-H3 may cause an increase in protein expression of B7-H3 relative to an equivalent cell not comprising the mutation.

[1080] In some embodiments, a mutation which causes increased expression of B7-H3 may cause an increase in the level of B7-H3 on or at the cell surface of a cell comprising the mutation, relative to an equivalent cell not comprising the mutation.

[1081] Cells having increased expression of B7-H3 relative to the level of expression of B7-H3 by a reference cell (e.g. as a result of mutation) may be described as ‘overexpressing’ B7-H3, or having ‘upregulated expression’ of B7-H3. For example, a cancer comprising cells harbouring a mutation resulting in increased expression of B7-H3 relative to equivalent cells lacking the mutation may be described as a cancer comprising cells displaying overexpression / upregulated expression of B7-H3. In some embodiments, the reference cell lacking the mutation may be a non-cancerous cell (e.g. of equivalent cell type) or a cancerous cell (e g. of equivalent cancer type).

[1082] A mutation which causes increased activity of B7-H3 may result in an increase in B7-H3-mediated signaling relative to the level of B7-H3-mediated signaling by an equivalent cell not comprising the mutation.

[1083] It will be appreciated that a mutation which causes increased expression / activity of B7-H3 may be a mutation which impacts a pathway regulating B7-H3 expression / activity. That is, a mutation may cause increased or decreased expression / activity of a component / molecule / protein / nucleic acid of a pathway that is associated with regulating B7-H3 expression / activity, and this may result in increased expression / activity of B7-H3.

[1084] In some embodiments, a cancer to be treated / prevented in accordance with the present disclosure may be characterised by an increase in the expression and / or activity of B7-H3 (i.e. gene and / or protein expression) in an organ / tissue / subject affected by the disease / condition e.g. as compared to normal organ / tissue / subject (i.e. in the absence of the disease / condition). In some embodiments, cells and / or a tumour of a cancer to be treated / prevented may be characterised by an increase in the expression and / or activity of B7-H3, e.g. as compared to the level of expression and / or activity observed in equivalent non- cancerous cells / non-tumour tissue.

[1085] B7-H3 and its association with and role in cancer is reviewed e.g. in Liu et a / ., Front Oncol. (2021) 11 :654684, and Zhou & Jin, Front Immunol. (2021) 12:701006, which are hereby incorporated by reference in their entirety.

[1086] High expression levels of B7-H3 are found in many cancers, including bladder cancer, endometrial cancer, pancreatic cancer, cervical cancer, breast cancer, intrahepatic cholangiocarcinoma, colorectal cancer, ovarian cancer, glioma, melanoma, lung cancer, prostate cancer, oral squamous cell carcinoma, kidney cancer, pancreatic cancer, gastric cancer, adrenocortical carcinoma, brain cancers, esophageal cancer, liver cancer, and squamous cell carcinoma, (see e.g. Liu et a / ., Front Oncol. (2021) 1 1 :654684 and Dong et a / ., Front Oncol (2018) 8:264, which are hereby incorporated by reference in their entirety). Accordingly, in some embodiments, the cancer to be treated is selected from: bladder cancer, endometrial cancer, pancreatic cancer, cervical cancer, breast cancer, intrahepatic cholangiocarcinoma, colorectal cancer, ovarian cancer, glioma, melanoma, lung cancer, prostate cancer, oral squamous cell carcinoma, kidney cancer, pancreatic cancer, gastric cancer, adrenocortical carcinoma, brain cancer, esophageal cancer, liver cancer and squamous cell carcinoma.

[1087] In some embodiments, the cancer to be treated is selected from: a cancer comprising cells expressing / overexpressing B7-H3, a solid tumour, metastatic cancer, unresectable cancer, lung cancer (e.g. squamous cell non-small cell lung cancer (sqNSCLC), non-small cell lung cancer adenocarcinoma (adNSCLC), small cell lung cancer (SCLC)), prostate cancer (e.g. castration-resistant prostate cancer (CRPC), metastatic castration-resistant prostate cancer (mCRPC)), esophageal cancer (e.g. esophageal squamous-cell carcinoma (ESCC), esophageal adenocarcinoma), bladder cancer, endometrial cancer, skin cancer (e.g. melanoma, squamous cell carcinoma), sarcoma, head and neck cancer (e.g. head and neck squamous cell carcinoma (HNSCC)), breast cancer, liver cancer (e.g. hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma), salivary cancer, ovarian cancer, colorectal cancer, pancreatic cancer, kidney cancer (e.g. renal cell carcinoma (RCC)), biliary tract cancer, gastric cancer, thyroid cancer, cervical cancer, glioma, oral cancer (e.g. oral squamous cell carcinoma), adrenal cancer (e.g. adrenocortical carcinoma) and brain cancer.

[1088] In some embodiments, the cancer to be treated is selected from: small cell lung cancer (SCLC), squamous cell non-small cell lung cancer (sqNSCLC), head and neck squamous cell carcinoma (HNSCC), esophageal squamous-cell carcinoma (ESCC), endometrial cancer, castration-resistant prostate cancer (CRPC), and bladder cancer.

[1089] In some embodiments, the cancer may be a relapsed cancer. As used herein, a ‘relapsed’ cancer refers to a cancer which responded to a treatment (e.g. a first line therapy for the cancer), but which has subsequently re-emerged / progressed, e.g. after a period of remission. For example, a relapsed cancer may be a cancer whose growth / progression was inhibited by a treatment (e.g. a first line therapy for the cancer), and which has subsequently grown / progressed. A cancer that is relapsed with respect to given treatment may be described as having acquired resistance to such treatment.

[1090] In some embodiments, the cancer may be a refractory cancer. As used herein, a ‘refractory’ cancer refers to a cancer which has not responded to a treatment (e.g. a first line therapy for the cancer). For example, a refractory cancer may be a cancer whose growth / progression was not inhibited by a treatment (e.g. a first line therapy for the cancer). In some embodiments a refractory cancer may be a cancer for which a subject receiving treatment for the cancer did not display a partial or complete response to the treatment. A cancer that is refractory with respect to given treatment may be described as having intrinsic resistance to such treatment.

[1091] In some embodiments, administration of an antigen-binding molecule / ADC / composition according to the present disclosure may be associated with one or more of: reducing the number of cancer cells in the subject, reducing the size of a cancerous tumour / lesion in the subject, inhibition (e g. prevention or slowing) of growth of cancer cells in the subject, inhibition (e.g. prevention or slowing) of growth of a cancerous tumour / lesion in the subject, inhibition (e.g. prevention or slowing) of the development / progression of the cancer (e.g. to a later stage, or metastasis), a delay to / prevention of onset of the cancer, a reduction in / delay to / prevention of tumour growth, a reduction in / delay to / prevention of tissue invasion, a reduction in / delay to / prevention of metastasis, a reduction in the severity of one or more symptoms of the cancer, a reduction in the number of cancer cells, a reduction in the cancer burden, a reduction in tumour size / volume, and / or an increase in survival of subjects having the cancer (e.g. progression free survival or overall survival).

[1092] In accordance with various aspects of the present disclosure, a method of treating and / or preventing a cancer according to the present disclosure may comprise inhibiting the growth of a tumour, reducing the size / volume of a tumour and / or increasing the survival of a subject having the cancer.

[1093] In accordance with various aspects of the present disclosure, methods are provided which are for, or which comprise (e.g. in the context of treatment / prevention of a cancer, e.g. a cancer described herein), one or more of the following: binding to cells expressing B7-H3; inhibiting B7-H3-mediated signalling; inhibiting the proliferation of B7-H3-expressing cells (particularly B7-H3-expressing cancer cells); killing cells expressing B7-H3 (particularly cancer cells expressing B7-H3); inhibiting tumour growth and / or reducing tumour size / volume, e.g. of a B7-H3-expressing cancer; increasing the survival of subjects having a cancer, e.g. a B7-H3-expressing cancer increasing immune cell (e.g. T cell and / or NK cell) activity (e.g. in a subject with cancer); increasing tumour-infiltrating lymphocyte (TIL) activity (e.g. in a subject with cancer); and / or increasing immune cell-mediated killing of tumour cells (e.g. in a subject with cancer).

[1094] Also provided are antigen-binding molecules, ADCs, immune cells expressing a CAR and compositions according to the present disclosure for use in such methods, and the use of antigen-binding molecules, ADCs, immune cells expressing a CAR and compositions according to the present disclosure in manufacture of compositions (e.g. medicaments) for use in such methods. It will be appreciated that the methods typically comprise administering an antigen-binding molecule or ADC according to the present disclosure to a subject.

[1095] Similarly, one or more of the following may be observed in a subject following therapeutic or prophylactic intervention in accordance with the present disclosure (e.g. compared to the level / number / proportion etc. prior to intervention): inhibition of proliferation of B7-H3-expressing cells (particularly B7-H3-expressing cancer cells); killing of cells expressing B7-H3 (particularly cancer cells expressing B7-H3); inhibition of tumour growth and / or reduction of tumour size / volume, e.g. of a B7-H3-expressing cancer; increased survival of a subject having a cancer, e.g. a B7-H3-expressing cancer; increased immune cell (e.g. T cell and / or NK cell) activity; increased tumour-infiltrating lymphocyte (TIL) activity; and / or increased immune cell-mediated killing of tumour cells.

[1096] In some embodiments, therapeutic / prophylactic intervention in accordance with the present disclosure may be described as being ‘associated with’ one or more of the effects described in the preceding paragraph. The skilled person is readily able to evaluate such properties using techniques that are routinely practiced in the art.

[1097] Administration of the antigen-binding molecules, ADCs, immune cells expressing a CAR and compositions of the present disclosure is preferably in a ‘therapeutically-effective’ or prophylactically- effective’ amount, this being sufficient to show therapeutic or prophylactic benefit to the subject. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease / condition and the particular article administered. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disease / disorder to be treated, the condition of the individual subject, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s ‘The Science and Practice of Pharmacy’ (Ed. A. Adejare), 23rdEdition (2020), Academic Press.

[1098] Administration of the antigen-binding molecules, ADCs, immune cells expressing a CAR and compositions of the present disclosure may be e.g. parenteral, systemic, topical, intracavitary, intravascular, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral or transdermal. Administration may be by injection, infusion or ingestion.

[1099] In some aspects and embodiments, articles of the present disclosure may be administered to a tissue / organ of interest e.g. a tissue / organ affected by the disease / condition, e.g. a tissue / organ in which symptoms of the disease / condition manifest). In some aspects and embodiments, articles of the present disclosure may be administered to the blood ( / .e. intravenous / intra-arterial administration) by injection or infusion (e.g. via cannula), or may be administered subcutaneously or orally. In some aspects and embodiments, articles of the present disclosure may be administered to a tumour.

[1100] Multiple doses of the antigen-binding molecules, ADCs, immune cells expressing a CAR and compositions may be provided. Multiple doses may be separated by a predetermined time interval, which may be selected to be one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1 , 2, 3, 4, 5, or 6 months. By way of example, doses may be given once every 7, 14, 21 or 28 days (plus or minus 3, 2, or 1 days).

[1101] In some embodiments, therapeutic or prophylactic intervention according to the present disclosure may further comprise administering another (i.e. a second) agent for the treatment / prevention of the relevant disease / condition. Administration of antigen-binding molecules, ADCs and compositions described herein may be alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated. Simultaneous administration refers to administration with another therapeutic agent together, for example as a pharmaceutical composition containing both agents (combined preparation), or immediately after each other (e.g. within 1 , 4, 6, 8 or 12 hours) and optionally via the same route of administration (e.g. to the same tissue, artery, vein or other blood vessel). Sequential administration refers to administration of one agent followed after a given time interval by separate administration of another agent. It is not required that the two agents are administered by the same route, although this is the case in some embodiments. The time interval may be any time interval.

[1102] Said other agent / treatment may be selected from e.g. chemotherapy, immunotherapy, radiotherapy, surgery, vaccination and / or hormone therapy. In some embodiments, the additional treatment comprises leukapheresis. In some embodiments, the additional treatment comprises a stem cell transplant.

[1103] Methods of detection

[1104] The invention also provides the articles of the present invention for use in methods for detecting, localizing or imaging B7-H3, or cells expressing B7-H3. The antigen-binding molecules described herein may be used in methods that involve detecting the antigen-binding molecule binding to B7-H3. Such methods may involve detection of the bound complex of the antigen-binding molecule and B7-H3.

[1105] In particular, detection of B7-H3 may be useful in methods of diagnosing / prognosing a disease / condition in which cells expressing B7-H3 are pathologically implicated, identifying subjects at risk of developing such diseases / conditions, and / or may be useful in methods of predicting a subject’s response to a therapeutic intervention.

[1106] As such, a method is provided, comprising contacting a sample containing, or suspected to contain, B7-H3 with an antigen-binding molecule as described herein, and detecting the formation of a complex of the antigen-binding molecule and B7-H3. Also provided is a method comprising contacting a sample containing, or suspected to contain, a cell expressing B7-H3 with an antigen-binding molecule as described herein and detecting the formation of a complex of the antigen-binding molecule and a cell expressing B7-H3.

[1107] A sample may be taken from any tissue or bodily fluid. The sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the individual’s blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a tissue sample or biopsy; pleural fluid; cerebrospinal fluid (CSF); or cells isolated from said individual. In some embodiments, the sample may be obtained or derived from a tissue or tissues which are affected by the disease / condition (e.g. tissue or tissues in which symptoms of the disease manifest, or which are involved in the pathogenesis of the disease / condition).

[1108] Suitable method formats are well known in the art, including immunoassays such as sandwich assays, e g. ELISA. The methods may involve labelling the antigen-binding molecule, or target(s), or both, with a detectable moiety, e.g. a fluorescent label, phosphorescent label, luminescent label, immuno-detectable label, radiolabel, chemical, nucleic acid or enzymatic label as described herein. Detection techniques are well known to those of skill in the art and can be selected to correspond with the labelling agent.

[1109] Methods comprising detecting B7-H3, or cells expressing B7-H3, include methods for diagnosing / prognosing a disease / condition described herein. Methods of this kind may be performed in vitro on a patient sample, or following processing of a patient sample. Once the sample is collected, the patient is not required to be present for the in vitro method to be performed, and therefore the method may be one which is not practised on the human or animal body. In some embodiments, the method is performed in vivo.

[1110] Such methods may involve detecting or quantifying B7-H3 and / or cells expressing B7-H3, e.g. in a patient sample. Where the method comprises quantifying the relevant factor, the method may further comprise comparing the determined amount against a standard or reference value as part of the diagnostic or prognostic evaluation. Other diagnostic / prognostic tests may be used in conjunction with those described herein to enhance the accuracy of the diagnosis or prognosis or to confirm a result obtained by using the tests described herein.

[1111] Detection in a sample may be used for the purpose of diagnosis of a disease / condition (e.g. a cancer), predisposition to a disease / condition, or for providing a prognosis (prognosticating) for a disease / condition, e.g. a disease / condition described herein. The diagnosis or prognosis may relate to an existing (previously diagnosed) disease / condition.

[1112] A subject may be selected for diagnostic / prognostic evaluation based on the presence of symptoms indicative of a disease / condition described herein, or based on the subject being considered to be at risk of developing a disease / condition described herein.

[1113] The present disclosure also provides methods for selecting / stratifying a subject for treatment with a B7-H3-targeted agent. In some embodiments a subject is selected for treatment / prevention in accordance with the methods of the present disclosure, or is identified as a subject which would benefit from such treatment / prevention, based on detection / quantification of B7-H3, or cells expressing B7-H3, e.g. in a sample obtained from the individual.

[1114] Subjects

[1115] The subject in accordance with aspects described herein may be any animal or human. The subject is preferably mammalian, more preferably human. The subject may be a non-human mammal, but is more preferably human. The subject may be male or female. The subject may be a patient. A subject may have been diagnosed with a disease or condition requiring treatment (e.g. a cancer, e.g. a cancer described herein), may be suspected of having such a disease / condition, or may be at risk of developing / contracting such a disease / condition.

[1116] In some embodiments, the subject to be treated according to a therapeutic or prophylactic method of the present disclosure herein is a subject having, or at risk of developing, a cancer, e.g. a cancer described herein. In embodiments according to the present disclosure, a subject may be selected for treatment according to the methods based on characterisation for certain markers of such disease / condition.

[1117] In some embodiments, a patient may be selected for treatment described herein based on the detection of a cancer expressing / overexpressing B7-H3, e.g. in a sample obtained from the subject (e.g. a biopsy, e g. of a tumour).

[1118] In some embodiments, a patient may be selected for treatment described herein based on detection of a relapsed / refractory cancer subsequent to administration of a therapy for the cancer, e.g. a first line therapy for the cancer or a second line therapy for the cancer. In some embodiments, a patient may be selected for treatment described herein based on detection of a relapsed / refractory cancer subsequent to administration of the standard-of-care therapy (e.g. the first line standard of care) for the given cancer.

[1119] Kits

[1120] The present disclosure also provides kits of parts. A kit according to the present disclosure may comprise components for performing a method described herein, in whole or in part. The kit may have at least one container having a predetermined quantity of an antigen-binding molecule or composition described herein.

[1121] In some aspects of the present disclosure a kit of parts is provided. In some embodiments, the kit may comprise an antigen-binding molecule, polypeptide, CAR, ADC, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell (or plurality thereof), or composition described herein, and which may be provided in a predetermined quantity.

[1122] The kit may provide an antigen-binding molecule or composition described herein together with instructions for administration to a patient in order to treat a specified disease / condition (e.g. a disease / condition described herein, e.g. a cancer).

[1123] The kit may provide a polypeptide complex comprising an antigen-binding moiety that binds to B7-H3 according to the disclosure, and a linker-payload moiety (e.g. according to the present disclosure). The kit may further comprise reagents for conjugating the antigen-binding polypeptide complex and the linkerpayload moiety.

[1124] The kit may further comprise reagents, buffers and / or standards required for execution of a method according to the present disclosure. Kits according to the present disclosure may include instructions for use, e g. in the form of an instruction booklet or leaflet. The instructions may include a protocol for performing any one or more of the methods described herein.

[1125] Sequence identity

[1126] As used herein, ‘sequence identity’ refers to the percent of nucleotides / amino acid residues in a subject sequence that are identical to nucleotides / amino acid residues in a reference sequence, after aligning the sequences and, if necessary, introducing gaps, to achieve the maximum percent sequence identity between the sequences. Pairwise and multiple sequence alignment for the purposes of determining percent sequence identity between two or more amino acid or nucleic acid sequences can be achieved in various ways known to a person of skill in the art, for instance, using publicly available computer software such as ClustalOmega (Sbding, J. 2005, Bioinformatics 21 , 951 -960), T-coffee (Notredame et al. 2000, J. Mol. Biol. (2000) 302, 205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6(298)) and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution, 30(4) 772-780) software. When using such software, the default parameters, e.g. for gap penalty and extension penalty, are preferably used. Sequences

[1127] All sequences are protein sequences:

[1128] In SEQ ID NOs: 165-175 the underlined residues are the FLAG tag.

[1129] ***

[1130] The present disclosure includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[1131] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[1132] Aspects and embodiments of the present disclosure will now be illustrated, by way of example, with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[1133] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word comprise,’ and variations such as ‘comprises’ and ‘comprising,’ will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In all cases, unless impossible in the context, the term ‘comprises’ or ‘comprising’ may be replaced with the term consists of or ‘consisting of’. The term ‘consists of or ‘consisting of will be understood to imply the inclusion of a stated integer or step or group of integers or steps, excluding any other integer or step or group of integers or steps. It must be noted that, as used in the specification and the appended claims, the singular forms ‘a’, ‘an’, and ‘the’ include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from ‘about’ one particular value, and / or to ‘about’ another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent ‘about’, it will be understood that the particular value forms another embodiment.

[1134] Where a nucleic acid sequence is disclosed or referred to herein, the reverse complement thereof is also expressly contemplated.

[1135] Methods described herein may preferably be performed in vitro. The term ‘in vitro’ is intended to encompass procedures performed with cells in culture whereas the term ‘in vivo' is intended to encompass procedures with / on intact multi-cellular organisms.

[1136] Values may be expressed herein as ‘about’ a particular value. Similarly, ranges may be expressed herein as from ‘about’ a particular value, and / or to ‘about’ another particular value. The term ‘about’ in relation to a numerical value is optional, and means for example + / - 10 %. By way of illustration, reference e.g. to ‘about 10 %' is to be construed as 9 % to 11 %. In instances herein where ‘about’ is recited, the value it precedes is also specifically contemplated. By way of illustration, reference e g. to ‘about 10 %’ also specifically contemplates 10 %.

[1137] Brief Description of the Figures

[1138] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures.

[1139] FIG. 1 shows the dose-response binding of the indicated antibodies to human (hu) B7-H3 and to cynomolgus (cy) and murine (mu) orthologues. Binding was determined by flow cytometry and normalized against positive control antibodies; Ifinatamab for huB7H3 and cyB7H3, and ABL-B5 for muB7H3.

[1140] FIG. 2 shows epitope mapping for the indicated antibodies by flow cytometry. The B7-H3 domain bound by the indicated antibodies was determined based on differential binding to full-length huB7-H3 and the lgC2-like domain of huB7-H3.

[1141] FIG. 3 shows the dose-response binding of the indicated antibodies to recombinant huB7H3. Binding was determined by ELISA and normalized against the positive control antibody ifinatamab.

[1142] FIG. 4 shows the specificity of the indicated antibodies for B7-H3 against other B7 family members. The binding specificity of the indicated antibodies was determined by flow cytometry using cells expressing the different B7 family members: B7-H3, B7-H1 , B7-H2, B7-H4, B7-H5, B7-H6, B7-H7, B7-1 , B7-2, B7- DC and BTNL-2. Anti-Flag-AF647 antibody that binds to the N-terminal FLAG-tag on each construct was used as positive control to detect expression. Non-transfected (NT) cells were used as negative control. The x-axis on each graph, from left to right, reads: B7H3, B7H1 , B7H2, B7H4, B7H5, B7H6, B7H7, B7-1 , B7-2, B7-DC, BTNL-2, NT.

[1143] FIG. 5 shows the internalization kinetics of the indicated antibodies into cancer cell line HCT116. Internalization of the indicated antibodies was monitored over a 24 hr period through tracking of fluorescence of a pH-dependent fluorophore.

[1144] FIG. 6 shows the binding of 1047 antibody variants to CHO-K1 overexpressing human B7-H3 and nontransfected (NT) cells. Dose-response binding of different 1047 variants to human B7-H3 was compared using flow cytometry.

[1145] FIG. 7 shows internalization kinetics of 1047 humanized variants into cancer cell line, HCT116. Internalization of the indicated antibodies was monitored over a 24 hr period through tracking of fluorescence of a pH dependent fluorophore.

[1146] FIG. 8 shows the binding of 2007 antibody variants to CHO-K1 overexpressing human B7-H3 and nontransfected (NT) cells. Dose-response binding of different 2007 variants to human B7-H3 was compared using flow cytometry.

[1147] FIG. 9 shows internalization kinetics of 2007 antibody variants into cancer cell line, HCT116. Internalization of the indicated antibodies was monitored over a 24 hr period through tracking of fluorescence of a pH dependent fluorophore.

[1148] FIG. 10 shows binding of antibodies to CHO-K1 cells overexpressing human (hu), cynomolgus (cy) and mouse (mu) B7-H3.

[1149] Examples

[1150] Methods

[1151] Generation of B7H3-specific monoclonal antibodies

[1152] Hyperimmune mice were first immunized with recombinant B7-H3-His-tag protein in Complete Freund’s Adjuvant (Sigma, Cat #F5881). Booster injections in Incomplete Freund’s Adjuvant (Sigma, Cat #F5506) were given every 2 weeks after the first injection for a total of 2 injections and mice were sacrificed. Extracted B-cells were used for hybridoma generation and antigen-specific single B-cell sorting to identify relevant antibody sequences which were cloned into expression vectors for production of recombinant antibodies. Production of recombinant antibodies for characterization

[1153] Transient expression in ExpiCHO cells (ThermoFisher, #A29133) was performed, following manufacturer’s instructions, using heavy and light chain constructs at a 1 :1 ratio. Antibodies were purified from the culture supernatant using AmMag Protein A magnetic beads (Genscript, Cat #L00695), following Manufacturer’s instructions.

[1154] Cloning of constructs for over-expression of proteins in CH0-K1 for flow cytometry cDNAs encoding different target proteins were cloned into pCMV3 expression vector using standard molecular biology techniques to create expression constructs for assessing species cross-reactivity, domain epitope mapping and off-target binding. For species cross-reactivity, this included cDNA encoding human, cynomolgus monkey and mouse B7-H3 (NCBI accessions: NP_001019907.1 , XP_005560056.1 , NP_598744.1 respectively). For domain epitope mapping, this was AMet1-Ala357 truncation of human B7-H3 (NP_001019907.1 ;). For off-target binding assessment, genes encoding human B7-family proteins B7-H3, B7-H1 , B7-H2, B7-H4, B7-H5, B7-H6, B7-H7, B7-1 , B7-2, B7-DC and BTNL-2 (NP_001019907.1 , NP_054862.1 , NP_056074.1 , NP_078902.2, NP_071436.1 ,

[1155] NP_001189368.1 , NP_001269485.1 , NP_005182.1 , NP_787058.4, NP_079515.2, NP_001291490.1) were cloned with a FLAG tag into pCMV3 expression vector for detection of cell surface expression with anti-FLAG-AF647 antibody. The FLAG-tagged proteins used had the following sequences: B7-H1-N-FLAG - SEQ ID NO: 165; B7-H2-N-FLAG - SEQ ID NO: 166; B7-H3-N-FLAG - SEQ ID NO: 167; B7-H4-N-FLAG - SEQ ID NO: 168; B7-H5-N-FLAG - SEQ ID NO: 169; B7-H6-N-FLAG - SEQ ID NO: 170; B7-H7-N-FLAG - SEQ ID NO: 171 ; B7-1 -N-FLAG - SEQ ID NO: 172; B7-2-N-FLAG - SEQ ID NO: 173; B7-DC-N-FLAG - SEQ ID NO: 174; and BTNL-2-N-FLAG - SEQ ID NO: 175.

[1156] Generation of over-expressing CHO-K1 for flow cytometry

[1157] CHO-K1 cells were transfected with the relevant expression constructs using Lipofectamine 2000 (ThermoFisher, Cat #11668027) according to the manufacturer’s instructions. Transfected cells were detached using Accutase (Sigma, Cat #A6964), 24 hr after transfection and 30,000 cells per well were seeded into 96-well plates for flow cytometry. Non-transfected cells were used as control.

[1158] Flow cytometry to determine antibody binding

[1159] For determining species differential cross-reactive binding, purified recombinant antibodies were serially diluted in PBS containing 2 % FBS and 2 mM EDTA starting from a concentration of 10 pg / ml and added to respective wells containing CHO-K1 cells expressing human, cynomolgus or mouse B7-H3. The antibody-cell mixture was incubated at 4°C for 60 minutes. Following this, cells were incubated with a secondary goat anti-human AF647 antibody (Invitrogen, Cat #A21445) at 4°C for 30 minutes. Cells were then resuspended in DAPI solution and acquired on Sartorius IQue3 Flow cytometer. Data was expressed as normalized binding to ifinatamab (for human and cynomolgus B7-H3) or ABL-B5 (for mouse B7-H3) control antibodies at the highest antibody concentration of 10 pg / ml. Normalized data was plotted using the Four-parameter Logistic Regression analysis in GraphPad Prism and presented as ECso and MFI max for each antibody tested. Ifinatamab (US 2013 / 0078234 A1) is a humanized lgG1-kappa antibody with the VH and VL of SEQ ID NOs: 106 and 107, respectively. ABL-B5 (US 11891445 B1) is a human lgG1-lambda antibody with the VH and VL of SEQ ID NOs: 108 and 109, respectively.

[1160] For domain epitope mapping, purified recombinant antibodies were diluted in PBS containing 2 % FBS and 2 mM EDTA to a concentration of 1 pg / ml and added to CHO-K1 cells expressing the ALeu29-Ala357 truncation of human B7-H3, then processed as described above.

[1161] For off-target binding assessment, purified recombinant antibodies were diluted in PBS containing 2 % FBS and 2 mM EDTA to a concentration of 10 pg / ml and added to CHO-K1 expressing the described FLAG-tagged B7 family members, then processed as described above. An anti-FLAG-AF647 antibody (Biolegend, Cat #637317) recognizing the FLAG-tag on each of the constructs was used as a positive control antibody to ensure expression.

[1162] Binding of antibodies to recombinant human B7H3 protein by ELISA

[1163] Binding specificity of the antibodies to recombinant human B7-H3 protein was determined by ELISA. Briefly, rabbit anti-6His antibody (Invitrogen, Cat #MA5-21315) diluted in PBS coating buffer was used to coat 384-well polystyrene plates overnight at 4°C. Recombinant human B7-H3-Histag protein (Sin obiolog ical , Cat #11188-H08H) was then added to the coated plates and incubated for 1 h. The B7-H3-specific antibodies were serially diluted starting from 10 pg / ml and added to respective wells and incubated for 1 h. Ifinatamab was tested alongside as control B7-H3-specific antibody. Following this, goat anti-human IgG Fc secondary antibody-HRP conjugate was added (Invitrogen, Cat #31413) and incubated for 1 h. Then, colorimetric development was performed by addition of TMB substrate (ThermoFisher, Cat #34022) and incubated for 10 min. The reaction was stopped by adding Stop solution (Invitrogen, Cat #SS04). The absorbance was read at 450 nm using Biotek Power Wave HT spectrophotometer. Data was expressed as normalized binding to ifinatamab at the highest antibody concentration of 10 pg / ml. Normalized data was plotted using the four-parameter Logistic Regression analysis in GraphPad Prism and presented as ECso for each antibody tested.

[1164] Determination of antibody internalization kinetics

[1165] Internalization kinetics were determined using Incucyte Fab-fluor internalization assay. Internalized antibodies were tracked using low pH-sensitive dye-conjugated Incucyte® Human Fabfluor-pH Red Antibody Labeling Reagent (Sartorius, Cat #4722) through an increase in fluorescence triggered in the acidic lysosomal environment. Briefly, HCT1 16 colon cancer cells (ATCC CCL-247) were seeded at 10,000 cells per well in complete medium: McCoy’s 5A (Gibco, Cat #16600082) supplemented with 10 % FBS for 24 h. Recombinant B7-H3-specific antibodies were mixed with Incucyte® Human Fabfluor-pH Red Antibody Labeling Reagent (Sartorius, Cat #4722) at a 1 :3 antibody:Fab-fluor molar ratio in complete media with a corresponding antibody concentration of 2 pg / ml. Ifinatamab was included as a B7-H3- specific control antibody for normalization and comparative internalization efficiency. The antibody-Fab- fluor mixture was incubated at 37°C for 15 min. After incubation, the antibody-Fab-fluor mixture was added to the seeded wells at a resulting antibody concentration of 1 pg / ml. Scanning was performed using the Sartorius Incucyte S3 Live Cell imaging system every 1 h for a total of 24 h. Data analysis was performed using the cell-by-cell analysis using the metric red mean intensity (Object Average, RCU). Fluorescence signals at each timepoint were normalized to timepoint 0 hour (t = 0 hr) and plotted as % RCU normalized to t = 0 hour. Efficiency of internalization of the recombinant antibodies was measured as the maximum internalization normalized to ifinatamab and as duration for half-maximum internalization.

[1166] Example 1 : Flow cytometry orthologue cross-reactivity binding characterization of B7-H3-specific monoclonal antibodies

[1167] Fig. 1 shows the dose-response cross-reactivity binding profiles of B7-H3-specific antibodies to human, cynomolgus and mouse B7-H3 expressed in CHO-K1 cells. All antibodies bound human B7-H3 in a dose- responsive manner with all showing strong cross-reactivity to cynomolgus B7-H3. ECso values are set out in Table 1 , and show that all antibodies bind to human and cynomolgus B7-H3 (HuB7H3 and CyB7H3 respectively) in the low nanomolar range and were comparable to the control antibody, ifinatamab. 6 antibodies (clones 1094, 1083, 2007, 1001 , 1074 and 2009) showed lower affinity binding to mouse orthologue with lower MFI max (%). Clones 1094, 1083 and 1074 showed the highest affinity to mouse orthologue.

[1168] Table 1: binding affinities of the indicated antibodies against human (hu), cynomolgus (cy) and mouse (mu) B7-H3 orthologues. Example 2: Flow cytometry epitope mapping of monoclonal antibodies

[1169] Fig. 2 shows the protein domain bound by the B7-H3-specific antibodies. Antibodies showing binding to CHO-K1 expressing full-length B7-H3 and B7-H3-C2(A Leu29 - Ala 357) mutant were determined as C-domain binders whereas antibodies that bound only full-length B7-H3 were inferred as V-domain binders. Clones 1094, 1083 and 1074 bound the C-domain whereas clones 1047, 2007, 1001 and 2009 bound the V-domain.

[1170] Example 3: ELISA binding of monoclonal antibodies to recombinan t B7-H3 protein

[1171] Fig. 3 shows the dose-response binding of B7-H3-specific monocl onal antibodies to recombinant huB7-H3. The ECso values are shown in Table 2. All antibodies sh owed low nanomolar affinity to recombinant huB7-H3. Clones 1083, 2007, 1001 , 1074 and 2009 s howed comparable affinity to the control antibody ifinatamab, whereas clones 1094 and 1047 showe d lower affinity.

[1172] Table 2: binding affinities of the indicated antibodies against human B7-H3 protein

[1173] Example 4: Flow cytometry off-target binding of monoclonal antibodies

[1174] Fig. 4 shows the binding specificity of the B7-H3-specific monoclonal antibodies to B7-H3. Binding to huB7-H3 was compared to binding to other human members of the B7 family. No binding to the other B7 family members was observed for any of the antibodies.

[1175] Example 5: Internalization kinetics of monoclonal antibodies on HCT116 cancer cells

[1176] Fig. 5 shows the internalization of monoclonal antibodies relative to control antibody ifinatamab on HCT116 cancer cells over 24 h. Compared to ifinatamab, clone 1094 showed higher internalization, clones 1047, 1083, 2007 and 1001 showed comparable internalization and clones 1074 and 2009 showed lower internalization. Table 3 shows the internalization rates calculated based on the time to achieve half-maximal internalization and the maximum internalization normalized to that of ifinatamab.

[1177] Clones 1094, 1047 and 1083 showed the highest internalization rates with higher maximum internalization than ifinatamab. Ifinatamab is under development in the context of the ADC ifinatamab deruxtecan. The similar or increased levels of internalization of the tested antibodies compared to ifinatamab indicate that they are good candidates for generation of further ADCs against B7-H3.

[1178] Table 3: internalization kinetics of the indicated antibodies against HCT-116 tumor cells

[1179] Example 6: Binding and internalization characterization of humanized 1047 antibodies

[1180] Fig. 6 compares the dose-response binding profiles of 1047-parental (1047) and its humanized variants, 1047-H1 L3 and 1047-H9L6, to human B7-H3 expressed on CHO-K1 cells or non-transfected CHO-K1 (CHO-NT) cells. 1047 humanized variants have comparable EC50 values to 1047 and show no nonspecific binding to non-transfected CHO-K1 cells (Table 4).

[1181] Fig. 7 shows the internalization of 1047 humanized variants, compared to control antibody Ifinatamab on HCT116 cancer cells over 24 hours. Both humanized 1047 variants showed higher maximum internalization at comparable internalization rates than control antibody, Ifinatamab.

[1182] Table 4. Binding affinities of indicated antibodies to human B7-H3 and their Internalization kinetics in HCT116 tumor cells.

[1183] Example 7: Binding and internalization characterization of humanized 2007 antibodies

[1184] FIG.. 8 compares the dose-response binding profiles of 2007-parental (2007) and its humanized variants, 2007-H0L0 and 2007-H7L6, to human B7-H3 expressed on CHO-K1 cells or non-transfected CHO-K1 (CHO-NT) cells. 2007 humanized variants have comparable EC50 values with 2007 and show no nonspecific binding to CHO-NT cells (Table 5).

[1185] FIG. 9 shows the internalization of 2007 antibody variants, compared to control antibody Ifinatamab on HCT116 cancer cells over 24 hours. 2007 and both humanized 2007 variants showed higher internalization rates and maximal internalization than control antibody, Ifinatamab (Table 5).

[1186] Table 5. Binding affinities of indicated antibodies to human B7-H3 and their Internalization kinetics in HCT116 tumor cells.

[1187] Example 8: Flow cytometry binding characterization of humanized B7-H3 antibodies to human, cynomolgus and mouse B7-H3

[1188] FIG. 10 shows the dose-response binding profiles of humanized antibodies, 1047-H9L6 and 2007-H7L6, to human, cynomolgus and mouse B7-H3 expressed in CHO-K1 cells. Similar to their parental counterparts, both 1047 and 2007 humanized variants bound human B7-H3 and had strong crossreactivity to cynomolgus B7-H3 (Table 6). Both antibodies had no...

Claims

1. Claims1 . An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67.

2. The antigen binding molecule of claim 1 , wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 63 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 64 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 66 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67.

3. The antigen-binding molecule of claim 1 or 2, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 68HC-FR2 having the amino acid sequence of SEQ ID NO: 69HC-FR3 having the amino acid sequence of SEQ ID NO: 70HC-FR4 having the amino acid sequence of SEQ ID NO: 71 .

4. The antigen-binding molecule of any one of claims 1 to 3, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 72LC-FR2 having the amino acid sequence of SEQ ID NO: 73LC-FR3 having the amino acid sequence of SEQ ID NO: 74 LC-FR4 having the amino acid sequence of SEQ ID NO: 75.

5. The antigen-binding molecule of any one of claims 1 to 4, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 61 ; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 62.

6. The antigen-binding molecule of claim 5, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 61 and a VL region comprising the amino acid sequence of SEQ ID NO: 62.

7. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

8. The antigen-binding molecule of claim 7, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 4 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6 LC-CDR2 comprising the amino acid sequence WAS (SEQ ID NO: 181) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

9. The antigen-binding molecule of claim 7 or 8, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 8HC-FR2 having the amino acid sequence of SEQ ID NO: 9HC-FR3 having the amino acid sequence of SEQ ID NO: 10HC-FR4 having the amino acid sequence of SEQ ID NO: 11 .

10. The antigen-binding molecule of any one of claims 7 to 9, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 12LC-FR2 having the amino acid sequence of SEQ ID NO: 13LC-FR3 having the amino acid sequence of SEQ ID NO: 14LC-FR4 having the amino acid sequence of SEQ ID NO: 15.11 . The antigen-binding molecule of any one of claims 7 to 10, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 2.

12. The antigen-binding molecule of claim 11 , wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1 and a VL region comprising the amino acid sequence of SEQ ID NO: 2.

13. An antigen-binding molecule that specifically binds B7-H3, comprising:(I) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

14. The antigen binding molecule of claim 13, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence NAR (SEQ ID NO: 182) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

15. The antigen-binding molecule of claim 13 or 14, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 23HC-FR2 having the amino acid sequence of SEQ ID NO: 24HC-FR3 having the amino acid sequence of SEQ ID NO: 25HC-FR4 having the amino acid sequence of SEQ ID NO: 26.

16. The antigen-binding molecule of any one of claims 13 to 15, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 27LC-FR2 having the amino acid sequence of SEQ ID NO: 28LC-FR3 having the amino acid sequence of SEQ ID NO: 29LC-FR4 having the amino acid sequence of SEQ ID NO: 30.

17. The antigen-binding molecule of any one of claims 13 to 16, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 16; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 17.

18. The antigen-binding molecule of claim 17, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 16 and a VL region comprising the amino acid sequence of SEQ ID NO: 17.

19. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

20. The antigen-binding molecule of claim 19, comprising:(I) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence ATS (SEQ ID NO: 183) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

21. The antigen-binding molecule of claim 19 or 20, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 38HC-FR2 having the amino acid sequence of SEQ ID NO: 39HC-FR3 having the amino acid sequence of SEQ ID NO: 40HC-FR4 having the amino acid sequence of SEQ ID NO: 41 .

22. The antigen-binding molecule of any one of claims 19 to 21 , wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 42LC-FR2 having the amino acid sequence of SEQ ID NO: 43LC-FR3 having the amino acid sequence of SEQ ID NO: 44LC-FR4 having the amino acid sequence of SEQ ID NO: 45.

23. The antigen-binding molecule of any one of claims 19 to 22, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 31 ; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 32.

24. The antigen-binding molecule of claim 23, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 31 and a VL region comprising the amino acid sequence of SEQ ID NO: 32.

25. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36 LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52.

26. The antigen binding molecule of claim 25, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 48 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 50; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36LC-CDR2 comprising the amino acid sequence GTS (SEQ ID NO: 184)LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 52.

27. The antigen-binding molecule of claim 25 or 26, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 53HC-FR2 having the amino acid sequence of SEQ ID NO: 54HC-FR3 having the amino acid sequence of SEQ ID NO: 55HC-FR4 having the amino acid sequence of SEQ ID NO: 26.

28. The antigen-binding molecule of any one of claims 25 to 27, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 57LC-FR2 having the amino acid sequence of SEQ ID NO: 58LC-FR3 having the amino acid sequence of SEQ ID NO: 59LC-FR4 having the amino acid sequence of SEQ ID NO: 45.

29. The antigen-binding molecule of any one of claims 25 to 28, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 46; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 47.

30. The antigen-binding molecule of claim 29, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 46 and a VL region comprising the amino acid sequence of SEQ ID NO: 47.31 . An antigen-binding molecule that specifically binds B7-H3, comprising:(I) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and / or(ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

32. The antigen binding molecule of claim 31 , wherein the antigen-binding molecule comprises:(I) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 80; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 LC-CDR2 comprising the amino acid sequence QMS (SEQ ID NO: 186) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

33. The antigen-binding molecule of claim 31 or 32, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 83HC-FR2 having the amino acid sequence of SEQ ID NO: 84HC-FR3 having the amino acid sequence of SEQ ID NO: 85HC-FR4 having the amino acid sequence of SEQ ID NO: 71 .

34. The antigen-binding molecule of any one of claims 31 to 33, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 87LC-FR2 having the amino acid sequence of SEQ ID NO: 88LC-FR3 having the amino acid sequence of SEQ ID NO: 89LC-FR4 having the amino acid sequence of SEQ ID NO: 30.

35. The antigen-binding molecule of any one of claims 31 to 34, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 76; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 77.

36. The antigen-binding molecule of claim 35, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 76 and a VL region comprising the amino acid sequence of SEQ ID NO: 77.

37. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 95; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

38. The antigen-binding molecule of claim 37, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 93 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 95; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 96 LC-CDR2 comprising the amino acid sequence NAK (SEQ ID NO: 187) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

39. The antigen-binding molecule of claim 37 or 38, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 98HC-FR2 having the amino acid sequence of SEQ ID NO: 99HC-FR3 having the amino acid sequence of SEQ ID NO: 100HC-FR4 having the amino acid sequence of SEQ ID NO: 71 .

40. The antigen-binding molecule of any one of claims 37 to 39, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 102LC-FR2 having the amino acid sequence of SEQ ID NO: 103LC-FR3 having the amino acid sequence of SEQ ID NO: 104LC-FR4 having the amino acid sequence of SEQ ID NO: 15.41 . The antigen-binding molecule of any one of claims 37 to 40, wherein the antigen-binding molecule comprises:(I) a VH region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 91 ; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 92.

42. The antigen-binding molecule of claim 41 , wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 91 and a VL region comprising the amino acid sequence of SEQ ID NO: 92.

43. An antigen-binding molecule that specifically binds B7-H3, comprising:(I) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

44. The antigen-binding molecule of claim 43, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 227; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81LC-CDR2 comprising the amino acid sequence SEQ ID NO: 228LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

45. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 190; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

46. The antigen-binding molecule of claim 45, wherein the antigen-binding molecule comprises:(I) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 78HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 190; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81LC-CDR2 comprising the amino acid sequence SEQ ID NO: 191LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 82.

47. The antigen-binding molecule of any one of claims 43 to 46, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 231HC-FR2 having the amino acid sequence of SEQ ID NO: 232HC-FR3 having the amino acid sequence of SEQ ID NO: 233HC-FR4 having the amino acid sequence of SEQ ID NO: 234.

48. The antigen-binding molecule of any one of claims 43 to 47, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 235LC-FR2 having the amino acid sequence of SEQ ID NO: 88LC-FR3 having the amino acid sequence of SEQ ID NO: 236LC-FR4 having the amino acid sequence of SEQ ID NO: 237.

49. The antigen-binding molecule of any one of claims 43 to 48, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 229; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 230.

50. The antigen-binding molecule of claim 49, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 229 and a VL region comprising the amino acid sequence of SEQ ID NO: 230.51 . The antigen-binding molecule of any one of claims 43 to 50, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 192HC-FR2 having the amino acid sequence of SEQ ID NO: 193HC-FR3 having the amino acid sequence of SEQ ID NO: 194HC-FR4 having the amino acid sequence of SEQ ID NO: 195.

52. The antigen-binding molecule of any one of claims 43 to 51 , wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 196LC-FR2 having the amino acid sequence of SEQ ID NO: 88LC-FR3 having the amino acid sequence of SEQ ID NO: 197LC-FR4 having the amino acid sequence of SEQ ID NO: 198.

53. The antigen-binding molecule of any one of claims 43 to 52, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 188; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 189.

54. The antigen-binding molecule of claim 53, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 188 and a VL region comprising the amino acid sequence of SEQ ID NO: 189.

55. The antigen-binding molecule of any one of claims 43 to 50, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 201HC-FR2 having the amino acid sequence of SEQ ID NO: 202HC-FR3 having the amino acid sequence of SEQ ID NO: 203HC-FR4 having the amino acid sequence of SEQ ID NO: 204.

56. The antigen-binding molecule of any one of claims 43 to 50 or claim 55, wherein the antigenbinding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 205LC-FR2 having the amino acid sequence of SEQ ID NO: 88LC-FR3 having the amino acid sequence of SEQ ID NO: 206LC-FR4 having the amino acid sequence of SEQ ID NO: 207.

57. The antigen-binding molecule of any one of claims 43 to 50, claim 55 or claim 56, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 199; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 200.

58. The antigen-binding molecule of claim 57, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 199 and a VL region comprising the amino acid sequence of SEQ ID NO: 200.

59. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

60. The antigen-binding molecule of claim 59, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 239; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.61 . An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

62. The antigen-binding molecule of claim 61 , wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 238HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

63. The antigen-binding molecule of any one of claims 59 to 62, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 242HC-FR2 having the amino acid sequence of SEQ ID NO: 243HC-FR3 having the amino acid sequence of SEQ ID NO: 244HC-FR4 having the amino acid sequence of SEQ ID NO: 245.

64. The antigen-binding molecule of any one of claims 59 to 63, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 246LC-FR2 having the amino acid sequence of SEQ ID NO: 247LC-FR3 having the amino acid sequence of SEQ ID NO: 248LC-FR4 having the amino acid sequence of SEQ ID NO: 249.

65. The antigen-binding molecule of any one of claims 59 to 64, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 240; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 241 .

66. The antigen-binding molecule of claim 65, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 240 and a VL region comprising the amino acid sequence of SEQ ID NO: 241 .

67. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

68. The antigen-binding molecule of claim 67, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 18HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

69. The antigen-binding molecule of claim 67 or 68, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 211HC-FR2 having the amino acid sequence of SEQ ID NO: 212HC-FR3 having the amino acid sequence of SEQ ID NO: 213HC-FR4 having the amino acid sequence of SEQ ID NO: 204.

70. The antigen-binding molecule of any one of claims 67 to 69, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 214LC-FR2 having the amino acid sequence of SEQ ID NO: 215LC-FR3 having the amino acid sequence of SEQ ID NO: 216LC-FR4 having the amino acid sequence of SEQ ID NO: 217.71 . The antigen-binding molecule of any one of claims 67 to 70, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 208; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 209.

72. The antigen-binding molecule of claim 71 , wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 208 and a VL region comprising the amino acid sequence of SEQ ID NO: 209.

73. An antigen-binding molecule that specifically binds B7-H3, comprising:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and / or(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

74. The antigen-binding molecule of claim 73, wherein the antigen-binding molecule comprises:(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 220 HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 210; and(ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 LC-CDR2 comprising the amino acid sequence SEQ ID NO: 182 LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

75. The antigen-binding molecule of claim 73 or 74, wherein the antigen-binding molecule comprises a VH region incorporating the following framework regions (FRs):HC-FR1 having the amino acid sequence of SEQ ID NO: 221HC-FR2 having the amino acid sequence of SEQ ID NO: 222HC-FR3 having the amino acid sequence of SEQ ID NO: 223HC-FR4 having the amino acid sequence of SEQ ID NO: 195.

76. The antigen-binding molecule of any one of claims 73 to 75, wherein the antigen-binding molecule comprises a VL region incorporating the following framework regions:LC-FR1 having the amino acid sequence of SEQ ID NO: 224LC-FR2 having the amino acid sequence of SEQ ID NO: 225LC-FR3 having the amino acid sequence of SEQ ID NO: 226LC-FR4 having the amino acid sequence of SEQ ID NO: 30.

77. The antigen-binding molecule of any one of claims 73 to 76, wherein the antigen-binding molecule comprises:(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 218; and / or(ii) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 219.

78. The antigen-binding molecule of claim 77, wherein the antigen-binding molecule comprises a VH region comprising the amino acid sequence of SEQ ID NO: 218 and a VL region comprising the amino acid sequence of SEQ ID NO: 219.

79. The antigen-binding molecule of any one of claims 1 , 2, 5, 7, 8, 11 , 13, 14, 17, 19, 20, 23, 25, 26, 29, 31 , 32, 35, 37, 38, 41 , 43, 44, 45, 46, 49, 53, 57, 59, 60, 61 , 62, 65, 67, 68, 71 , 73, 74 or 77, wherein the antigen-binding molecule is humanised.

80. The antigen-binding molecule of any one of claims 1 to 79, wherein the antigen-binding molecule comprises a heavy chain comprising a constant region comprising an amino acid sequence having at least 70 % sequence identity to the amino acid sequence of SEQ ID NO: 110 and comprising an alanine residue at the position corresponding to position 180 of SEQ ID NO: 110.81 . The antigen-binding molecule of any one of claims 1 to 80, wherein the antigen-binding molecule comprises:(a) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 113; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 114 or 115;(b) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 116; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 117 or 118;(c) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 119; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 120 or 121 ;(d) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 122; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 123 or 124;(e) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 125; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 126 or 127;(f) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 128; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 129 or 130;(g) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 131 ; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 132 or 133(h) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 250; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 251 or 252; or(i) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 253; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 254 or 255; or(j) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 256; and / ora light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 257 or 258; or(k) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 259; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 260 or 261 ; or(l) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 262; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 263 or 264; or(m) a heavy chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 265; and / or a light chain comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 266 or 267.

82. An antibody-drug conjugate comprising an antigen-binding molecule according to any one of claims 1 to 81.

83. A nucleic acid, or a plurality of nucleic acids, encoding an antigen-binding molecule according to any one of claims 1 to 81 .

84. An expression vector, or a plurality of expression vectors, comprising the nucleic acid or plurality of nucleic acids according to claim 83.

85. A cell comprising an antigen-binding molecule according to any one of claims 1 to 81 , a nucleic acid or a plurality of nucleic acids according to claim 83 or an expression vector or a plurality of expression vectors according to claim 84.

86. A composition comprising an antigen-binding molecule according to any one of claims 1 to 81 , an antibody-drug conjugate according to claim 82, a nucleic acid or a plurality of nucleic acids according to claim 83, an expression vector or a plurality of expression vectors according to claim 84, or a cell of claim 85, optionally further comprising a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

87. An antigen-binding molecule according to any one of claims 1 to 81 , an antibody-drug conjugate according to claim 82, a nucleic acid or a plurality of nucleic acids according to claim 83, an expression vector or a plurality of expression vectors according to claim 84, a cell according to claim 85 or a composition according to claim 86, for use in a method of medical treatment or prophylaxis, or in a method of diagnosis or prognosis.

88. An antigen-binding molecule according to any one of claims 1 to 81 , an antibody-drug conjugate according to claim 82, a nucleic acid or a plurality of nucleic acids according to claim 83, an expression vector or a plurality of expression vectors according to claim 84, a cell according to claim 85 or a composition according to claim 86, for use in a method of treating or preventing cancer.

89. Use of an antigen-binding molecule according to any one of claims 1 to 81 , an antibody-drug conjugate according to claim 82, a nucleic acid or a plurality of nucleic acids according to claim 83, an expression vector or a plurality of expression vectors according to claim 84, a cell according to claim 85 or a composition according to claim 86, in the manufacture of a medicament for treating or preventing cancer.

90. A method of treating or preventing cancer, comprising administering to a subject a therapeutically- or prophylactically-effective amount of an antigen-binding molecule according to any one of claims 1 to 81 , an antibody-drug conjugate according to claim 82, a nucleic acid or a plurality of nucleic acids according to claim 83, an expression vector or a plurality of expression vectors according to claim 84, a cell according to claim 85 or a composition according to claim 86.91 . The antigen-binding molecule, antibody-drug conjugate, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, composition or cell for use according to claim 88, the use according to claim 89 or the method according to claim 90, wherein the cancer comprises cells expressing or overexpressing B7-H3.

92. An in vitro complex comprising an antigen-binding molecule according to any one of claims 1 to 81 or an antibody-drug conjugate according to claim 82 bound to B7-H3.

93. A method comprising contacting a sample containing, or suspected to contain, B7-H3 with an antigen-binding molecule according to any one of claims 1 to 81 , and detecting the formation of a complex of the antigen-binding molecule with B7-H3.

94. Use of an antigen-binding molecule according to any one of claims 1 to 81 as an in vitro or in vivo diagnostic or prognostic agent.

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