Bispecific molecules

Abstract

The present disclosure provides antigen-binding molecules comprising a gp130-binding moiety and an antagonist of an angiogenic factor. Also provided are nucleic acids encoding such antigen-binding molecules, vectors comprising such nucleic acids, cells comprising such antigen-binding molecules, and compositions comprising such antigen-binding molecules, nucleic acids, vectors, and / or cells. Further provided are methods for treating / preventing diseases / conditions using such antigen-binding molecules, nucleic acids, vectors, cells and / or compositions.

Description

[0001] Bispecific Molecules

[0002] This application claims priority from GB 2500886.3 filed 22 January 2025 and GB 2517148.9 filed 15 October 2025, the contents and elements of which are herein incorporated by reference for all purposes.

[0003] Technical Field

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

[0005] Background

[0006] Fibrosis is an essential process that is a critical part of wound healing. Excessive fibrosis is common in many rare and common disease conditions and is important in disease pathogenesis. Diseases characterized by excessive fibrosis include but are not restricted to: systemic sclerosis, scleroderma, hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, ventricular fibrillation, myocarditis, liver cirrhosis, kidney diseases, asthma, diseases of the eye, cystic fibrosis, arthritis and idiopathic pulmonary fibrosis.

[0007] Angiogenesis is an essential process in normal growth and development, as well as in wound healing. Abnormal angiogenesis is linked to a number of diseases and conditions, including age-related wet macular degeneration (wet AMD). Angiogenesis is also closely linked with inflammation and fibrosis, with many studies demonstrating a relationship between angiogenesis and fibrotic disease progression (see, for example, Matsuda etal. Molecular Therapy Nucleic Acids. (2019) 17:819-828; Wan etal. Respir Res. (2013) 14(1):56; Liu etal. Nature Materials. (2017) 16:1252-1261).

[0008] Gp130 is a constituent protein of receptors of a diversity of cytokines including IL-6, IL-11 , OSM, LIF, CNTF, CT-1 , CLC, IL-27 and IL-35, which are often referred to collectively as IL-6 family cytokines. Certain IL-6 family cytokines such as IL-6 and IL-11 are implicated in the pathology of a broad spectrum of diseases / conditions characterised by inflammation and / or fibrosis (see e.g. Rose-John, F1000Res. (2020) 9:F1000 Faculty Rev-1013, Tanaka et al., Cold Spring Harb Perspect Biol. (2014) 6(10): a016295, Hirano etal. International Immunology (2021) 33(3): 127-148, Putoczki and Ernst, Immunotherapy (2015) 7(4): 441-453, Nguyen etal. Growth Factors (2019) 37(1-2):1-11 , Cook and Schafer Annu. Rev. Med. (2020) 71:263-276 and Fung et al., Cytokine (2022) 149:155750).

[0009] Despite the large impact on human health, therapeutic and diagnostic approaches to fibrosis are still an unmet medical need.

[0010] Monoclonal antibodies that bind to gp130 and antagonise gp130-mediated signalling have previously been described, including mAb16673 which is described in WO 2019 / 126071 A1. Combination therapy using VEGF decoy receptor aflibercept in combination with anti-IL6R antibody (sarilumab) has been described in Zhang etal. Cancer Res. (2012) 72:2723-2723.Summary

[0011] In a first aspect, the present disclosure provides an antigen-binding molecule that binds to gp130, comprising (i) a gp130-binding moiety, and (ii) an antagonist of an angiogenic factor.

[0012] In some embodiments, the gp130-binding moiety inhibits IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and LIF-mediated signalling.

[0013] In some embodiments, the gp130-binding moiety contacts the region of gp130 shown in SEQ ID NO:89.

[0014] In some embodiments, the gp130-binding moiety comprises:

[0015] (a) (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0016] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0017] HC-CDR2 having the amino acid sequence of SEQ ID NO:3

[0018] HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and

[0019] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0020] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10

[0021] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0022] LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0023] (b)

[0024] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0025] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0026] HC-CDR2 having the amino acid sequence of SEQ ID NO:3

[0027] HC-CDR3 having the amino acid sequence of SEQ ID NO:185; and

[0028] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0029] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10

[0030] LC-CDR2 having the amino acid sequence of SEQ ID NO:192

[0031] LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0032] (c)

[0033] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0034] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0035] HC-CDR2 having the amino acid sequence of SEQ ID NO:3

[0036] HC-CDR3 having the amino acid sequence of SEQ ID NO:185; and

[0037] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0038] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10

[0039] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0040] LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0041] (d)

[0042] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0043] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0044] HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and

[0045] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0046] LC-CDR1 having the amino acid sequence of SEQ ID NO:10

[0047] LC-CDR2 having the amino acid sequence of SEQ ID NO:192

[0048] LC-CDR3 having the amino acid sequence of SEQ ID NO:12.

[0049] In some embodiments, the gp130-binding moiety comprises:

[0050] (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 68, 71, 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, and

[0051] (ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 68, 71, 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C,

[0052] wherein the VH and VL sequences are selected from the same row of Table C.

[0053] In some embodiments, the gp130-binding moiety comprises:

[0054] (a)

[0055] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0056] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0057] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0058] HC-CDR3 having the amino acid sequence of SEQ ID NO:218; and

[0059] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0060] LC-CDR1 having the amino acid sequence of SEQ ID NO:26

[0061] LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0062] LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0063] (b)

[0064] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0065] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0066] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0067] HC-CDR3 having the amino acid sequence of SEQ ID NQ:204; and

[0068] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0069] LC-CDR1 having the amino acid sequence of SEQ ID NO:26

[0070] LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0071] LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0072] (c)

[0073] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0074] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0075] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0076] HC-CDR3 having the amino acid sequence of SEQ ID NQ:20; and

[0077] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0078] LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0079] LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0080] (d)

[0081] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0082] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0083] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0084] HC-CDR3 having the amino acid sequence of SEQ ID NO:195; and

[0085] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0086] LC-CDR1 having the amino acid sequence of SEQ ID NO:26

[0087] LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0088] LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0089] (e)

[0090] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0091] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0092] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0093] HC-CDR3 having the amino acid sequence of SEQ ID NO:214; and

[0094] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0095] LC-CDR1 having the amino acid sequence of SEQ ID NO:26

[0096] LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0097] LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0098] (f)

[0099] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0100] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0101] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0102] HC-CDR3 having the amino acid sequence of SEQ ID NO:215; and

[0103] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0104] LC-CDR1 having the amino acid sequence of SEQ ID NO:26

[0105] LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0106] LC-CDR3 having the amino acid sequence of SEQ ID NO:28.

[0107] In some embodiments, the gp130-binding moiety comprises:

[0108] (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 89, 90, 80-88, 74-79 or 2 of Table C, and

[0109] (ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 89, 90, 80-88, 74-79 or 2 of Table C,

[0110] wherein the VH and VL sequences are selected from the same row of Table C.

[0111] In some embodiments, the angiogenic factor is selected from vascular endothelial growth factor (VEGF), a fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).

[0112] In some embodiments, the angiogenic factor is VEGF.In some embodiments, the antagonist of an angiogenic factor is selected from: a VEGF decoy receptor, an antigen-binding moiety that binds to VEGF, and an antigen-binding moiety that binds to a VEGF receptor.

[0113] In some embodiments, the antigen-binding molecule is a bispecific antigen-binding molecule.

[0114] In some embodiments, the antagonist of an angiogenic factor is an antigen-binding moiety that binds to VEGF, or an antigen-binding moiety that binds to a VEGF receptor.

[0115] In some embodiments, the antagonist of an angiogenic factor comprises:

[0116] (a)

[0117] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0118] HC-CDR1 having the amino acid sequence of SEQ ID NO:266

[0119] HC-CDR2 having the amino acid sequence of SEQ ID NO:267

[0120] HC-CDR3 having the amino acid sequence of SEQ ID NO:268; and

[0121] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0122] LC-CDR1 having the amino acid sequence of SEQ ID NQ:270

[0123] LC-CDR2 having the amino acid sequence of SEQ ID NO:271

[0124] LC-CDR3 having the amino acid sequence of SEQ ID NO:272; or

[0125] (b)

[0126] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0127] HC-CDR1 having the amino acid sequence of SEQ ID NO:274

[0128] HC-CDR2 having the amino acid sequence of SEQ ID NO:275

[0129] HC-CDR3 having the amino acid sequence of SEQ ID NO:276; and

[0130] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0131] LC-CDR1 having the amino acid sequence of SEQ ID NO:278

[0132] LC-CDR2 having the amino acid sequence of SEQ ID NO:192

[0133] LC-CDR3 having the amino acid sequence of SEQ ID NO:279; or

[0134] (c)

[0135] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0136] HC-CDR1 having the amino acid sequence of SEQ ID NO:281

[0137] HC-CDR2 having the amino acid sequence of SEQ ID NO:282

[0138] HC-CDR3 having the amino acid sequence of SEQ ID NO:283; and

[0139] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0140] LC-CDR1 having the amino acid sequence of SEQ ID NO:285

[0141] LC-CDR2 having the amino acid sequence of SEQ ID NO:286

[0142] LC-CDR3 having the amino acid sequence of SEQ ID NO:287; or

[0143] (d)

[0144] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0145] HC-CDR1 having the amino acid sequence of SEQ ID NO:385

[0146] HC-CDR2 having the amino acid sequence of SEQ ID NO:267

[0147] HC-CDR3 having the amino acid sequence of SEQ ID NO:386; and(ii) a light chain variable (VL) region incorporating the following CDRs:

[0148] LC-CDR1 having the amino acid sequence of SEQ ID NO:270

[0149] LC-CDR2 having the amino acid sequence of SEQ ID NO:271

[0150] LC-CDR3 having the amino acid sequence of SEQ ID NO:272.

[0151] In some embodiments, the antagonist of an angiogenic factor is a decoy receptor.

[0152] In some embodiments, the antagonist of an angiogenic factor is aflibercept.

[0153] In some embodiments, the antagonist of an angiogenic factor comprises or consists of SEQ ID NO:296 or 297.

[0154] The present disclosure also provides a nucleic acid, or a plurality of nucleic acids, encoding an antigenbinding molecule according to the present disclosure.

[0155] The present disclosure also provides an expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to the present disclosure.

[0156] The present disclosure also provides a cell comprising an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, or an expression vector or a plurality of expression vectors according to the present disclosure.

[0157] The present disclosure also provides a method comprising culturing a cell according to the present disclosure under conditions suitable for expression of an antigen-binding molecule by the cell.

[0158] The present disclosure also provides a composition comprising an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, or a cell according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0159] The present disclosure also provides an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present disclosure, for use in a method of medical treatment or prophylaxis.

[0160] The present disclosure also provides an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present disclosure, for use in a method of treating or preventing fibrosis, a disease / condition characterised by fibrosis, pathological angiogenesis, a disease / condition characterised by angiogenesis, pathological inflammation and / or a disease / condition characterised by inflammation.The present disclosure also provides use of an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present disclosure, in the manufacture of a medicament for use in a method of treating or preventing fibrosis, a disease / condition characterised by fibrosis, pathological angiogenesis, a disease / condition characterised by angiogenesis, pathological inflammation and / or a disease / condition characterised by inflammation.

[0161] The present disclosure also provides a method of treating or preventing fibrosis, a disease / condition characterised by fibrosis, pathological angiogenesis, a disease / condition characterised by angiogenesis, pathological inflammation and / or a disease / condition characterised by inflammation comprising administering to a subject a therapeutically- or prophylactically-effective amount of an antigen-binding molecule, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present disclosure.

[0162] In some embodiments, the fibrosis, disease / condition characterised by fibrosis, pathological angiogenesis, disease / condition characterised by angiogenesis, pathological inflammation and / or disease / condition characterised by inflammation, affects tissue of the eye.

[0163] In some embodiments, the fibrosis, disease / condition characterised by fibrosis, pathological angiogenesis, disease / condition characterised by angiogenesis, pathological inflammation and / or disease / condition characterised by inflammation is selected from: choroidal neovascularization, retinal fibrosis, epiretinal fibrosis, idiopathic pre-macular fibrosis, retinal detachment, macular degeneration, subretinal fibrosis associated with wet age-related macular degeneration, diabetic retinopathy, glaucoma, geographic atrophy, corneal fibrosis, post-surgical fibrosis, post-surgical fibrosis of the posterior capsule following cataract surgery, post-surgical fibrosis of the bleb following trabeculectomy for glaucoma, conjunctival fibrosis, subconjunctival fibrosis, proliferative retinal vasculopathy, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, autoimmune uveitis, infectious uveitis, Bechet’s disease, cataracts, keratic precipitates, conjunctival ulcers, corneal immune ring opacities, post-surgical inflammation, dry eye disease, retinitis pigmentosa, glaucoma, toxic anterior segment syndrome (TASS), Eales’ disease, diabetic retinopathy, retinal dystrophy (e.g. retinitis pigmentosa) and Sjogrens syndrome.

[0164] In some embodiments, the fibrosis, disease / condition characterised by fibrosis, pathological angiogenesis, disease / condition characterised by angiogenesis, pathological inflammation and / or disease / condition characterised by inflammation is selected from: choroidal neovascularization, retinal fibrosis, epiretinal fibrosis, subretinal fibrosis, dacryoadenitis, uveitis, autoimmune uveitis, infectious uveitis, Bechet’s disease, and dry eye disease.

[0165] The present disclosure also provides an in vitro complex, optionally isolated, comprising an antigenbinding molecule according to the present disclosure bound to gp130 and / or an angiogenic factor.The present disclosure also provides a method for detecting gp130 and / or an angiogenic factor in a sample, comprising contacting a sample containing, or suspected to contain, gp130 and / or an angiogenic factor with an antigen-binding molecule according to the present disclosure, and detecting the formation of a complex of the antigen-binding molecule with gp130 and / or an angiogenic factor.

[0166] The present disclosure also provides use of an antigen-binding molecule according to the present disclosure as an in vitro or in vivo diagnostic or prognostic agent.

[0167] Description

[0168] qp130

[0169] Human gp130 (also known as IL6ST, CD130) is the protein identified by UniProt P40189. The structure and function of gp130 is described e.g. in Silver and Hunter, J Leukoc Biol. (2010) 88(6): 1145-1156 and Rose-John, Cold Spring Harb Perspect Biol. (2018) 10(2):a028415, which are hereby incorporated by reference in their entirety.

[0170] The canonical isoform of human gp130 (isoform 1) has the amino acid sequence shown in SEQ ID NO:70. Alternative splicing of mRNA encoded by the human IL6ST gene yields three main gp130 isoforms: isoform 1 (SEQ ID NO:70), isoform 2 (also known as gp130-RAPS; SEQ ID NO:71) and isoform 3 (SEQ ID NO:72). Isoform 2 differs from isoform 1 in that positions 325 to 329 of SEQ ID NOTO are different, and positions 330-918 are absent. Positions 423 to 483 of SEQ ID NOTO are absent from isoform 3.

[0171] The canonical isoform of human gp130 comprises an N-terminal signal peptide (SEQ ID NO:73), followed by an extracellular domain (SEQ ID NO:75), a single-pass transmembrane domain (SEQ ID NO:76) and a cytoplasmic domain (SEQ ID NO:77) at the C-terminus. The mature form of human gp130 isoform 1 is shown in SEQ ID NO:74.

[0172] The extracellular domain comprises an N-terminal Ig-like C2-type domain (SEQ ID NO:78), followed by five fibronectin type III (FNIII) domains (shown in SEQ ID NOs:79, 80, 82, 83 and 84, respectively). The cytokine-binding module (CBM) of gp130 is formed by the Ig-like C2-type domain, and FNIII domains 1 and 2 (SEQ ID NO:85). FNIII domain 2 comprises the WSXWS motif shown in SEQ ID NO:81. WSXWS motifs are conserved among type I cytokine receptor polypeptides, and the WSXWS motif of gp130 is thought to be important for cytokine binding.

[0173] gp130 is a constituent polypeptide of all receptors in the IL-6 receptor family, providing for signal transduction. Two gp130 polypeptides associate with two IL-6Ra polypeptides to form the receptor for IL-6, and similarly two gp130 polypeptides associate with two IL-11 Ra polypeptides to form the receptor for IL-11. gp130 associates with OSMRp to form the type II receptor for OSM, or with LIFRp to form the type I receptor for OSM, which also serves as a receptor for LIF and CT-1. gp130 also associates with LIFRp and CNTFRa to form the receptor for CNTF and CLC. gp130 associates with IL-27Ra to form the receptor for IL-27, and associates with IL-12Rp2 to form the receptor for IL-35.Following the formation of complexes with its receptor interaction partner(s) and cognate ligand, gp130 is phosphorylated at tyrosine residues in its cytoplasmic domain (particularly Y767, Y814, Y905 and Y915), triggering downstream signalling through the JAK / STAT and MAPK / ERK signal transduction pathways. gp130 can also trigger signalling through PI3K / AKT. Receptor engagement leads to phosphorylation and activation of JAK1 and JAK2, which then phosphorylate STAT1, STAT3 and STAT5. Phosphorylation of gp130 tyrosine residues also results in the recruitment and activation of SHP2, which in turn activates signalling through the Ras-ERK1 / ERK2 MAPK and PI3K / AKT signalling pathways.

[0174] In this specification ‘gp130’ refers to gp130 from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments gp130 is gp130 from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the gp130 is human gp130, rhesus gp130, mouse gp130, rat gp130 or canine gp130. In some embodiments, the gp130 is human gp130 or mouse gp130.

[0175] As used herein, isoforms, fragments, variants or homologues of a given reference protein (e.g. gp130) may be characterised as having at least 70% sequence identity, preferably one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of the reference protein.

[0176] A ‘fragment’ generally refers to a fraction of the reference protein. A ‘variant’ generally refers to a protein having an amino acid sequence comprising one or more amino acid substitutions, insertions, deletions or other modifications relative to the amino acid sequence of the reference protein, but retaining a considerable degree of sequence identity (e.g. at least 60%) to the amino acid sequence of the reference protein. An ‘isoform’ generally refers to a variant of the reference protein expressed by the same species as the species of the reference protein. A ‘homologue’ generally refers to a variant of the reference protein produced by a different species as compared to the species of the reference protein. Homologues include orthologues. Homologues of human gp130 include e.g. mouse gp130 (UniProt Q00560) and rat gp130 (UniProt P40190).

[0177] Isoforms, fragments, variants or homologues of a given reference protein may optionally be characterised as having at least 70%, preferably one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature ( / .e. after processing to remove signal peptide) form of a specified isoform of the relevant protein from a given species, e.g. human.

[0178] Isoforms, fragments, variants or homologues of gp130 according to the present disclosure may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature gp130 isoform from a given species, e.g. human.Isoforms, fragments, variants or homologues may optionally be functional isoforms, fragments, variants or homologues, e.g. having a functional property / activity of the reference gp130 (e.g. human gp130 isoform 1), as determined by analysis by a suitable assay for the functional property / activity. For example, an isoform, fragment, variant or homologue of gp130 may associate with IL-6Ra, IL-11Ra, OSMRp, LIFRp and / or CNTFRa.

[0179] In some embodiments, the gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:70, 71 or 72.

[0180] In some embodiments, the gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:70 or 74.

[0181] A ‘fragment’ of a reference protein may be of any length (by number of amino acids), although may optionally be at least 25% of the length of the reference protein (that is, the protein from which the fragment is derived) and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.

[0182] A fragment of gp130 may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800 or 900 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800 or 900 amino acids.

[0183] In some embodiments, a fragment of gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:74.

[0184] In some embodiments, a fragment of gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:75.

[0185] In some embodiments, a fragment of gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:85.

[0186] In this specification ‘gp130-mediated signalling’ refers to signalling mediated by gp130 and / or multimeric receptor complexes comprising gp130 (e.g. comprising gp130 and another member of the IL-6 receptor family). ‘Signalling’ refers to signal transduction and other cellular processes governing cellular activity.

[0187] gp130-mediated signalling may be mediated by a gp130-containing polypeptide complex ( / .e. a polypeptide complex comprising one or more gp130 polypeptides). Polypeptide complexes according tothe present disclosure may be characterised by non-covalent, protein: protein interaction between constituent polypeptide(s) / peptide(s). In some embodiments, the association comprises electrostatic interaction (e.g. ionic bonding, hydrogen bonding) and / or Van der Waals forces.

[0188] gp130-mediated signalling may be mediated by heteromultimeric polypeptide complexes comprising one or more gp130 polypeptides, and additionally comprising one or more polypeptides of one or more polypeptides of the IL-6 receptor family (e.g. selected from IL-6Ra, IL-11Ra, OSMRp, LIFRp, CNTFRa, IL-27Ra and IL-12Rp2).

[0189] In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex forming a receptor for an IL-6 family cytokine. For example, gp130-mediated signalling may be mediated by a polypeptide complex forming a receptor for IL-6, IL-11 , OSM, LIF, CNTF, CT-1 , CLC, IL-27 or IL-35.

[0190] In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and another polypeptide of the IL-6 receptor family (e.g. selected from IL-6Ra, IL-11Ra, OSMRp, LIFRp, CNTFRa, IL-27Ra and IL-12Rp2). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-6Ra ( / .e. a gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-11Ra ( / .e. a gp130:IL-11Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and OSMRp ( / .e. a gp130:OSMRp complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and LIFRp ( / .e. a gp130:LIFRp complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130, LIFRp and CNTFRa ( / .e. a gp130:LIFRp:CNTFRa complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-27Ra ( / .e. a gp130:IL-27Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-12Rp2 ( / .e. a gp130:IL-12Rp2 complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising more than one gp130 polypeptide. In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising two gp130 polypeptides. In some embodiments gp130-mediated signalling may be mediated by a polypeptide complex comprising two gp130 polypeptides and IL-6Ra ( / .e. a gp130:gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising two gp130 polypeptides and IL-11Ra ( / .e. a gp130:gp130:IL-11Ra complex).

[0191] gp130-mediated signalling through the polypeptide complexes described in the preceding paragraph may be triggered by binding of their cognate cytokine(s). That is, in some embodiments, gp130-mediated signalling through a polypeptide complex comprising (i) gp130 and (ii) another polypeptide of the IL-6 receptor family may be triggered by binding of a cytokine to the polypeptide complex formed by proteinprotein interaction between (i) and (ii). In some embodiments, gp130-mediated signalling is triggered by binding of IL-6 to a polypeptide complex comprising gp130 and IL-6Ra ( / .e. a gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-11 to a polypeptide complexcomprising gp130 and IL-11Ra ( / .e. a gp130:IL-11Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of OSM to a polypeptide complex comprising gp130 and OSMRp ( / .e. a gp130:OSMRp complex). In some embodiments, gp130-mediated signalling is triggered by binding of OSM, LIF or CT-1 to a polypeptide complex comprising gp130 and LIFRp ( / .e. a gp130:LIFRp complex). In some embodiments, gp130-mediated signalling is triggered by binding of CNTF or CLC to a polypeptide complex comprising gp130, LIFRp and CNTFRa ( / .e. a gp130:LIFRp:CNTFRa complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-27 to a polypeptide complex comprising gp130 and IL-27Ra ( / .e. a gp130:IL-27Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-35 to a polypeptide complex comprising gp130 and IL-12Rp2 ( / .e. a gp130:IL-12Rp2 complex).

[0192] Antigen-binding molecules and antigen-binding moieties

[0193] 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 of the present disclosure comprise an antigen-binding moiety that binds to gp130 ( / .e. a gp130-binding moiety), and an antagonist of an angiogenic factor. In some embodiments, the antigen-binding molecules comprise an antigen-binding polypeptide complex comprising an antigen-binding moiety that binds to gp130, and an antagonist of an angiogenic factor. In some embodiments, the antigen-binding molecules comprise an antigen-binding moiety that binds to gp130 ( / .e. a gp130-binding moiety), and an antigen-binding moiety that binds to an angiogenic factor. In some embodiments, the antigen-binding molecules comprise an antigen-binding polypeptide complex comprising an antigen-binding moiety that binds to gp130, and an antigen-binding polypeptide complex comprising an antigen-binding moiety that binds to an angiogenic factor.

[0194] Antigen-binding moieties may comprise, or may be derived from, antibodies ( / .e. immunoglobulins (Igs)) and antigen-binding fragments of antibodies. As used herein, ‘antibodies’ include monoclonal antibodies, 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.

[0195] Antigen-binding moieties also include target antigen-binding aptamers, e.g. a nucleic acid aptamers (reviewed, for example, in Zhou and Rossi, Nat Rev Drug Discov. (2017) 16(3):181-202). In some embodiments, an antigen-binding moiety comprises or consists of an antigen-binding peptide / polypeptide, e.g. a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, fynomer, atrimer, DARPin, affibody, nanobody ( / .e. a single-domain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody or fibronectin - reviewed e.g. in Reverdatto et al., CurrTop Med Chem. 2015; 15(12): 1082-1101, which is hereby incorporated by reference in its entirety (see also e.g. Boersma etal., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).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). Antigen-binding moieties may be derived from antibodies. Antibody-derived antigen-binding moieties may comprise, or consist of, the antigen-binding region of an antibody (e.g. an antigen-binding fragment of an antibody). The antigen-binding moieties of the present disclosure generally comprise an antigen-binding domain comprising a VH and a VL of an antibody capable of specific binding to the target antigen. The antigen-binding domain formed by a VH and a VL may also be referred to herein as an Fv region.

[0196] 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 a given target antigen, or the whole antibody.

[0197] 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 scFv comprising VH and VL, or in the case of scFab comprising VH-CH1 and VL-CL).

[0198] In some embodiments, an antigen-binding moiety according to the present disclosure comprises, or consists of, a polypeptide complex formed by proteimprotein interaction 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 antigen-binding moiety comprising a heavy chain polypeptide and a light chain polypeptide.

[0199] The antigen-binding moieties of the present disclosure may be designed and prepared using the sequences of monoclonal antibodies (mAbs) capable of binding to gp130. The antigen-binding moieties of the present disclosure may be designed and prepared using the sequences of monoclonal antibodies (mAbs) capable of binding to an angiogenic factor. Antigen-binding regions of antibodies, such as single chain variable fragment (scFv), Fab and F(ab’)2 fragments may also be used / provided. An ‘antigenbinding region’ is any fragment of an antibody that binds to the target for which the given antibody is specific.

[0200] Antibodies generally comprise six complementarity-determining regions CDRs; three in the heavy chain variable (VH) region: HC-CDR1, HC-CDR2 and HC-CDR3, and three in the light chain variable (VL) region: LC-CDR1 , LC-CDR2, and LC-CDR3. The six CDRs together define the paratope of the antibody, which is the part of the antibody that binds to the target antigen.

[0201] 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.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 eta!., 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 etal., 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 moieties referred to herein are defined according to the IMGT information system.

[0202] It will be appreciated that the antigen-binding molecules of the present disclosure may be 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 1 , 2, 3, 4, 5, 6 or more target antigens).

[0203] 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. In some embodiments, the antigen-binding molecule comprises at least two different antigen-binding domains ( / .e. at least two antigen-binding domains, e.g. comprising non-identical VHs and VLs).

[0204] In some embodiments, the antigen-binding molecule binds to gp130 and another target (e.g. an antigen other than gp130), and so is at least bispecific. The term ‘bispecific’ means that the antigen-binding molecule is able to bind specifically to at least two distinct antigenic determinants.

[0205] The antigen-binding molecules of the present disclosure may bind to gp130 and an angiogenic factor, and so are at least bispecific. It will be appreciated that an antigen-binding molecule according to the present disclosure may comprise antigen-binding moieties capable of binding to the targets for which the antigenbinding molecule is specific. It will further be appreciated that an antigen-binding molecule according to the present disclosure may comprise (i) an antigen-binding moiety that binds to gp130, and (ii) an antigen-binding moiety that binds to an angiogenic factor.

[0206] It will also be appreciated that an antigen-binding molecule according to the present disclosure may comprise antigen-binding polypeptides or antigen-binding polypeptide complexes capable of binding to the targets for which the antigen-binding molecule is specific. In some embodiments, the antigen-binding molecule comprises an antigen-binding polypeptide complex, comprising (i) an antigen-binding moiety that binds to gp130, and (ii) an antigen-binding moiety that binds to an angiogenic factor.

[0207] In some embodiments, the antigen-binding molecule comprises: (i) an antigen-binding polypeptide (e.g. a scFv, scFab, polypeptide aptamer or VhH) or an antigen-binding polypeptide complex (e.g. a Fv, Fab or whole antibody) that binds to gp130, and (ii) an antigen-binding polypeptide (e.g. a scFv, scFab,polypeptide aptamer orVhH) or an antigen-binding polypeptide complex (e.g. a Fv, Fab or whole antibody) that binds to an angiogenic factor.

[0208] In some embodiments, the antigen-binding molecule comprises: (i) an antigen-binding moiety comprising the VH and VL of an antibody that binds to gp130, and (ii) an antigen-binding moiety comprising the VH and VL of an antibody that binds to an angiogenic factor.

[0209] In some embodiments, the antigen-binding molecules of the present disclosure display at least monovalent binding with respect to gp130, and also display at least monovalent binding with respect to the angiogenic factor. Binding valency refers to the number of binding sites in an antigen-binding molecule for a given antigenic determinant. Accordingly, in some embodiments, the antigen-binding molecule comprises at least one binding site for gp130 and one binding site for an angiogenic factor.

[0210] Multispecific antigen-binding molecules according to the present disclosure may be provided in any suitable format, such as those formats described in described in Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212, which is hereby incorporated by reference in its entirety. Multispecific antigenbinding 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’)2 or CovX-Body; IgG or IgG-like molecules, e.g. IgG, chimeric IgG, KA-body common HC; CH1 / CL fusion proteins, e.g. scFv2-CH1 / CL, VHH2-CH1 / CL;

[0211] ‘variable domain only’ bispecific antigen-binding molecules, e.g. tandem scFv (taFV), triplebodies, diabodies (Db), dsDb, Db(kih), DART, scDB, dsFv-dsFv, tandAbs, triple heads, tandem dAbA / HH, tetravalent dAb.VHH; Non-lg fusion proteins, e.g. scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-lgG-cytokine2, ImmTAC (TCR-scFv); modified Fc and CH3 fusion proteins, e.g. scFv-Fc(kih), scFv-Fc(CH3 charge pairs), scFv-Fc (EW-RVT), scFv-fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc(kih), scFv-Fc(kih)-Fv, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc (SEEDbody), DART-Fc, scFv-CH3(kih), TriFabs; Fc fusions, e.g. Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-lg, scFv2-Fcab; CH3 fusions, e.g. Dia-diabody, scDb-CH3; IgE / IgM CH2 fusions, e.g. scFv-EHD2-scFv, scFvMHD2-scFv; Fab fusion proteins, e.g. Fab-scFv (bibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, orthogonal Fab-Fab; non-lg fusion proteins, e.g. DNL-Fabs, DNL-Fab2-scFv, DNL-Fab2-lgG-cytokine2; asymmetric IgG or IgG-like molecules, e.g. IgG(kih), IgG(kih) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMab, CrossMab(kih), scFab-lgG(kih), Fab-scFab-lgG(kih), orthogonal Fab IgG(kih), DuetMab, CH3 charge pairs + CH1 / CL charge pairs, hinge / CH3 charge pairs, SEED-body, Duobody, four-in-one-CrossMab(kih), LUZ-Y common LC; LUZ-Y scFab-IgG, FcFc*; appended and Fc-modified IgGs, e.g. lgG(kih)-Fv, IgG HA-TF-Fv, lgG(kih)scFab, scFab-Fc(kih)-scFv2, scFab-Fc(kih)-scFv, half DVD-lg, DVI-lg (four-in-one), CrossMab-Fab; modified Fc and CH3 fusion proteins, e.g. Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc-SEEDbody, TriFab; appended IgGs - HC fusions, e.g. IgG-HC, scFv, IgG-dAb, IgG-taFV, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaCp) Fab, scFv-HC-IgG, tandem Fab-IgG (orthogonal Fab), Fab-lgG(CaCp Fab), Fab-lgG(CR3), Fab-hinge-lgG(CR3); appended IgGs - LC fusions, e.g. IgG-scFv(LC), scFv(LC)-lgG, dAb-IgG; appended IgGs - HC and LC fusions, e.g. DVD-lg, TVD-lg, CODV-lg, scFv4-lgG, Zybody; Fc fusions, e.g. Fab-scFv-Fc, scFv4-lg; F(ab’)2 fusions, e.g. F(ab’)2-scFv2;CH1 / CL fusion proteins e.g. scFv2-CH1-hinge / CL; modified IgGs, e.g. DAF (two-in one-IgG), DutaMab, Mab2; and non-lg fusions, e.g. DNL-Fab4-lgG.

[0212] In some embodiments, the antigen-binding molecule is in a CrossMab format (e.g. CrossMabFab, CrossMabVH VL, CrossMabCH1 CL). To enable correct pairing of the cognate heavy and light chains, in the CrossMab format, the light chain of one Fab arm may be exchanged by the Fd of the corresponding heavy chain (CrossMabFab). The Fd region is approximately the first 220 amino acids from the N-terminus of the heavy chain, contained within the Fab' region. Alternatively, only one pair of the variable (CrossMabVH VL) or constant domain (CrossMabCH1 CL) of one Fab is swapped between the light and heavy chain. This results in pairing of the unmodified light chain with the corresponding unmodified heavy chain and pairing of the modified light chain with the corresponding modified heavy chain. Correct heterodimerisation of the heavy chains can be achieved by modified Fc regions (e.g. KiH, KiHs-s, HA-TF, ZW1 , 7.8.60, DD-KK, EW-RVT, EW-RVTS-S, SEED or A107).

[0213] In some embodiments, the antigen-binding molecule is a Fab-scFv-Fc fusion. In such configurations, the antigen-binding molecule comprises a Fab arm capable of binding to a given antigen fused to an Fc region, and an scFv capable of binding to a different antigen fused to an Fc region. Assembly of heterodimers of the Fab arm-Fc fusion and the scFv-Fc fusion can be favoured by using modified Fc regions (e.g. KiH, KiHs.s, HA-TF, ZW1 , 7.8.60, DD-KK, EW-RVT, EW-RVTS.S, SEED or A107).

[0214] In some embodiments, the antigen-binding molecule is an IgG-scFv fusion. In such configurations, the antigen-binding molecule comprises an IgG molecule capable of binding to a given antigen, fused to an scFv capable of binding to a different antigen.

[0215] In some embodiments, the antigen-binding molecule is a diabody or diabody derivative. Diabodies (Db) are bivalent molecules composed of two chains, each comprising a VH and VL domain, either from the same or from different antibodies. In the diabody format, the two variable domains are connected by a short linker that is usually 5 residues, e.g., GGGGS. Because the linker length is substantially shorter than that required to allow intrachain assembly of an antigen-binding site, which would result in a scFv, two chains dimerize in a head-to-tail orientation resulting in a compact molecule with a molecular mass similar to tandem scFv (~50 kDa). Expressing two chains within the same cell, with either configuration VH(A)-VL(B) and VH(B)-VL(A) (A and B representing two different specificities) or VL(A)-VH(B) and VL(B)-VH(A), results in bispecific heterodimers with correct pairing of the corresponding variable domains.

[0216] In some embodiments, the antigen-binding molecule is a tandem scFv molecule. The single-chain Fv (scFv) format is a commonly used derivative of the VH and VL domains representing the minimal antigenbinding site of an antibody. Due to the single-chain configuration, bispecific antibodies can be built by connecting two scFvs through a linker (connector). Thus, these molecules are bivalent with one valency for each antigen, with a typically size in the range of 50-60 kDa.In some embodiments, the antigen-binding molecule comprises (i) an antigen-binding moiety that binds to gp130, and (ii) an antagonist of an angiogenic factor. In some embodiments, the antigen-binding molecule comprises an antigen-binding polypeptide complex, comprising (i) an antigen-binding moiety that binds to gp130, and (ii) an antagonist of an angiogenic factor. In some embodiments, the antigenbinding molecule comprises: (i) an antigen-binding polypeptide (e.g. a scFv, scFab, polypeptide aptamer or VhH) or an antigen-binding polypeptide complex (e.g. a Fv, Fab or whole antibody) that binds to gp130, and (ii) an antagonist of an angiogenic factor.

[0217] The VH and VL region of an antigen-binding region of an antibody together constitute the Fv region. In some embodiments, an antigen-binding moiety according to the present disclosure comprises, or consists of, an Fv region that binds to gp130. In some embodiments, the VH and VL regions of the Fv are provided as single polypeptide joined by a linker sequence, i.e. a single chain Fv (scFv). In some embodiments, the VH and VL regions of the Fv are provided as separate polypeptides stabilised by the introduction of one or more cysteine residues for the formation of an interchain disulfide bond, i.e. a disulfide stabilised Fv (dsFv).

[0218] In some embodiments, an Fv region (e.g. an scFv) according to the present disclosure comprises a stabilising disulfide bond which is described in e.g. Weatherill et al., PEDS. (2012) 25(7):321-329, which is hereby incorporated by reference in its entirety. In such embodiments, each of the VH and VL regions comprise an amino acid substitution to a cysteine to enable the formation of a disulfide bond between the VH and VL regions. In some embodiments, a VH region of the present disclosure comprises a cysteine residue at position 44, and a VL region of the present disclosure comprises a cysteine residue at position 100 (numbering of positions / substitutions herein is according to the EU numbering system as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0219] The VL and light chain constant (CL) region, and the VH region and heavy chain constant 1 (CH1) region of an antigen-binding region of an antibody together constitute the Fab region. In some embodiments, the antigen-binding molecule comprises a Fab region comprising a VH, a CH1 , a VL and a CL (e.g. CK or CA). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CH1 (e.g. a VH-CH1 fusion polypeptide), and a polypeptide comprising a VL and a CL (e.g. a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CL (e.g. a VH-CL fusion polypeptide) and a polypeptide comprising a VL and a CH (e.g. a VL-CH1 fusion polypeptide); that is, in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1, VL and CL regions of the Fab or CrossFab are provided as single polypeptide joined by linker regions, i.e. as a single chain Fab (scFab) or a single chain CrossFab (scCrossFab).

[0220] In some embodiments, an antigen-binding moiety described herein comprises, or consists of, a whole antibody that binds to gp130. In some embodiments, an antigen-binding moiety described herein comprises, or consists of, a whole antibody that binds to an angiogenic factor. As used herein, ‘whole antibody’ refers to an antibody having a structure which is substantially similar to the structure of animmunoglobulin (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.

[0221] Immunoglobulins of type G ( / .e. IgG) are -150 kDa glycoproteins comprising two heavy chains and two light chains. From N- to C-terminus, the heavy chains comprise a VH followed by a heavy chain constant region comprising three constant domains (CH1 , CH2, and CH3), and similarly the light chains comprise a VL followed by a CL. Depending on the heavy chain, immunoglobulins may be classed as IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM. The light chain may be kappa (K) or lambda (A).

[0222] 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 etal., Proc Natl Acad Sci USA (1969) 63(1): 78-85). A ‘CH3 domain’ refers to an amino acid sequence corresponding to the CH3 domain of an immunoglobulin (Ig). The CH3 domain is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant domain, according to the EU numbering system. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 domains of an immunoglobulin (Ig). The CH2-CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant domain, according to the EU numbering system.

[0223] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM that binds to gp130. In some embodiments, the antigen-binding molecule described herein comprises, or consists of, an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM that binds to an angiogenic factor.

[0224] In some embodiments, the antigen-binding molecule of the present disclosure comprises one or more regions (e.g. CH1, CH2, CH3, etc.) of an immunoglobulin heavy chain constant sequence. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. Ig A1 , lgA2), IgD, IgE or IgM, e.g. a human IgG (e.g. hlgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlg E or hlgM. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of a human lgG1 allotype (e.g. G1m1, G1m2, G1m3 orG1m17).

[0225] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:33 or 38. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:48 or 49. In some embodiments, theantigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:41 or 50. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:300, 304, or 307.

[0226] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:42, 43, 46 or 47. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:44 or 57. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:303, 306, or 308.

[0227] In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:34 or 39. In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:51. In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:298.

[0228] In some embodiments, the antigen-binding molecule comprises a hinge region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:35. In some embodiments, the antigen-binding molecule comprises a hinge region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:52 or 53.In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:36 or 45. In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:54 or 55. In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:301.

[0229] In some embodiments, the antigen-binding molecule comprises a CH3 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:37 or 40. In some embodiments, the antigen-binding molecule comprises a CH3 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:56. In some embodiments, the antigen-binding molecule comprises a CH3 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:302 or 305.

[0230] It will be appreciated that CH2 and / or CH3 regions may be provided with further substitutions in accordance with modification to an Fc region of the antigen-binding molecule as described herein.

[0231] In some embodiments, the antigen-binding molecule 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). In some embodiments, the immunoglobulin light chain constant sequence is a human immunoglobulin lambda constant (IGLC; CA), e.g. IGLC1 , IGLC2, IGLC3, IGLC6 or IGLC7.

[0232] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:58, 59, 60, 61, 62, 63, or 309. In preferred embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:58 or 309.The immunoglobulin light chain constant sequence may comprise one or more substitutions. In some embodiments, an immunoglobulin light chain constant sequence may comprise an alanine residue at position 108 and a serine residue at position 109 (according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85).

[0233] In some embodiments, an antigen-binding moiety is or comprises a monoclonal antibody, or an antigenbinding fragment thereof.

[0234] In some embodiments, an antigen-binding moiety is or comprises a fully human antibody / antibody fragment. A fully human antibody / antibody fragment may be encoded by human nucleic acid sequence(s). A fully human antibody / antibody fragment may be devoid of non-human amino acid sequences. Commonly employed techniques for the production of fully human antibodies include (i) phage display, in which human antibody genes are expressed in phage display libraries, and (ii) production of antibodies in transgenic mice engineered to have human antibody genes (described in Park and Smolen, Advances in Protein Chemistry (2001) 56: 369-421). Briefly, in the human antibody genephage display technique, genes encoding the VH and VL chains are generated by PCR amplification and cloning from ‘naive’ human lymphocytes, and assembled into a library from which they can be expressed either as disulfide-linked Fab fragments or as single-chain Fv (scFv) fragments. The Fab- or scFv-encoding genes are fused to a surface coat protein of filamentous bacteriophage and Fab or scFv capable of binding to the target of interest can then be identified by screening the library with antigen. Molecular evolution or affinity maturation procedures can be employed to enhance the affinity of the Fab / scFv fragment. In the transgenic mouse technique, mice in which the endogenous murine Ig gene loci have been replaced by homologous recombination with their human homologues are immunised with antigen, and monoclonal antibody is prepared by conventional hybridoma technology, to yield a fully human monoclonal antibody.

[0235] In some embodiments, the antigen-binding moiety / molecule of the present disclosure is a mouse antibody / antibody fragment. In some embodiments, the antibody / antibody fragment is obtained from phage display using a human naive antibody gene library.

[0236] In some embodiments, the antigen-binding moiety / molecule is a mouse / human chimeric antigen-binding moiety / molecule ( / .e. an antigen-binding moiety / molecule comprising mouse antibody variable domains and human antibody constant regions). In some embodiments, the antigen-binding moiety / molecule is a humanized antigen-binding moiety / molecule ( / .e. an antigen-binding moiety / molecule comprising variable domains derived by humanization of the variable domains of an antibody from a non-human animal, e.g. a mouse) comprising mouse antibody variable domains and human antibody constant regions. In some embodiments, the antigen-binding moiety / molecule comprises mouse antibody CDRs and human antibody framework and constant regions.

[0237] Mouse / human chimeric antigen-binding molecules can be prepared from mouse antibodies by the process of chimerisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols,Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 8 thereof, in particular section 3 of Chapter 8.

[0238] Humanized antigen-binding moieties / molecules can be prepared from mouse antibodies by the process of humanization, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 7 thereof, in particular section 3.1 of Chapter 7 entitled ‘Antibody Humanization’. Techniques for antibody humanization are also described e.g. in Safdari etal., Biotechnol Genet Eng Rev (2013) 29:175-86.

[0239] qp130-bindinq moieties

[0240] The antigen-binding molecules of the present disclosure comprise an antigen-binding molecule that binds to gp130.

[0241] In some embodiments, the antigen-binding moiety comprises the CDRs of an antigen-binding molecule that binds to gp130. In some embodiments, the antigen-binding moiety comprises the FRs of an antigenbinding molecule that binds to gp130. In some embodiments, the antigen-binding moiety comprises the CDRs and the FRs of an antigen-binding molecule that binds to gp130. That is, in some embodiments, the antigen-binding moiety comprises the VH region and the VL region of an antigen-binding molecule that binds to gp130.

[0242] In some embodiments, the antigen-binding moiety comprises the CDRs, FRs and / or the VH and / or VL regions of an antibody described herein (e.g. an antibody of Table C herein), or CDRs, FRs and / or VH and / or VL regions which are derived from those of an antibody described herein (e.g. an antibody of Table C herein). In some embodiments, the antigen-binding moiety comprises the CDRs, FRs and / or the VH and / or VL regions of a gp130-binding antibody described herein, or CDRs, FRs and / or VH and / or VL regions which are derived from those of a gp130-binding antibody described herein. In some embodiments, a gp130-binding antibody is selected from an antibody of Table C herein.

[0243] In some embodiments, a gp130-binding antibody is selected from B035-C03-A3, A3_4.2 VH I A3_3 VL,

[0244]

[0245] 5H8GVH4_D98G 15H8CVL4 and 5H8GVH4_D98G 15H8GVL3. In some embodiments, a gp130-binding antibody is selected from B035-C03-A3, A3_6.2_I1OOT / A3_3_G51A, A3_3.2_I1OOT / A3_4_G51A, CSP-S-5H8, 5H8CVH4_D98G I 5H8CVL3, 5H8CVH4_D98G I 5H8CVL4, 5H8CVH4_D98G I 5H8GVL3, 5H8GVH4_D98G 15H8CVL4 and 5H8GVH4_D98G 15H8GVL3. In some embodiments, a gp130-binding antibody is A3_6.2_I1OOT I A3_3_G51A.

[0246] In some embodiments, the antigen-binding moiety comprises:a VH region comprising HC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 are substituted with another amino acid), HC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR2 are substituted with another amino acid) and HC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid) as indicated in Column A of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the HC-CDR1 , HC-CDR2 and HC-CDR3 sequences of Column A are selected from the same row of Table A.

[0247] By way of illustration, in some embodiments the antigen-binding moiety comprises a VH region comprising HC-CDR1 having the amino acid sequence of SEQ ID NO:2 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:2 are substituted with another amino acid), HC-CDR2 having the amino acid sequence of SEQ ID NO:3 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:3 are substituted with another amino acid) and HC-CDR3 having the amino acid sequence of SEQ ID NO:4 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:4 are substituted with another amino acid). It will be appreciated that the HC-CDR1, HC-CDR2 and HC-CDR3 sequences of the preceding sentence are selected from Column A of the same row (row 1) of Table A.

[0248] In some embodiments, the antigen-binding moiety comprises:

[0249] a VH region comprising HC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 are substituted with another amino acid), HC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR2 are substituted with another amino acid), HC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR3 are substituted with another amino acid) and HC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid) as indicated in Column A of row 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of Column A are selected from the same row of Table B.

[0250] By way of illustration, in some embodiments, the antigen-binding moiety comprises a VH region comprising HC-FR1 having the amino acid sequence of SEQ ID NO:5 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:5 are substituted with another amino acid), HC-FR2 having the amino acid sequence of SEQ ID NO:6 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:6 are substituted with another amino acid), HC-FR3 having the amino acid sequence of SEQ ID NOT (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NOT are substituted with another amino acid) and HC-FR4 having the amino acid sequence of SEQ ID NO:8 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:8 are substituted with another amino acid). It will be appreciated that the HC-FR1, HC-FR2, HC-FR3 and HC-FR4 sequences of the preceding sentence are selected from Column A of the same row (row 1) of Table B.In some embodiments, the antigen-binding moiety comprises:

[0251] a VH region comprising:

[0252] HC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 are substituted with another amino acid), HC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR2 are substituted with another amino acid) and HC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid) as indicated in Column A of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the HC-CDR1 , HC-CDR2 and HC-CDR3 sequences of Column A are selected from the same row of Table A; and

[0253] HC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 are substituted with another amino acid), HC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC- FR2 are substituted with another amino acid), HC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR3 are substituted with another amino acid) and HC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid) as indicated in Column A of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the HC- FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of Column A are selected from the same row of Table B.

[0254] In some embodiments, the antigen-binding moiety comprises:

[0255] a VH region comprising:

[0256] HC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 are substituted with another amino acid), HC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR2 are substituted with another amino acid) and HC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid) as indicated in Column A of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A; and

[0257] HC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 are substituted with another amino acid), HC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC- FR2 are substituted with another amino acid), HC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR3 are substituted with another amino acid) and HC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid) as indicated in Column A of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B;

[0258] wherein the HC-CDR1 , HC-CDR2, HC-CDR3 sequences of Column A of Table A and the HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of Column B of Table B are selected from rows having the same number.

[0259] By way of illustration, in some embodiments, the antigen-binding moiety comprises a VH region comprising: HC-CDR1 having the amino acid sequence of SEQ ID NO:2 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:2 are substituted with another amino acid), HC-CDR2 having the amino acid sequence of SEQ ID NO:3 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:3 are substituted with another amino acid) and HC-CDR3 having the amino acid sequence of SEQ ID NO:4 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:4 are substituted with another amino acid), HC-FR1 having the amino acid sequence of SEQ ID NO:5 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:5 are substituted with another amino acid), HC-FR2 having the amino acid sequence of SEQ ID NO:6 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:6 are substituted with another amino acid), HC-FR3 having the amino acid sequence of SEQ ID NOT (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NOT are substituted with another amino acid) and HC-FR4 having the amino acid sequence of SEQ ID NO:8 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:8 are substituted with another amino acid). It will be appreciated that the HC-CDR1 , HC-CDR2 and HC-CDR3 sequences of the preceding sentence are selected from Column A of row 1 of Table A, and that the HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences are selected from Column A of the row of Table B having the same number (row 1).

[0260] In some embodiments, the antigen-binding moiety comprises a VH region comprising at least 70%, preferably one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of a VH region sequence selected from Column A of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table C.

[0261] In some embodiments, the antigen-binding moiety comprises:

[0262] a VL region comprising LC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 are substituted with another amino acid), LC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR2 are substituted with another amino acid) and LC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid) as indicated in Column B of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86,87, 88, 89, or 90 of Table A, wherein the LC-CDR1 , LC-CDR2 and LC-CDR3 sequences of Column B are selected from the same row of Table A.

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

[0264] a VL region comprising LC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 are substituted with another amino acid), LC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR2 are substituted with another amino acid), LC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR3 are substituted with another amino acid) and LC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid) as indicated in Column B of row 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the LC-FR1 , LC-FR2, LC-FR3 and LC-FR4 sequences of Column B are selected from the same row of Table B.

[0265] In some embodiments, the antigen-binding moiety comprises:

[0266] a VL region comprising:

[0267] LC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 are substituted with another amino acid), LC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR2 are substituted with another amino acid) and LC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid) as indicated in Column B of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the LC-CDR1 , LC- CDR2 and LC-CDR3 sequences of Column B are selected from the same row of Table A; and LC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 are substituted with another amino acid), LC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR2 are substituted with another amino acid), LC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR3 are substituted with another amino acid) and LC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid) as indicated in Column B of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the LC-FR1 , LC-FR2, LC-FR3 and LC-FR4 sequences of Column B are selected from the same row of Table B.

[0268] In some embodiments, the antigen-binding moiety comprises:

[0269] a VL region comprising:

[0270] LC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 are substituted with another amino acid), LC-CDR2 (or a variant thereof in which 1 or 2 or 3 aminoacids in LC-CDR2 are substituted with another amino acid) and LC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid) as indicated in Column B of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A; and

[0271] LC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 are substituted with another amino acid), LC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR2 are substituted with another amino acid), LC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR3 are substituted with another amino acid) and LC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid) as indicated in Column B of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B;

[0272] wherein the LC-CDR1, LC-CDR2, LC-CDR3 sequences of Column B of Table A and the LC-FR1, LC-FR2, LC-FR3 and LC-FR4 sequences of Column B of Table B are selected from rows having the same number.

[0273] In some embodiments, the antigen-binding moiety comprises a VL region comprising at least 70%, preferably one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of a VL region sequence selected from Column B of row 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, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table C.

[0274] In some embodiments, the antigen-binding moiety comprises the CDRs, FRs and / or the VH and / or VL regions of an antibody described in WO2024 / 121233 A1, which is hereby incorporated by reference in its entirety (e.g. an antibody of Table C in WO2024 / 121233 A1), or CDRs, FRs and / or VH and / or VL regions which are derived from those of an antibody described in WO2024 / 121233 A1 (e.g. an antibody of Table C in WO2024 / 121233 A1). In some embodiments, the antigen-binding moiety comprises the CDRs, FRs and / or the VH and / or VL regions of a gp130-binding antibody described in WO2024 / 121233 A1 , or CDRs, FRs and / or VH and / or VL regions which are derived from those of a gp130-binding antibody described in WO2024 / 121233 A1. In some embodiments, a gp130-binding antibody is selected from an antibody of Table C in WO2024 / 121233 A1.

[0275] In some embodiments, the antigen-binding moiety comprises a VH region according to any one of (1) to (115) as described on pages 18 to 29 in WO2024 / 121233 A1. In some embodiments, the antigen-binding moiety / molecule comprises a VL region according to any one of (116) to (229) as described on pages 29 to 41 in WO2024 / 121233 A1. In some embodiments, the antigen-binding moiety / molecule comprises aVH region according to any one of (1) to (115) and a VL region according to any one of (116) to (229) as described on pages 18 to 41 in WO2024 / 121233 A1.

[0276] In some embodiments, the antigen-binding moiety comprises a VH region according to any one embodiment as described herein, and a VL region according to any one embodiment as described herein.

[0277] In embodiments in accordance with the present disclosure, one or more amino acids are substituted with another amino acid. A substitution comprises substitution of an amino acid residue with a non-identical 'replacement' amino acid residue. A replacement amino acid residue of a substitution according to the present disclosure may be a naturally-occurring amino acid residue ( / .e. encoded by the genetic code) which is non-identical to the amino acid residue at the relevant position of the equivalent, unsubstituted amino acid sequence, selected from: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie): leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Vai). In some embodiments, a replacement amino acid may be a non-naturally occurring amino acid residue - i.e. an amino acid residue other than those recited in the preceding sentence. Examples of non-naturally occurring amino acid residues include norleucine, ornithine, norvaline, homoserine, aib, and other amino acid residue analogues such as those described in Ellman, et al., Meth. Enzym. 202 (1991) 301-336.

[0278] 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:

[0279]

[0280] 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.

[0281] 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:

[0282]

[0283] 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.

[0284] In some embodiments, substitution(s) may be functionally conservative. That is, in some embodiments, the substitution may not affect (or may not substantially affect) one or more functional properties (e.g. target binding) of the antigen-binding molecule comprising the substitution as compared to the equivalent unsubstituted molecule.

[0285] In some embodiments, substitution(s) may reduce polyreactivity of the antigen-binding molecule.

[0286] As used herein, ‘polyreactivity’ refers to low-affinity interactions via general nonspecific chemistry to molecules other than the target antigen of the antigen-binding molecule. Polyreactivity of an antigen-binding molecule may also be referred to as ‘stickiness’ of an antigen-binding molecule. High polyreactivity / stickiness of an antigen-binding molecule may result in unacceptably poor PK, potency, bioavailability and / or immunogenicity.

[0287] In some embodiments, one or more amino acids are substituted with another amino acid to reduce / prevent polyreactivity of the antigen-binding molecule.

[0288] Polyreactivity in therapeutic antibodies is reviewed e.g. in Cunningham et al., MAbs, 2021,

[0289] 13(1):1999195, which is hereby incorporated by reference in its entirety. The polyreactivity of an antigenbinding molecule may be assessed e.g. by ELISA assays using a range of structurally diverse coating antigens (e.g. E.coli LPS, cardiolipin, insulin, dsDNA, ssDNA, KLH) or by in silica methods (e.g. as reviewed in Harvey et al., Nature Communications, 2022, 13:7554, which is hereby incorporated by reference in its entirety).

[0290] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:4, comprising substitution of I at position 8 of SEQ ID NO:4 with another amino acid.

[0291] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:1 , 94, 98, 174, 112 or 117, wherein the VH region comprises substitution of I at position 100 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 104 of SEQ ID NO:1) with another amino acid.

[0292] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:64, 65, 130, 132, 176, 134, 136, 131, 133, 177, 135 or 137, wherein the VH region comprises substitution of I at position 100 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 104 of SEQ ID NO:64) with another amino acid.

[0293] In some embodiments in accordance with the preceding three paragraphs, I is substituted with T, S, E, Q, K, H, G, V, Y, A, C, L, F, P, D, N, M, W or R. In some embodiments, I is substituted with T, S, E, Q, K or H. In some embodiments, I is substituted with T or K. In some embodiments, I is substituted with T.

[0294] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:4, comprising substitution of V at position 7 of SEQ ID NO:4 with another amino acid.

[0295] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:1 , 94, 98, 174, 112 or 117, wherein the VH region comprises substitution ofV at position 99 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest,5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 103 of SEQ ID NO:1) with another amino acid.

[0296] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:64, 65, 130, 132, 176, 134, 136, 131, 133, 177, 135 or 137, wherein the VH region comprises substitution ofV at position 99 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 103 of SEQ ID NO:64) with another amino acid.

[0297] In some embodiments in accordance with the preceding three paragraphs, V is substituted with G, S, T, E, Q, K, H, I, C, Y, A, L, F, P, D, N, M, W or R. In some embodiments, V is substituted with G or S.

[0298] In some embodiments, substitution(s) may prevent / reduce degradation of the antigen-binding molecule. Degradation of an antigen-binding molecule may occur during manufacturing, processing, storage, handling and / or administration. The degradation may be physical and / or chemical. Degradation processes, e.g. chemical degradation processes, include isomerisation, oxidation, fragmentation, deamination, hydrolysis, deglycosylation, racemization, disulphide bond breakage and formation, Maillard reaction, and p-elimination.

[0299] Oxidation is a common chemical modifications in monoclonal antibodies and may be induced by reactive oxygen species. Oxidation may occur at cysteine, methionine, tryptophan, tyrosine, lysine and other amino acid residues. Oxidation of amino acid residues may impact protein structure and / or function. In some embodiments, one or more amino acids are substituted with another amino acid to remove an oxidation site. In some embodiments, one or more amino acids susceptible to oxidation are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptible to oxidation). In some embodiments, one or more amino acids identified as being oxidised, or identified as being susceptible to oxidation, are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptible to oxidation).

[0300] Amino acid residues susceptible to oxidation may be identified e.g. by in silico methods (e.g. as reviewed in Vatsa S, Mabs, 2022, 14(1):2023938, which is hereby incorporated by reference in its entirety) or by forced oxidation assays (e.g. as reviewed in Nowak C et al, Mabs, 2017, 9(8):1217-1230, and DyckYFK et al, Bioengineering (Basel), 2019, 6(3):62, which are hereby incorporated by reference in their entirety). Aspartic acid (Asp) isomerization is a spontaneous non-enzymatic post-translation modification causing a change in the structure of the protein backbone, which is commonly observed in therapeutic antibodies during manufacturing and storage. The Asps in Asp-Gly (DG), Asp-Ser (DS), and Asp-Thr (DT) motifs in the structurally flexible regions, such as complementarity-determining regions (CDRs) in antibodies, are often found to have high rate of isomerization. In some embodiments, one or more amino acids susceptible to isomerisation are substituted with another amino acid (e.g. an amino acid which is not susceptible to isomerisation or is less susceptible to isomerisation). In some embodiments, one or moreamino acids present in an amino acid motif susceptible to isomerisation (e.g. Asp-Gly (DG), Asp-Ser (DS), or Asp-Thr (DT)), are substituted with another amino acid (e.g. an amino acid which reduces the susceptibility of an amino acid in the motif to isomerisation).

[0301] The susceptibility of an antigen-binding molecule to isomerisation may be assessed in in vitro assays e.g. as described in Lu et al., MAbs, 2019, 11 (1):45-57, which is hereby incorporated by reference in it’s entirety.

[0302] In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:11 , comprising substitution of D at position 1 of SEQ ID NO:11 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:192, comprising substitution of D at position 1 of SEQ ID NO:192 with another amino acid.

[0303] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121, 126, 9, 102, 106, 109, 186, 187, 188, 189, 190, or 191 wherein the VL region comprises substitution of D at position 50 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 50 of SEQ ID NO:9) with another amino acid.

[0304] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 245, 246, 247, 248, 249 or 250, wherein the polypeptide comprises substitution of D at position 50 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 50 of SEQ ID NO:66) with another amino acid.

[0305] In some embodiments in accordance with the preceding three paragraphs, D is substituted with A, E, N, C, G, I, L, M, F, P, S, T, W, Y, V, R, K, H or Q. In some embodiments, D is substituted with A, E, N, C, G, I, L, M, F, P, S, T, W, Y or V. In some embodiments, D is substituted with A or E. In some embodiments, D is substituted with A.

[0306] In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:11 , comprising substitution of G at position 2 of SEQ ID NO:11 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:149, comprising substitution of G at position 2 of SEQ ID NO:149 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:162, comprising substitution of G at position 2 of SEQ ID NO:162 with another amino acid.In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121, 126, 9, 102, 106, 109, 143, 144, 145, 146, 147, 148, 156, 157, 158, 159, 160 or 161, wherein the VL region comprises substitution of G at position 51 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 51 of SEQ ID NO:9) with another amino acid.

[0307] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 150, 151, 152, 153, 154, 155, 163, 164, 165, 166, 167 or 168, wherein the polypeptide comprises substitution of G at position 51 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 51 of SEQ ID NO:66) with another amino acid.

[0308] In some embodiments in accordance with the preceding three paragraphs, G is substituted with A, E, N, C, I, D, L, M, F, P, S, T, W, Y, V, R, K, H or Q. In some embodiments, G is substituted with A.

[0309] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 according to SEQ ID NO:15, comprising substitution of L at position 2 of SEQ ID NO:15 with another amino acid.

[0310] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121, 126, 9, 102, 106, 109, 143, 144, 145, 146, 147, 148, 156, 157, 158, 159, 160 or 161, wherein the VL region comprises substitution of L at position 54 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 54 of SEQ ID NO:9) with another amino acid.

[0311] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 150, 151, 152, 153, 154, 155, 163, 164, 165, 166, 167 or 168, wherein the polypeptide comprises substitution of L at position 54 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 54 of SEQ ID NO:66) with another amino acid.

[0312] In some embodiments in accordance with the preceding three paragraphs, L is substituted with S, A, E, N, C, I, D, G, M, F, P, T, W, Y, V, R, K, H or Q. In some embodiments, L is substituted with S.In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 according to SEQ ID NO:108, comprising substitution of V at position 6 of SEQ ID NO:108 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 according to SEQ ID NO:111, comprising substitution ofV at position 6 of SEQ ID NO:111 with another amino acid.

[0313] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 106, 109, 145, 146, 147, 148, 158, 159, 160 or 161 , wherein the VL region comprises substitution of V at position 58 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 58 of SEQ ID NO:106) with another amino acid.

[0314] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 139, 140, 152, 153, 154, 155, 165, 166, 167 or 168, wherein the polypeptide comprises substitution of V at position 58 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 58 of SEQ ID NO:139) with another amino acid.

[0315] In some embodiments in accordance with the preceding three paragraphs, V is substituted with G, A, E, N, C, I, D, L, M, F, P, S, T, W, Y, R, K, H or Q. In some embodiments, V is substituted with G.

[0316] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or greater amino acid sequence identity to SEQ ID NO:124, 129, 15, 104, 108 or 111, wherein the amino acid at the position corresponding to position 30 of SEQ ID NO:15 is D.

[0317] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121, 126, 9, 102, 106, 109, 147, 148, 143, 144, 145, 146, 160, 161, 156, 157, 158 or 159 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, or 109; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:147, 148, 143, 144, 145 or 146; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NQ:160, 161 , 156, 157, 158 or 159), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 82 of SEQ ID NO:9) is D.In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 154, 155, 150, 151, 152, 153, 167, 168, 163, 164, 165 or 166 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139 or 140; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:154, 155, 150, 151 , 152 or 153; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:167, 168, 163, 164, 165 or 166), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 82 of SEQ ID NO:66) is D.

[0318] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 having at least 60%, preferably one of 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or greater amino acid sequence identity to SEQ ID NO:124, 129, 15, 104, 108 or 111, wherein the amino acid at the position corresponding to position 30 of SEQ ID NO:15 is D, and wherein the amino acid sequence comprises one or more (e.g. one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) amino acid substitutions relative to the reference amino acid sequence ( / .e. the amino acid sequence selected from SEQ ID NO:124, 129, 15, 104, 108 and 111), wherein the one or more amino acid substitutions are provided at the position(s) corresponding to the following positions of the reference sequence: 22, 23, 24, 25, 26, 27, 28, 29, 31 , 32, 33, 34, 35, 36 (that is, the one or more amino acid substitutions are provided within the 8 positions immediately N-terminal to (in the context of the amino acid sequence of the LC-FR3) position 30, and / or are provided within the 6 positions immediately C-terminal to position 30).

[0319] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121, 126, 9, 102, 106, 109, 147, 148, 143, 144, 145, 146, 160, 161, 156, 157, 158 or 159 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, or 109; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:147, 148, 143, 144, 145 or 146; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NQ:160, 161 , 156, 157, 158 or 159), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 82 of SEQ ID NO:9) is D, and wherein the amino acid sequence comprises one or more (e.g. one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16) amino acid substitutions relative to the reference amino acid sequence, wherein the one or more amino acid substitutions are provided at the position(s) corresponding to the following positions of the reference sequence: 74, 75, 76, 77, 78, 79, 80, 81 , 83, 84, 85, 86, 87, 88, 89, 90 (that is, the one or more aminoacid substitutions are provided within the 8 positions immediately N-terminal to (in the context of the amino acid sequence of the VL region) position 82, and / or are provided within the 8 positions immediately C-terminal to position 82).

[0320] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 154, 155, 150, 151, 152, 153, 167, 168, 163, 164, 165 or 166 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139 or 140; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:154, 155, 150, 151 , 152 or 153; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:167, 168, 163, 164, 165 or 166), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 82 of SEQ ID NO:66) is D, and wherein the amino acid sequence comprises one or more (e.g. one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) amino acid substitutions relative to the reference amino acid sequence, wherein the one or more amino acid substitutions are provided at the position(s) corresponding to the following positions of the reference sequence: 74, 75, 76, 77, 78, 79, 80, 81 , 83, 84, 85, 86, 87, 88, 89, 90 (that is, the one or more amino acid substitutions are provided within the 8 positions immediately N-terminal to (in the context of the amino acid sequence of the polypeptide) position 82, and / or are provided within the 8 positions immediately C-terminal to position 82).

[0321] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:20, comprising substitution of D at position 6 of SEQ ID NQ:20 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:195, comprising substitution of D at position 6 of SEQ ID NO:195 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:204, comprising substitution of D at position 6 of SEQ ID NQ:204 with another amino acid.

[0322] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:17, 193, 194, 202 or 203, wherein the polypeptide comprises substitution of D at position 98 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 101 of SEQ ID NO:17) with another amino acid.

[0323] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:67, 68, 251 , 252, 253, or 254, wherein the VH region comprisessubstitution of D at position 98 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991, which corresponds to position 101 of SEQ ID NO:67) with another amino acid.

[0324] In some embodiments in accordance with the preceding three paragraphs, D is substituted with G, S, E, A, N, C, I, L, M, F, P, T, W, Y, V, R, K, H or Q. In some embodiments, D is substituted with G, S, E, or A. In some embodiments, D is substituted with G or S. In some embodiments, D is substituted with G.

[0325] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:20, comprising substitution of G at position 7 of SEQ ID NQ:20 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:195, comprising substitution of G at position 7 of SEQ ID NO:195 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:204, comprising substitution of G at position 7 of SEQ ID NQ:204 with another amino acid.

[0326] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:17, 193, 194, 202, 203, 211, 212, 213, 216 or 217 wherein the polypeptide comprises substitution of G at position 99 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 102 of SEQ ID NO:17) with another amino acid.

[0327] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:67, 68, 251 , 252, 253, 254, 255, 256, 257, 258 or 259, wherein the VH region comprises substitution of G at position 99 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 102 of SEQ ID NO:67) with another amino acid.

[0328] In some embodiments in accordance with the preceding three paragraphs, G is substituted with A, Y, D, S, E, N, C, I, L, M, F, P, T, W, V, R, K, H or Q. In some embodiments, G is substituted with A or Y.

[0329] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column B of Table D, wherein the sequences of columns A and B are selected from the same row of Table D.In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column A of Table D of WO 2024 / 121233 A1, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column B of Table D of WO 2024 / 121233 A1, wherein the sequences of columns A and B are selected from the same row of Table D of WO 2024 / 121233 A1.

[0330] Angiogenic factors

[0331] Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. It is a vital process in growth and would healing. Dysregulation of angiogenesis has been linked to several diseases and conditions, including tumour malignancy, inflammation, and fibrosis. Upregulation of angiogenesis is a common feature in diseases of the eye, and especially in neovascular diseases of the retina, many of which result in fibrosis.

[0332] Numerous inducers of angiogenesis have been identified, including the members of the vascular endothelial growth factor (VEGF) family, angiopoietins, transforming growth factors (TGF), members of the platelet-derived growth factor family, tumour necrosis factor-a, interleukins and the members of the fibroblast growth factor (FGF) family. The cellular and molecular mechanisms of angiogenesis are described in Adams & Alitalo, Nature Reviews Molecular Cell Biology volume 8, pages 464-478 (2007), and Otrock et al, Understanding the biology of angiogenesis: Review of the most important molecular mechanisms, Blood Cells, Molecules, and Diseases, Volume 39, Issue 2, 2007, Pages 212-220, which are herein incorporated by reference in their entirety.

[0333] As used herein, an ‘angiogenic factor’ refers to any factor (e.g. peptide / polypeptide, glycoprotein, lipoprotein, glycan, glycolipid, lipid, nucleic acid or fragment thereof) capable of inducing / potentiating / promoting angiogenesis.

[0334] Factors capable of inducing / potentiating / promoting angiogenesis can be identified e.g. by analysis in an in vitro or in vivo assay of angiogenesis. Suitable assays for analysis of angiogenesis include endothelial cell migration assays, endothelial cell proliferation assays, and endothelial tube formation assays.

[0335] Angiogenesis assays are described in detail in Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010, Chapter 2, Angiogenesis Assays, which is herein incorporated by reference in its entirety.

[0336] In some embodiments, an angiogenic factor is a polypeptide or a polypeptide complex capable of inducing / promoting angiogenesis. An angiogenic factor may be soluble or membrane-bound, and may be a polypeptide or polypeptide complex ligand, or a polypeptide or polypeptide complex receptor for such a ligand. An angiogenic factor may be from any species, and includes isoforms, fragments, variants or homologues of an angiogenic factor from any species. In preferred embodiments the species is human(Homo sapiens). Isoforms, fragments, variants or homologues of an angiogenic factor may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of immature or mature angiogenic factor from a given species, e.g. human. Isoforms, fragments, variants or homologues of an angiogenic factor may optionally be characterised by ability to bind to an interaction partner for the angiogenic factor (e.g. a receptor for the angiogenic factor, or a ligand for the angiogenic factor) and / or ability to induce / promote angiogenesis. For example, an angiogenic factor may be a VEGF, a VEGF receptor, an FGF, an FGF receptor, a PDGF, or a PDGF receptor, or a fragment, variant, isoform or homologue of a VEGF, a VEGF receptor, an FGF, an FGF receptor, a PDGF, or a PDGF receptor.

[0337] A fragment of a polypeptide of an angiogenic factor may be of any length (by number of amino acids), although may optionally be at least 25% of the length of mature angiogenic factor and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the mature angiogenic factor. An angiogenic factor may be a complex comprising one or more subunits, such as a hetero or homodimer.

[0338] As used herein, an ‘interaction partner for an angiogenic factor’ refers to any factor (e.g. polypeptide or polypeptide complex) capable of interacting with (e.g. binding to) an angiogenic factor. The interaction may be non-covalent association.

[0339] An angiogenic factor and an interaction partner for the angiogenic factor preferably associate to form a biologically-functional complex, e.g. a receptor:ligand complex capable of initiating / promoting signalling (e.g. proangiogenic signalling). An interaction partner for an angiogenic factor may e.g. be a receptor for the angiogenic factor, or a ligand for the angiogenic factor. In some embodiments, interaction between an interaction partner for an angiogenic factor and the angiogenic factor induces / promotes proangiogenic signalling and / or angiogenesis. For example, binding of VEGF to a VEGF receptor is capable of triggering intracellular signalling by cells expressing the VEGF receptor, inducing / promoting angiogenic processes.

[0340] For example, an interaction partner for an angiogenic factor may be an angiogenic factor receptor. In some embodiments an angiogenic factor receptor may be a polypeptide or polypeptide complex capable of binding a VEGF, an FGF, a PDGF, or a fragment, variant, isoform or homologue of a VEGF, an FGF, or a PDGF. Angiogenic factor receptors include e.g. VEGF receptors, FGF receptors, and PDGF receptors. It will be appreciated that angiogenic factor receptors are angiogenic factors according to the present disclosure. For example, VEGFR is both an angiogenic factor (i.e. a factor capable of inducing / potentiating / promoting angiogenesis) and an angiogenic factor receptor (i.e. a receptor for VEGF).

[0341] Similarly, an interaction partner for an angiogenic factor may be a ligand for an angiogenic factor receptor. In some embodiments a ligand for an angiogenic factor receptor may be a polypeptide or polypeptide complex capable of binding a VEGF receptor, an FGF receptor, a PDGF receptor, or a fragment, variant, isoform or homologue of a VEGF receptor, an FGF receptor, or a PDGF receptor.Angiogenic factor ligands include e.g. VEGF, FGF, and PDGF. It will be appreciated that angiogenic factor ligands are angiogenic factors according to the present disclosure. For example, VEGF is both an angiogenic factor ( / .e. a factor capable of inducing / potentiating / promoting angiogenesis) and a ligand for an angiogenic factor receptor ( / .e. a ligand for VEGF receptor).

[0342] In some embodiments herein, the angiogenic factor is a VEGF. VEGF is a growth factor, encoded by a gene family that includes placental growth factor (PIGF, AAD30179.1 Gl: 4809334), VEGF-A (AAP86646.1 Gl: 32699990), VEGF-B (AAC50721.1 Gl: 1488259), VEGF-C (CAA63907.1 Gl: 1182005), VEGF-D (BAA24264.1 Gl: 2766190), and the orf virus encoded VEGF-E (ABA00650.1 Gl: 74230845). In some embodiments, the VEGF is VEGF-A. Differences in exon splicing result in the generation of four main VEGF-A isoforms: VEGF121 , VEGF165, VEGF189, and VEGF206, which have 121, 165, 189, and 206 amino acids after cleavage of the signal sequence, respectively (Alitalo et al. Nature. (2005) 438:946-953). VEGF165 appears to be the dominant isoform.

[0343] VEGF stimulates the growth of vascular endothelial cells derived from arteries, veins, and the lymphatic system, as well as inducing angiogenesis in a variety of in vivo models ( / .e. the formation of thin-walled endothelium-lined structures), inducing rapid elevations in microvascular permeability (Lee et al. J Cell Biol. (2005)169:681-691; Leung etal. Science. (1989) 246:1306-1309; Alon etal. Nat Med. (1995) 1:1024-1028).

[0344] In this specification, ‘VEGF’ refers to a VEGF (e.g. VEGF-A, B, C, D or E) from any species and includes isoforms, fragments, variants or homologues of a VEGF from any species. In preferred embodiments the species is human (Homo sapiens). A fragment of VEGF may be of any length (by number of amino acids), although may optionally be at least 25% of the length of mature VEGF and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of mature VEGF. A fragment of VEGF may have a minimum length of 10 amino acids, and a maximum length of one of 15, 20, 25, 30, 40, 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220 or 225 amino acids.

[0345] VEGF exerts its biological effects through binding to three receptors - VEGFR1 (AAH39007.1 Gl:

[0346] 24660372), VEGFR2 (P35968.2 Gl: 9087218) and VEGFR3 (AAA85215.1 Gl: 1150991). Each receptor has extracellular binding domains for VEGF, a transmembrane sequence and intracellular tyrosine kinase moieties. VEGF binding to the extracellular receptor domain dimerizes the receptors and results in phosphorylation of the intracellular tyrosine kinase moieties.

[0347] In this specification, ‘a receptor for VEGF’ or ‘a VEGF receptor’ refers to a polypeptide or polypeptide complex capable of binding VEGF. In some embodiments a VEGF receptor is capable of binding VEGF and inducing signal transduction in cells expressing the receptor. In some embodiments, ‘a receptor for VEGF’ refers to a VEGFR. In this specification, unless otherwise stated, ‘VEGFR’ refers to VEGFR1 , VEGFR2 and / or VEGFR3. In some embodiments herein, the angiogenic factor is VEGFR. In some embodiments herein, the angiogenic factor is VEGFR2.VEGFR may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of VEGFR from a given species, e.g. human. Isoforms, fragments, variants or homologues of VEGFR may optionally be characterised by ability to bind VEGF (preferably from the same species) and stimulate signal transduction in cells expressing the VEGFR. A fragment of an VEGF receptor may be of any length (by number of amino acids), although may optionally be at least 25% of the length of the mature VEGFR and have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the mature VEGFR. A fragment of an VEGF receptor fragment may have a minimum length of 10 amino acids, and a maximum length of one of 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550, 1560, 1570, 1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1660, 1670, 1680, 1690, 1700, 1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790, or 1795 amino acids.

[0348] In some embodiments, the angiogenic factor is an FGF. Acidic and basic fibroblast growth factors, aFGF and bFGF respectively, are heparin-binding protein mitogens that are thought to play an important role in angiogenesis. There are 22 distinct FGFs and four different tyrosine kinase receptors (FGFRs). FGF and its receptors are reviewed in Presta et al. Cytokine Growth Factor Rev. (2005), 16:159-178, which is herein incorporated by reference in its entirety.

[0349] As used herein, ‘FGF’ refers to an aFGF or bFGF from any species and includes isoforms, fragments, variants or homologues thereof. For example and FGF may be: FGF1 (AAH32697.1 Gl: 21595687), FGF2 (P09038.3 GI: 261260095), FGF3 (P11487.1 Gl: 122748), FGF4 (NP_001998.1 Gl: 4503701), FGF5 (P12034.4 Gl: 85700417), FGF6 (P10767.4 Gl: 1169676), FGF7 (P21781.1 Gl: 122756), FGF8 (NP_001193318.1 Gl: 329755303), FGF9 (NP_002001.1 Gl: 4503707), FGF10 (CAG46466.1 Gl:

[0350] 49456291), FGF11 (Q92914.1 Gl: 2494457), FGF12 (P61328.1 Gl: 47117683), FGF13 (Q92913.1 Gl: 2494461), FGF14 (NP_001308867.1 Gl: 1013165743), FGF15 (AAO13811.1 Gl: 27448228), FGF16 (NP_003859.1 Gl: 4503691), FGF17 (AAQ89228.1 Gl: 37182856), FGF18 (AAQ89954.1 Gl: 37222209), FGF19 (NP_005108.1 Gl: 4826726), FGF20 (AAH98339.1 Gl: 68226699), FGF21 (AAQ89444.1 Gl: 37183289), or FGF22 (Q9HCT0.1 Gl: 13626689), or isoforms, fragments, variants or homologues thereof. An ‘FGF receptor’ refers to a polypeptide or polypeptide complex capable of binding an FGF, and isoforms, fragments, variants or homologues thereof. FGF receptors include FGFR1 (AAH15035.1 Gl: 21955340), FGFR2 (AAA61188.1 Gl: 3397110), FGFR3 (P22607.1 Gl: 120050), and FGFR4

[0351] (AAH11847.1 Gl: 15080148), and isoforms, fragments, variants or homologues thereof. In someembodiments, the FGF receptor is capable of binding FGF and inducing signal transduction in cells expressing the FGF receptor.

[0352] In some embodiments, the angiogenic factor is a PDGF. PDGF was initially purified from platelets and was then identified in fibroblasts, astrocytes, keratinocytes, epithelial cells and other cell types. PDGFs exist as heterodimers (PDGF-AB) or homodimers (PDGF-AA or-BB) composed of chains A (P04085.1 Gl: 129719) and B (CAG46606.1 Gl: 49456571). There are two forms of the PDGF-R, alpha (P16234.1 Gl: 129892) and beta (P09619.1 Gl: 129890) each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes. PDGF and its receptors are described in Ross etal, Cell. (1986) 46:155-169, which is herein incorporated by reference in its entirety.

[0353] As used herein, ‘PDGF’ refers to PDGF-A, PDGF-B, PDGF-AB, PDGF-AA, PDGF-BA, or PDGF-BB from any species and includes isoforms, fragments, variants or homologues thereof. A ‘PDGF receptor’ refers to a polypeptide or polypeptide complex capable of binding a PDGF, or isoforms, fragments, variants or homologues thereof. In some embodiments, the PDGF receptor is PDGF-R alpha, PDGF-R beta, PDGF-R alpha-alpha homodimer, PDGF-R beta-beta homodimer, or the PDGF-R alpha-beta heterodimer. In some embodiments, the PDGF receptor is capable of binding PDGF and inducing signal transduction in cells expressing the PDGF receptor.

[0354] Other angiogenic factors include angiogenin (NP_001091046.1 Gl: 148277046), angiopoietin

[0355] (AAD19608.1 Gl: 4378598), integrins (e.g. selected from NP_001004439.1 Gl: 52485853, NP_002194.2 Gl: 116295258, NP_002195.1 Gl: 4504747, NP_000876.3 Gl: 67191027, NP_002196.4 Gl: 1017029567, NP_001303235.1 Gl: 937834186, NP_001138468.1 Gl: 222418613, NP_003629.2 Gl: 612407851, NP_002198.2 Gl: 52485941 , NP_001273304.1 Gl: 556503454, NP_001004439.1 Gl: 52485853, NP_001305114.1 Gl: 970949440, NP_001273304.1 Gl: 556503454, NP_002200.2 Gl: 167466215, NP_001139280.1 Gl: 224831239, NP_002201.1 Gl: 4504763, EAW51597.1 Gl: 119571982, NP_001273304.1 Gl: 556503454, NP_391988.1 Gl: 19743819, NP_001120963.2 Gl: 735367803, NP_000203.2 Gl: 47078292, NP_000204.3 Gl: 54607035, NP_001341694.1 Gl: 1269208512, NP_001269282.1 Gl: 538916664, NP_000880.1 Gl: 4504777, NP_002205.1 Gl: 4504779), TGF-p (AAA36738.1 Gl: 339564) and TNFa (AQY77150.1 Gl: 1159611449).

[0356] Antagonists of angiogenic factors

[0357] Aspects of the present invention involve antagonism ( / .e. inhibition) of angiogenesis, e.g. by antagonism of one or more angiogenic factors.

[0358] Herein, ‘inhibition’ refers to a reduction, decrease or lessening relative to a control condition. For example, inhibition of angiogenic signalling by an antagonist of an angiogenic factor refers to a reduction, decrease or lessening of the level / extent / degree of angiogenic signalling in the presence of the moiety / agent, as compared to the level / extent / degree of angiogenic signalling in the absence of the moiety / agent or in the presence of an appropriate control moiety / agent.Inhibition may herein also be referred to as neutralisation or antagonism. An antagonist of an angiogenic factor (e.g. an antagonist of an activity mediated by an angiogenic factor, or an antagonist of angiogenic signalling) may be said to be a ‘neutralising’ or ‘antagonist’ agent with respect to the relevant function or process. For example, an agent which is capable of inhibiting an angiogenic factor may be referred to as an agent which is capable of neutralising an angiogenic factor or may be referred to as an antagonist of an angiogenic factor. Additionally, an agent which is capable of inhibiting angiogenic signalling may be referred to as an agent which is capable of neutralising angiogenic signalling or may be referred to as an antagonist of angiogenic signalling.

[0359] Angiogenic signalling pathways offer multiple routes for inhibition of signalling. An antagonist of angiogenic signalling may inhibit the action of an angiogenic factor through inhibiting the action of one or more factors involved in, or necessary for, signalling through a receptor for that factor.

[0360] For example, inhibition may be achieved by disrupting interaction between an angiogenic factor (e.g. VEGF) and a receptor for that factor (e.g. VEGFR1 , 2 or 3).

[0361] In some embodiments, an antagonist of an angiogenic factor may bind to an angiogenic factor. In some embodiments, an antagonist of an angiogenic factor may bind to an interaction partner for an angiogenic factor. In some embodiments, an antagonist of an angiogenic factor may bind to a receptor for an angiogenic factor (e.g. VEGFR1 , VEGFR2 or VEGFR3 for VEGF). Binding of such agents may inhibit angiogenic factor-mediated signalling by reducing / preventing the ability of an angiogenic factor ligand to bind to receptors, thereby inhibiting downstream signalling.

[0362] Moieties capable of binding to an angiogenic factor or an interaction partner for an angiogenic factor may be of any kind, but in some embodiments the moiety may be an antigen-binding moiety e.g. an antibody or an antigen-binding fragment thereof, a polypeptide, a peptide, a nucleic acid, an oligonucleotide, an aptamer or a small molecule.

[0363] In some embodiments, an antagonist of an angiogenic factor is an antigen-binding moiety (e.g. an antibody, or an antigen-binding fragment thereof). In some embodiments, an antagonist of an angiogenic factor is a polypeptide, e.g. a decoy binding partner molecule e.g. a decoy receptor. In some embodiments, an antagonist of an angiogenic factor may be an aptamer.

[0364] Moieties / agents capable of binding to an angiogenic factor or a complex comprising the angiogenic factor or an interaction partner for an angiogenic factor according to the present invention may exhibit one or more of the following properties:Specific binding to an angiogenic factor or a complex comprising the angiogenic factor or an interaction partner for the angiogenic factor;

[0365] Binding to an angiogenic factor or a complex comprising the angiogenic factor or an interaction partner for the angiogenic factor, with a KD of 10pM or less, preferably one of < 5pM < 1pM, < 100nM, <10nM, <1nM or<100pM;

[0366] Inhibition of interaction between an angiogenic factor and an interaction partner for the angiogenic factor;

[0367] Reduction or inhibition of angiogenesis and / or

[0368] Reduction or inhibition of choroidal neovascularization (e.g. reduction in size of CNV lesions and / or reduction in CNV leakage area).

[0369] These properties can be determined by analysis of the relevant moiety / agent in a suitable assay, which may involve comparison of the performance of the moiety to suitable control agents. The skilled person is able to identify appropriate control conditions for a given assay. As explained herein, an interaction partner for an angiogenic factor may e.g. be a ligand for an angiogenic factor (e.g. where the angiogenic factor is a receptor, e.g. a VEGF receptor, an FGF receptor or a PDGF receptor), or may be a receptor for an angiogenic factor (e.g. where the angiogenic factor is a ligand, e.g. a VEGF, an FGF or a PDGF).

[0370] For example, a suitable negative control for the analysis of the ability of a test antibody / antigen-binding fragment to bind to an angiogenic factor / a complex comprising the angiogenic factor / an interaction partner for the angiogenic factor may be an antibody / antigen-binding fragment directed against a nontarget protein ( / .e. which is not specific for an angiogenic factor / a complex comprising the angiogenic factor / interaction partner for the angiogenic factor). A suitable positive control may be a known, validated (e.g. commercially available) angiogenic factor- or angiogenic factor interaction partner-binding antibody. Controls may be of the same isotype as the putative an angiogenic factor / a complex comprising the angiogenic factor / interaction partner-binding antibody / antigen-binding fragment being analysed, and may e.g. have the same constant regions.

[0371] In some embodiments, the antagonist of an angiogenic factor may be capable of binding specifically to an angiogenic factor or a complex comprising the angiogenic factor, or an interaction partner for the angiogenic factor. A moiety / agent which specifically binds to a given target molecule preferably binds the target with greater affinity, and / or with greater duration than it binds to other, non-target molecules.

[0372] In some embodiments, the extent of binding of a binding moiety / agent to a non-target is less than about 10% of the binding of the agent to the target as measured, e.g., by ELISA, SPR, Bio-Layer Interferometry (BLI), MicroScale Thermophoresis (MST), or by a radioimmunoassay (RIA). Alternatively, the binding specificity may be reflected in terms of binding affinity, where the binding moiety / agent binds to an angiogenic factor, a complex comprising the angiogenic factor or an interaction partner for an angiogenic factor with a KD that is at least 0.1 order of magnitude ( / .e. 0.1 x 10n, where n is an integer representing the order of magnitude) greater than the KD towards another, non-target molecule. This may optionally be one of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0.Binding affinity for a given binding moiety / agent for its target is often described in terms of its dissociation constant (KD). Binding affinity can be measured by methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty etal., Methods Mol Biol (2012) 907:411-442; or Rich et al., Anal Biochem. (2008) 1; 373(1):112-20), Bio-Layer Interferometry (see e.g. Lad etal., J Biomol Screen (2015) 20(4):498-507; or Concepcion etal., Comb Chem High Throughput Screen. (2009) 12(8):791 -800), MicroScale Thermophoresis (MST) analysis (see e.g. Jerabek-Willemsen et al., Assay Drug Dev Technol. (2011) 9(4):342-353), or by a radiolabelled antigen binding assay (RIA).

[0373] In some embodiments, the antagonist of an angiogenic factor binds to an angiogenic factor or a complex comprising the angiogenic factor, or an interaction partner for the angiogenic factor with a KD of 50 pM or less, preferably one of <10 pM, <5 pM, <4 pM, <3 pM, <2 pM, <1 pM, <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, or <100 pM.

[0374] In some embodiments, the antagonist of an angiogenic factor binds to an angiogenic factor, a complex comprising the angiogenic factor or an interaction partner for the angiogenic factor with an affinity of binding (e.g. as determined by ELISA) of EC50 = 10,000 ng / mL or less, preferably one of <5,000 ng / mL, <1000 ng / mL, <900 ng / mL, <800 ng / mL, <700 ng / mL, <600 ng / mL, <500 ng / mL, <400 ng / mL, <300 ng / mL, <200 ng / mL, <100 ng / mL, <90 ng / mL, <80 ng / mL, <70 ng / mL, <60 ng / mL, <50 ng / mL, <40 ng / mL, <30 ng / mL, <20 ng / mL, <15 ng / mL, <10 ng / mL, <7.5 ng / mL, <5 ng / mL, <2.5 ng / mL, or <1 ng / mL. Such ELISAs can be performed e.g. as described in Antibody Engineering, vol. 1 (2ndEdn), Springer Protocols, Springer (2010), PartV, pp657-665.

[0375] In some embodiments, the antagonist of an angiogenic factor binds to an angiogenic factor or a complex comprising the angiogenic factor in a region which is important for binding to an interaction partner for the angiogenic factor or a complex comprising the angiogenic factor, and thereby inhibits interaction between an angiogenic factor or a complex comprising the angiogenic factor and an interaction partner for the angiogenic factor (e.g. inhibiting signalling through an angiogenic factor receptor). In some embodiments, the moiety / agent binds to an interaction partner for the angiogenic factor in a region which is important for binding to the angiogenic factor or a complex comprising the angiogenic factor, and thereby inhibits interaction between an angiogenic factor or a complex comprising the angiogenic factor and an interaction partner for the angiogenic factor (e.g. inhibiting signalling through an angiogenic factor receptor).

[0376] The ability of a given binding moiety / agent (e.g. a moiety / agent capable of binding an angiogenic factor / a complex comprising the angiogenic factor or an interaction partner for the angiogenic factor) to inhibit interaction between two proteins can be determined for example by analysis of interaction in the presence of, or following incubation of, one or both of the interaction partners with the binding moiety / agent. An example of a suitable assay to determine whether a given binding moiety / agent is capable of inhibiting interaction between two interaction partners is a competition ELISA.A binding moiety / agent which is capable of inhibiting a given interaction (e.g. between an angiogenic factor and an interaction partner for the angiogenic factor, such as between VEGF and one or more of VEGFR1-3) is identified by the observation of a reduction / decrease in the level of interaction between the interaction partners in the presence of - or following incubation of one or both of the interaction partners with - the binding moiety / agent, as compared to the level of interaction in the absence of the binding moiety / agent (or in the presence of an appropriate control binding agent). Suitable analysis can be performed in vitro, e.g. using recombinant interaction partners or using cells expressing the interaction partners. Cells expressing interaction partners may do so endogenously, or may do so from nucleic acid introduced into the cell. For the purposes of such assays, one or both of the interaction partners and / or the binding moiety / agent may be labelled or used in conjunction with a detectable entity for the purposes of detecting and / or measuring the level of interaction. For example, the moiety / agent may be labelled with a radioactive atom or a coloured molecule or a fluorescent molecule or a molecule which can be readily detected in any other way. Suitable detectable molecules include fluorescent proteins, luciferase, enzyme substrates, and radiolabels. The binding moiety / agent may be directly labelled with a detectable label or it may be indirectly labelled. For example, the binding moiety / agent may be unlabelled, and detected by another binding moiety / agent which is itself labelled. Alternatively, the second binding moiety / agent may have bound to it biotin and binding of labelled streptavidin to the biotin may be used to indirectly label the first binding moiety / agent.

[0377] Ability of a binding moiety / agent to inhibit interaction between two binding partners can also be determined by analysis of the downstream functional consequences of such interaction, e.g. an angiogenic factor-mediated signalling.

[0378] In some embodiments, the binding moiety / agent may be capable of inhibiting interaction between an angiogenic factor and an interaction partner for the angiogenic factor to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of interaction between the angiogenic factor and the interaction partner for the angiogenic factor in the absence of the binding moiety / agent (or in the presence of an appropriate control binding agent). In some embodiments, the binding moiety / agent may be capable of inhibiting interaction between an angiogenic factor and an interaction partner for the angiogenic factor to less than 1 times, e.g. one of <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times the level of interaction between the angiogenic factor and the interaction partner for the angiogenic factor in the absence of the binding moiety / agent (or in the presence of an appropriate control binding moiety / agent).

[0379] In some embodiments, a moiety / agent capable of binding to an angiogenic factor or an interaction partner for the angiogenic factor is an antigen-binding moiety. In some embodiments, an antigen-binding moietycapable of binding to an angiogenic factor or an interaction partner for the angiogenic factor is an antibody or an antigen-binding fragment thereof.

[0380] Antigen-binding moieties that bind to angiogenic factors

[0381] In some embodiments, the antagonist of an angiogenic factor is an antigen-binding moiety that binds to an angiogenic factor ( / .e. an angiogenic factor-binding moiety) or an interaction partner of an angiogenic factor.

[0382] In some embodiments, the antagonist of an angiogenic factor is an antigen-binding moiety that binds to VEGF ( / .e. a VEGF-binding moiety), or an antigen-binding moiety that binds to a VEGF receptor ( / .e. a VEGF receptor-binding moiety). In some embodiments, an angiogenic factor-binding moiety is an antigen-binding moiety that binds to VEGF ( / .e. a VEGF-binding moiety), or an antigen-binding moiety that binds to a VEGF receptor ( / .e. a VEGF receptor-binding moiety).

[0383] Antigen-binding moieties according to the present disclosure may comprise the complementaritydetermining regions (CDRs) of an antibody which is capable of binding to the relevant target molecule ( / .e. an angiogenic factor / an interaction partner of an angiogenic factor).

[0384] Antibodies capable of binding to an angiogenic factor or an interaction partner of an angiogenic factor include e.g. anti-VEGF / anti-VEGF-interaction partner antibodies (including e.g. anti-VEGF-A humanized monoclonal antibody Ranibizumab (also known as Lucentis, #DB01270), anti-VEGFR2 fully human monoclonal antibody Ramucirumab (also known as Cyramza, #DB05578), anti-VEGF-A humanised monoclonal scFv Brolucizumab (also known as Beovu, #DB14864), anti-VEGF-A humanized monoclonal antibody Bevacizumab (also known as Avastin, drug bank accession No: #DB00112),); anti-PDGF / anti-PDGF-interaction partner antibodies (including e.g. anti-PDGF-F fully human monoclonal antibody CR002 (#DB05139), anti-PDGF Ra monoclonal antibody Olaratumab (also known as Lartruvo, #DB06043), anti-PDGF-CC monoclonal antibody clone 6B3, disclosed in Li etal. PLoS One (2018) 13(7):e0201089); anti-FGF / anti-FGF-interaction partner antibodies (including e.g. anti-FGFR3 human monoclonal antibody Vofatamab (also known as MFGR1877S, #DB14781), anti-FGFR2 antibody Bemarituzumab (#DB16105)); anti-angiopoietin antibodies (including e.g. anti-angiopoietin-2 antibody clones LC06 and LC08, disclosed in W02010069532A1 , and anti-angiopoietin 1 and 2 fully human monoclonal antibody AMG 780, disclosed in Bready et al. Cancer Res. (2014) 74(19): 1022)); anti-TGF / anti-TGF-interaction partner antibodies (including e.g. pan-TGFp binding monoclonal antibody clones XPA.42.089, XPA.42.068, and XPA.42.681 , disclosed in Bedinger et al. Mabs (2016) 8(2):389-404); anti-TNFa / interaction-partner for TNFa antibodies (including e.g. Infliximab (also known as Avsola, #DB00065), Adalimumab (also known as Humira, #DB00051), pegylated monoclonal antibody Certolizumab pegol (also known as Cimzia, #DB08904)).

[0385] The antibodies / fragments may be antagonist antibodies / fragments that inhibit or reduce a biological activity of an angiogenic factor. The antibodies / fragments may be neutralising antibodies that neutralisethe biological effect of an angiogenic factor, e.g. its ability to stimulate productive signalling via an angiogenic factor receptor.

[0386] In some embodiments, the antigen-binding moiety / molecule comprises the CDRs, FRs and / or the VH and / or VL regions of an antibody selected from Ranibizumab, Ramucirumab, Brolucizumab and Bevacizumab, or CDRs, FRs and / or VH and / or VL regions which are derived from those of an Ranibizumab, Ramucirumab, Brolucizumab and Bevacizumab. In some embodiments, the antibody is selected from Ranibizumab, Ramucirumab and Brolucizumab.

[0387] In some embodiments, the antigen-binding moiety / molecule comprises a VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:266, HC-CDR2 having the amino acid sequence of SEQ ID NO:267, HC-CDR3 having the amino acid sequence of SEQ ID NO:268, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid; and a VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NQ:270, LC-CDR2 having the amino acid sequence of SEQ ID NO:271, LC-CDR3 having the amino acid sequence of SEQ ID NO:272, or a variant thereof in which 1 or 2 or 3 amino acids in 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 moiety / molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:265 and a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:269.

[0388] In some embodiments, the antigen-binding moiety / molecule comprises a VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:274, HC-CDR2 having the amino acid sequence of SEQ ID NO:275, HC-CDR3 having the amino acid sequence of SEQ ID NO:276, 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; and a VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO:278, LC-CDR2 having the amino acid sequence of SEQ ID NO:192, LC-CDR3 having the amino acid sequence of SEQ ID NO:279, 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 moiety / molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:273 and a VL region comprising an amino acid sequence having at least 70% sequenceidentity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:277.

[0389] In some embodiments, the antigen-binding moiety / molecule comprises a VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:281 , HC-CDR2 having the amino acid sequence of SEQ ID NO:282, HC-CDR3 having the amino acid sequence of SEQ ID NO:283, 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; and a VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO:285, LC-CDR2 having the amino acid sequence of SEQ ID NO:286, LC-CDR3 having the amino acid sequence of SEQ ID NO:287, or a variant thereof in which 1 or 2 or 3 amino acids in 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 moiety / molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:280 and a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:284.

[0390] In some embodiments, the antigen-binding moiety / molecule comprises a VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:385, HC-CDR2 having the amino acid sequence of SEQ ID NO:267, HC-CDR3 having the amino acid sequence of SEQ ID NO:386, 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; and a VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NQ:270, LC-CDR2 having the amino acid sequence of SEQ ID NO:271, LC-CDR3 having the amino acid sequence of SEQ ID NO:272, or a variant thereof in which 1 or 2 or 3 amino acids in 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 moiety / molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:384 and a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:387.Decoy receptor

[0391] Peptide- or polypeptide-based moieties capable of binding to an angiogenic factor or a complex comprising the angiogenic factor may be based on an angiogenic factor receptor, e.g. an angiogenic factor-binding fragment of an angiogenic factor receptor.

[0392] In some embodiments, the moiety may comprise an angiogenic factor-binding fragment of the receptor extracellular domain, and may preferably be soluble and / or exclude one or more, or all, of the transmembrane domain(s). Such molecules may be described as decoy receptors. Decoy receptor technology is reviewed in, for example, Mantovani etal. Trends Immunol. (2001) 22(6):328-336.

[0393] In some embodiments the moiety may be a decoy receptor, e.g. a soluble receptor for an angiogenic factor and / or complexes comprising the angiogenic factor.

[0394] Decoy angiogenic factor receptors preferably bind to an angiogenic factor and / or complexes comprising the angiogenic factor, and thereby make these species unavailable for binding to their receptors. As such, they act as ‘decoy’ receptors, and angiogenic signalling is reduced as compared to the level of signalling in the absence of the decoy receptor.

[0395] In some embodiments a decoy receptor may be able to bind an angiogenic factor, e.g. with binding affinity of at least 100 pM or less, optionally one of 10 pM or less, 1 pM or less, 100 nM or less, or about 1 to 100 nM. In some embodiments a decoy receptor may comprise all or part of the angiogenic factor binding domain and may optionally lack all or part of the transmembrane domains. The decoy receptor may optionally be fused to an immunoglobulin constant region, e.g. IgG Fc region.

[0396] Decoy receptors for targeting growth factor signalling are reviewed in, for example, Kefaloyianni et al. FEBS Lett. (2022) 596(5):589-606, which is hereby incorporated by reference in its entirety. Decoy receptors according to the present invention include e.g. VEGF decoy receptors (including e.g. FP3, a selective VEGF decoy receptor disclosed in Yu et al. American Society of Gene and Cell Therapy (2012) 20(5):938-947; sVEGFR3-Fc disclosed in Lin etal. Cancer Research. (2005) 65(15)6901-6909; sVEGFR1 / R2 disclosed in Harding etal. Molecular Therapy. (2006) 13(5)956-966; and aflibercept (also known as Eylea, #DB08885)); PDGF decoy receptors; FGF decoy receptors (including FGF-2 decoyreceptor designated ‘FGF-T rap’ disclosed in Li etal. British Journal of Cancer. (2014) 111:68-77); angiopoietin decoy receptors (including e.g. angiopoietin-1 decoy receptor designated ‘TIE2-Fc’, disclosed in Davis et al. Cell. (1996) 87(7):1161-1169; and dual-targeting VEGF and angiopoietin decoy receptor designated ‘DAAP’, disclosed in Jun Koh et al. Cancer Cell. (2010) 18(2):171 -184); TGF decoy receptors (including e.g. TGF-p decoy receptor based on TGF-p receptor II, disclosed in WO 2018 / 138003 A1); TNFa decoy receptors (including e.g. Etanercept (#DB00005)).

[0397] In some embodiments, the antagonist of an angiogenic factor is a VEGF decoy receptor. In some embodiments, the antagonist of an angiogenic factor may comprise a recombinant fusion protein of the second immunoglobulin (Ig) domain of VEGFR-1 and the third Ig domain of VEGFR-2, fused to theconstant region (Fc) of human lgG1. Such agents include, for example, FP3 (disclosed in Yu etal.

[0398] American Society of Gene and Cell Therapy (2012) 20(5):938-947); sVEGFR1 / R2 disclosed in Harding et al. Molecular Therapy. (2006) 13(5)956-966; and aflibercept (also known as Eylea, drug bank accession No: #DB08885).

[0399] In some embodiments, the antagonist of an angiogenic factor may comprise the second immunoglobulin (Ig) domain ofVEGFR-1, the third Ig domain ofVEGFR-2, and optionally an Fc region e.g. an Fc region as disclosed herein.

[0400] In some embodiments, the antagonist of an angiogenic factor is, or comprises, a polypeptide comprising, or consisting of, an amino acid sequence having at least 70% sequence identity, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO:296 or 297. In some embodiments, the antagonist of an angiogenic factor is aflibercept or is derived from aflibercept.

[0401] In some embodiments, the antagonist of an angiogenic factor is an aptamer.

[0402] Aptamers, also called nucleic acid / peptide ligands, are nucleic acid or peptide molecules characterised by the ability to bind to a target molecule with high specificity and high affinity. Almost every aptamer identified to date is a non-naturally occurring molecule.

[0403] Aptamers to a given target (e.g. VEGF, a VEGF containing complex or a receptor for VEGF) may be identified and / or produced by the method of Systematic Evolution of Ligands by Exponential enrichment (SELEXTM), or by developing SOMAmers (slow off-rate modified aptamers) (Gold L etal. (2010) PLoS ONE 5(12):e15004). Aptamers and SELEX are described in Tuerk and Gold, Science (1990) 249(4968):505-10, and in WO 91 / 19813. Applying the SELEX and the SOMAmer technology includes for instance adding functional groups that mimic amino acid side chains to expand the aptamer's chemical diversity. As a result high affinity aptamers for a target may be enriched and identified.

[0404] Aptamers may be peptides selected or engineered to bind specific target molecules. Peptide aptamers and methods fortheir generation and identification are reviewed in Reverdatto etal., Curr Top Med Chem. (2015) 15(12): 1082-101 , which is hereby incorporated by reference in its entirety. Peptide aptamers may optionally have a minimum length of one of 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids. Peptide aptamers may optionally have a maximum length of one of 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 or 50 amino acids. Suitable peptide aptamers may optionally have a length of one of 2-30, 2-25, 2-20, 5-30, 5-25 or 5-20 amino acids.

[0405] Aptamers may have KD’S in the nM or pM range, e.g. less than one of 500nM, 100nM, 50nM, 10nM, 1nM, 500pM, 100pM.Aptamers according to the present invention include e.g. anti-VEGF / anti-VEGF interaction partner aptamers (including e.g. pegaptanib, which is disclosed in WO9818480 A1); anti-PDGF / anti-PDGF interaction partner aptamers (including e.g. the anti-PDGF-B aptamer designated ‘PDGF-BB’, disclosed in Quang Vu etal. J Mol Graph Model. (2018) 82:145-156); anti-FGF / anti-FGF interaction partner aptamers (including e.g. anti-FGF-2 aptamer designated RBM-007 disclosed in Matsuda etal. Molecular Therapy Nucleic Acids. (2019) 17:819-828); anti-angiopoietin / anti-angiopoietin interaction partner aptamers (including e.g. the anti-Ang2 aptamer disclosed in Sarraf-Yazdi et al. Journal of Surgical Research. (2008) 146(1 ):16-23); anti-TGF / anti-TGF interaction partner aptamers (including e.g. the anti-TGFp aptamer designated ‘APT-01’, disclosed in Takahashi etal. Molecular Therapy Nucleic Acids. (2022) 29:969-978); anti-TNFa / anti-TNFa interaction partner aptamers (including e.g. the anti-TNFa aptamer designated ‘VR11’, disclosed in Orava etal. ACS Chem Biol. (2013) 8(1):170-178; and aptTNF-a and its PEGylated-derivative, disclosed in Lai etal. Theranostics. (2019) 9(6):1741 -1751).

[0406] In some embodiments, the antagonist of an angiogenic factor is the anti-VEGF aptamer pegaptanib, which is disclosed in WO 9818480 A1, herein incorporated by reference in its entirety.

[0407] In some embodiments, the antagonist of an angiogenic factor is an inhibitor capable of binding to one or more of an angiogenic factor, a complex comprising the angiogenic factor, or an interaction partner for an angiogenic factor, and inhibiting angiogenic signalling.

[0408] In some embodiments the agent is a peptide or polypeptide based binding agent based on an angiogenic factor, e.g. mutant, variant or binding fragment of an angiogenic factor. Suitable peptide or polypeptide based agents may bind to a receptor for an angiogenic factor (e.g. VEGFR1 , 2 and / or 3) in a manner that does not lead to initiation of signal transduction, or which produces sub-optimal signalling. Mutants of this kind may act as competitive inhibitors of endogenous angiogenic factors.

[0409] Fc regions

[0410] In some embodiments, the antigen-binding molecules / moieties of the present disclosure comprise an Fc region.

[0411] 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.

[0412] Herein, a ‘CH2 region’ refers to an amino acid sequence corresponding to the CH2 region of an immunoglobulin (Ig). The CH2 region is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant region, according to the EU numbering system described in Edelman etal., Proc Natl Acad Sci USA (1969) 63(1): 78-85. A ‘CH3 region’ refers to an amino acid sequence corresponding to the CH3 region of an immunoglobulin (Ig). The CH3 region is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman etal., Proc Natl Acad Sci USA (1969) 63(1): 78-85. A ‘CH2-CH3 region’ refers toan amino acid sequence corresponding to the CH2 and CH3 regions of an immunoglobulin (Ig). The CH2-CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman etal., Proc Natl Acad Sci USA (1969) 63(1): 78-85.

[0413] In some embodiments, a CH2 region, CH3 region and / or a CH2-CH3 region according to the present disclosure corresponds to the CH2 region / CH3 region / CH2-CH3 region of an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. Ig A1 , lgA2), IgD, IgE or IgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human IgG (e.g. hlgG1, hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1, hlgA2), hlgD, hlgE or hlgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human lgG1 allotype (e.g. G1m1, G1m2, G1m3 orG1m17).

[0414] Fc regions may comprise modifications e.g. to promote the association of desired combinations of polypeptides or to influence an Fc-mediated function. Where an Fc region / CH2 / CH3 is described as comprising modification(s) ‘corresponding to’ reference substitution(s), equivalent substitution(s) in the homologous Fc / CH2 / CH3 are contemplated. By way of illustration, L234A / L235A substitutions in human lgG1 (numbered according to the EU numbering system as described in Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) correspond to L to A substitutions at positions 117 and 118 of the mouse Ig gamma-2A chain C region (UniProtKB: P01863-1 , v1).

[0415] Where an Fc region is described as comprising a modification, the modification may be present in one or both of the polypeptide chains which together form the Fc region.

[0416] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification in one or more of the CH2 and / or CH3 regions.

[0417] Recombinant co-expression of constituent polypeptides of multispecific antigen-binding polypeptide complexes 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 etal., Front Immunol. (2016) 7:394, which is hereby incorporated by reference in its entirety.

[0418] In some embodiments, an antigen-binding molecule / moiety 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 etal., Front. Immnol (2016) 7:394: KiH, KiHs-s, HA-TF, ZW1, 7.8.60, DD-KK, EW-RVT, EW-RVTS-S, SEED or A107.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 etal., 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 ofthe 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) ofthe 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 ofthe CH3 regions of an Fc region ofthe present disclosure comprises the substitution (numbering of positions / substitutions in the Fc, CH2 and CH3 regions herein is according to the EU numbering system as described in Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) T366W, and the other CH3 region ofthe Fc region comprises the substitution Y407V. In some embodiments, one ofthe CH3 regions ofthe Fc region comprises the substitution T366W, and the other CH3 region comprises the substitutions T366S and L368A. In some embodiments, one ofthe CH3 regions ofthe Fc region comprises the substitution T366W, and the other CH3 region comprises the substitutions Y407V, T366S and L368A. In some embodiments, one ofthe CH3 regions ofthe Fc region comprises, or consists of, an amino acid sequence having at least 70% sequence identity, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO:302, and the other CH3 region comprises, or consists of, an amino acid sequence having at least 70% sequence identity, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO:305.

[0419] In some embodiments, an Fc region according to the present disclosure comprises the ‘DD-KK’ modification as described e.g. in US 8592562 B2. In some embodiments, one ofthe CH3 regions comprises the substitutions K392D and K409D, and the other CH3 region ofthe Fc region comprises the substitutions E356K and D399K. The modifications promote electrostatic interaction between the CH3 regions.

[0420] In some embodiments, an Fc region according to the present disclosure comprises modification as described in Labrijn etal., Proc Natl Acad Sci U S A. (2013) 110(13):5145-50, referred to as ‘Duobody’ format. In some embodiments, one ofthe CH3 regions comprises the substitution K409R, and the other CH3 region ofthe Fc region comprises the substitution F405L.

[0421] In some embodiments, an Fc region according to the present disclosure comprises the ‘EEE-RRR’ modification as described in Strop et al., J Mol Biol. (2012) 420(3):204-19. In some embodiments, one ofthe CH3 regions comprises the substitutions D221E, P228E and L368E, and the other CH3 region of the Fc region comprises the substitutions D221R, P228R and K409R.

[0422] In some embodiments, an Fc region according to the present disclosure comprises the ‘EW-RVT’ modification described in Choi etal., Mol Cancer Ther (2013) 12(12):2748-59. In some embodiments, one of the CH3 regions comprises the substitutions K360E and K409W, and the other CH3 region of the Fc region comprises the substitutions Q347R, D399V and F405T.

[0423] In some embodiments, one of the CH3 regions of an Fc region according to the present disclosure comprises the substitution S354C, and the other CH3 region comprises the substitution Y349C.

[0424] Introduction of these cysteine residues results in formation of a disulphide bridge between the two CH3 regions of the Fc region, further stabilizing the heterodimer (Carter (2001), J Immunol Methods 248, 7-15).

[0425] In some embodiments, an Fc region according to the present disclosure comprises the ‘KiHs-s’ modification. In some embodiments one of the CH3 regions comprises the substitutions T366W and S354C, and the other CH3 region of the Fc region comprises the substitutions T366S, L368A, Y407V and Y349C.

[0426] In some embodiments, an Fc region according to the present disclosure comprises the ‘SEED’ modification as described in Davis etal., Protein Eng Des Sei (2010) 23(4):195-202, in which p-strand segments of human lgG1 CH3 and IgA CH3 are exchanged.

[0427] In some embodiments, one of the CH3 regions of an Fc region according to the present disclosure comprises the substitutions S364H and F405A, and the other CH3 region comprises the substitutions Y349T and T394F (see e.g. Moore et al., MAbs (2011) 3(6):546-57).

[0428] In some embodiments, one of the CH3 regions of an Fc region according to the present disclosure comprises the substitutions T350V, L351Y, F405A and Y407V, and the other CH3 region comprises the substitutions T350V, T366L, K392L and T394W (see e.g. Von Kreudenstein etal., MAbs (2013) 5(5):646-54).

[0429] In some embodiments, one of the CH3 regions of an Fc region according to the present disclosure comprises the substitutions K360D, D399M and Y407A, and the other CH3 region comprises the substitutions E345R, Q347R, T366V and K409V (see e.g. Leaver-Fay et al., Structure (2016) 24(4):641-51).

[0430] In some embodiments, one of the CH3 regions of an Fc region according to the present disclosure comprises the substitutions K370E and K409W, and the other CH3 region comprises the substitutions E357N, D399V and F405T (see e.g. Choi etal., PLoS One (2015) 10(12):e0145349).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 etal., 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.

[0431] Modifications to antibody Fc regions that influence Fc-mediated functions are known in the art, such as those described e.g. in Wang etal., Protein Cell (2018) 9(1):63-73, which is hereby incorporated by reference in its entirety. Exemplary Fc region modifications known to influence antibody effector function are summarised in Table 1 of Wang et al., Protein Cell (2018) 9(1):63-73. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification to increase or reduce an Fc-mediated function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0432] In some embodiments, the Fc region comprises modification to increase an Fc-mediated function. In some embodiments, the Fc region comprises modification to increase ADCC. In some embodiments, the Fc region comprises modification to increase ADCP. In some embodiments, the Fc region comprises modification to increase CDC. An antigen-binding molecule comprising an Fc region comprising modification to increase an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces an increased level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0433] In some embodiments, the Fc region comprises modification to increase binding to an Fc receptor. In some embodiments, the Fc region comprises modification to increase binding to an Fey receptor. In some embodiments, the Fc region comprises modification to increase binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRI I la and FcyRlllb. In some embodiments, the Fc region comprises modification to increase binding to FcyRllla. In some embodiments, the Fc region comprises modification to increase binding to FcyRlla. In some embodiments, the Fc region comprises modification to increase binding to FcyRllb. In some embodiments, the Fc region comprises modification to increase binding to FcRn. In some embodiments, the Fc region comprises modification to increase binding to a complement protein. In some embodiments, the Fc region comprises modification to increase binding to C1q. In some embodiments, the Fc region comprises modification to promote hexamerisation of the antigen-binding molecule. In some embodiments, the Fc region comprises modification to increase antigen-binding molecule half-life. In some embodiments, the Fc region comprises modification to increase coengagement.In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions F243L / R292P / Y300L / V305I / P396L as described in Stavenhagen etal. 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 etal., 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 etal., 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 etal., MAbs. (2013): 5:229-236. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions G236A / S239D / I332E as described in Richards etal., Mol Cancer Ther. (2008) 7:2517-2527.

[0434] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions K326W / E333S as described in Idusogie etal. 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 etal. MAbs. (2010) 2(2):181-9. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Natsume etal., 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.

[0435] 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.

[0436] In some embodiments, the Fc region comprises a CH2-CH3 region comprising an amino acid difference at one or more of the following positions, relative to the amino acid sequence of a CH2-CH3 region of a reference Fc region: 252, 254 or 256 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following specified amino acid residues: Y252, T254 or E256 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising Y252, T254 and E256. In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following amino acid substitutions, relative to the amino acid sequence of a CH2-CH3 region of the reference Fc region: M252Y, S254T or T256E (according to the EU numbering system).

[0437] These so called ‘YTE’ modifications located at the CH2-CH3 interface of the Fc region have been shown to increase the binding affinity at pH 6.0 to the MHC Class I neonatal Fc receptor (FcRn), localised within the acidic endosomes of endothelial and hematopoietic cells, which increases efficient recycling of administered mAb and longer half-life in the plasma.In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M428L / N434S as described in Zalevsky etal. Nat Biotechnol. (2010) 28:157-159.

[0438] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / L328F as described in Chu etal., Mol Immunol. (2008) 45:3926-3933. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions N325S / L328F as described in Shang etal. Biol Chem. (2014) 289:15309-15318.

[0439] In some embodiments, the Fc region comprises modification to reduce / prevent an Fc-mediated function. In some embodiments, the Fc region comprises modification to reduce / prevent ADCC. In some embodiments, the Fc region comprises modification to reduce / prevent ADCP. In some embodiments, the Fc region comprises modification to reduce / prevent CDC. An antigen-binding molecule comprising an Fc region comprising modification to reduce / prevent an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces a reduced level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0440] 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.

[0441] In some embodiments, the Fc region is not able to induce one or more Fc-mediated functions ( / .e. lacks the ability to elicit the relevant Fc-mediated function(s)). Accordingly, antigen-binding molecules comprising such Fc regions also lack the ability to induce the relevant function(s). Such antigen-binding molecules may be described as being devoid of the relevant function(s).

[0442] In some embodiments, the Fc region is not able to induce ADCC. In some embodiments, the Fc region is not able to induce ADCP. In some embodiments, the Fc region is not able to induce CDC. In some embodiments, the Fc region is not able to induce ADCC and / or is not able to induce ADCP and / or is not able to induce CDC.

[0443] In some embodiments, the Fc region is not able to bind to an Fc receptor. In some embodiments, the Fc region is not able to bind to an Fey receptor. In some embodiments, the Fc region is not able to bind to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fcregion is not able to bind to FcyRI II a. In some embodiments, the Fc region is not able to bind to FcyRlla. In some embodiments, the Fc region is not able to bind to FcyRllb. In some embodiments, the Fc region is not able to bind to FcRn. In some embodiments, the Fc region is not able to bind to a complement protein. In some embodiments, the Fc region is not able to bind to C1q. In some embodiments, the Fc region is not glycosylated at the amino acid residue corresponding to N297.

[0444] In some embodiments, the Fc region comprises modification corresponding to N297A or N297Q or N297G as described in Leabman etal., MAbs. (2013) 5:896-903. In some embodiments, the Fc region comprises modification corresponding to L235E as described in Alegre etal., 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 etal., Cell Immunol. (2000) 200:16-26. In some embodiments, the Fc region comprises modification corresponding to P329A or P329G as described in Schlothauer etal., Protein Engineering, Design and Selection (2016), 29(10):457-466. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G as described in Lo etal. J. Biol. Chem (2017) 292(9):3900-3908. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Rotheret 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 etal., Clin. Immunol. (2001) 98:164-174. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions H268QA / 309L / A330S / P331S as described in An etal., MAbs. (2009) 1:572-579. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions V234A / G237A / P238S / H268AA / 309L / A330S / P331S as described in Vafa et al., Methods. (2014) 65:114-126. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S as described in US 2015 / 0044231 A1.

[0445] The combination of substitutions ‘L234A / L235A’ and corresponding substitutions (such as e.g.

[0446] F234A / L235A in human lgG4) are known to disrupt binding of Fc to Fey receptors and inhibit ADCC, ADCP, and also to reduce C1q binding and thus CDC (Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466, hereby incorporated by reference in entirety). The substitutions ‘P329G’ and ‘P329A’ reduce C1q binding (and thereby CDC). Substitution of ‘N297’ with ‘A’, ‘G’ or ‘Q’ is known to eliminate glycosylation, and thereby reduce Fc binding to C1q and Fey receptors, and thus CDC and ADCC. Lo etal. J. Biol. Chem (2017) 292(9):3900-3908 (hereby incorporated by reference in its entirety) reports that the combination of substitutions L234A / L235A / P329G eliminated complement binding and fixation as well as Fc y receptor dependent, antibody-dependent, cell-mediated cytotoxicity in both murine lgG2a and human lgG1.

[0447] The combination of substitutions L234A / L235E / G237A / A330S / P331S in lgG1 Fc is disclosed in US 2015 / 0044231 A1 to abolish induction of phagocytosis, ADCC and CDC.In some embodiments, the Fc region comprises modification corresponding to the substitution S228P as described in Silva etal., J Biol Chem. (2015) 290(9):5462-5469. The substitution S228P in lgG4 Fc reduces Fab-arm exchange (Fab-arm exchange can be undesirable).

[0448] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A. In some embodiments, the Fc region comprises modification corresponding to the substitution P329G. In some embodiments, the Fc region comprises modification corresponding to the substitution N297Q.

[0449] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G.

[0450] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G / N297Q.

[0451] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331 S.

[0452] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P, e.g. in lgG4.

[0453] It may be desirable for the antigen-binding molecule to have a relatively-short half-life. Because the antigen-binding molecules of the present disclosure influence signalling mediated by multiple cytokines / through multiple cytokine receptors, it might be desirable for their functional effects to be relatively short-lived. Accordingly, in some embodiments the antigen-binding molecule of the present disclosure may comprise an Fc region comprising modification to decrease antigen-binding molecule halflife.

[0454] Fc modifications that reduce half-life include H345A, and the triple substitution I253A / H310A / H345A, which have been reported to reduce binding to FcRn and decrease half-life of antigen-binding molecules bearing Fc regions comprising such modifications relative to their unmodified wildtype counterparts (see e.g. Kruijsen etal., J Virol. (2013) 87(13): 7550-7557, which is hereby incorporated by reference in its entirety.

[0455] In some embodiments, the Fc region comprises modification corresponding to the substitution H345A. In some embodiments, the Fc region comprises modification corresponding to the substitution I253A. In some embodiments, the Fc region comprises modification corresponding to the substitution H310A. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions I253A / H310A / H345A.In some embodiments, the Fc region comprises a lysine residue at the C-terminus (e.g. K447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman etal., Proc Natl Acad Sci USA (1969) 63(1): 78-85). In some embodiments, the Fc region does not comprise K447 according to the EU numbering system described in Edelman etal., Proc Natl Acad Sci USA (1969) 63(1): 78-85). For example, a polypeptide constituent of an antigen-binding molecule described herein may comprise a CH3 region as described herein but wherein the CH3 region does not comprise K447.

[0456] In some embodiments, the antigen-binding moiety or antigen-binding molecule does not comprise an Fc region. In some embodiments, the antigen-binding moiety consists essentially of an Fv moiety (e.g. is a scFv or a dsFv). In some embodiments, the antigen-binding moiety or antigen-binding molecule consists essentially of a Fab moiety (e.g. is a Fab, CrossFab, scFab, scCrossFab or F(ab’)2).

[0457] As used herein, an antigen-binding molecule / moiety that ‘consists essentially of’ a reference polypeptide domain(s) / amino acid sequence(s) either (i) consists of the reference domain(s) / amino acid sequence(s), or (ii) comprises the reference domain(s) / amino acid sequence(s), wherein the reference domain(s) / amino acid sequence(s) constitute at least 80% (e.g. one of >85% >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%) of the molecule. It will be appreciated that an antigen-binding molecule that ‘consists essentially of’ a reference polypeptide domain(s) / amino acid sequence(s) may comprise the reference domain(s) / amino acid sequence(s), and additional amino acid(s) at one or both of the N-terminal and C-terminal ends of the reference domain(s) / amino acid sequence(s), provided that the additional amino acid(s) constitute <20% of the molecule. By way of illustration, antigen-binding molecules that consist essentially of an Fv moiety include scFv molecules, which comprise a VH and VL connected via a linker moiety.

[0458] Particular exemplary polypeptides and antigen-binding molecules

[0459] The present disclosure also provides polypeptide constituents of antigen-binding molecules. The polypeptides may be provided in isolated or substantially purified form.

[0460] The antigen-binding molecule of the present disclosure may be, or may comprise, a complex of polypeptides.

[0461] In the present specification where a polypeptide comprises more than one domain or region, it will be appreciated that the plural domains / regions are preferably present in the same polypeptide chain. That is, the polypeptide comprising more than one domain or region is a fusion polypeptide comprising the domains / regions.

[0462] In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, a VH as described herein. In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, a VL as described herein. In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, an antagonist of an angiogenic factor as described herein.In some embodiments, the polypeptide additionally comprises one or more antibody heavy chain constant regions (CH). In some embodiments, the polypeptide additionally comprises one or more antibody light chain constant regions (CL). In some embodiments, the polypeptide comprises a CH1, CH2 region and / or a CH3 region of an immunoglobulin (Ig).

[0463] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin heavy chain constant sequence. In some embodiments, the polypeptide comprises a CH1 region as described herein. In some embodiments, the polypeptide comprises a CH1-CH2 hinge region as described herein. In some embodiments, the polypeptide comprises a CH2 region as described herein. In some embodiments, the polypeptide comprises a CH3 region as described herein. In some embodiments, the polypeptide comprises a CH2-CH3 region as described herein.

[0464] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin light chain constant sequence. In some embodiments, the polypeptide comprises a CL region as described herein.

[0465] The antigen-binding molecule of the present disclosure comprises a gp130-binding moiety and an antagonist of an angiogenic factor. The antigen-binding molecule of the present disclosure may be a bispecific antigen-binding molecule. In some embodiments, the antigen-binding molecule comprises at least two different antigen-binding domains ( / .e. at least two antigen-binding domains, e.g. comprising non-identical VHs and VLs). In some embodiments, the gp130-binding moiety comprises a VH and a VL, and the antagonist of an angiogenic factor comprises a VH and a VL.

[0466] In the below polypeptides (i) to (xx) and combinations of polypeptides (A) to (L), VH(A) and VL(A) represent an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specific binding to a given target antigen, and VH(B) and VL(B) represent an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specific binding to a different target antigen.

[0467] In some embodiments, VH(A) and VL(A) represent a VH and VL of an antibody capable of specific binding to gp130. In some embodiments, VH(B) and VL(B) represent a VH and VL of an antibody capable of specific binding to gp130. In some embodiments, VH(A) and VL(A) represent a VH and VL of an antibody capable of specific binding to an angiogenic factor. In some embodiments, VH(B) and VL(B) represent a VH and VL of an antibody capable of specific binding to an angiogenic factor.

[0468] In some embodiments, VH(A) and VL(A) represent a VH and VL of an antibody capable of specific binding to gp130 and VH(B) and VL(B) represent a VH and VL of an antibody capable of specific binding to an angiogenic factor. In some embodiments, VH(B) and VL(B) represent a VH and VL of an antibody capable of specific binding to gp130 and VH(A) and VL(A) represent a VH and VL of an antibody capable of specific binding to an angiogenic factor.The antibody capable of specific binding to gp130 may be any antibody as described herein. The antibody capable of specific binding to an angiogenic factor may be any antibody as described herein.

[0469] In some embodiments, the polypeptide according to the present disclosure comprises a structure from N-to C-terminus according to one of the following:

[0470] (i) VL(A)-CH1-CH2-CH3

[0471] (ii) VH(A)-CL

[0472] (iii) VH(B)-CH1-CH2-CH3

[0473] (iv) VL(B)-CL

[0474] (v) VH(A)-CL-CH2-CH3

[0475] (vi) VL(A)-CH1

[0476] (vii) VH(A)-CH1-CH2-CH3

[0477] (viii) VH(B)-VL(B)-CH2-CH3

[0478] (ix) VL(B)-VH(B)-CH2-CH3

[0479] (x) VL(A)-CL

[0480] (xi) VH(A)-CH1 -CH2-CH3-VH(B)-VL(B)

[0481] (xii) VH(A)-CH1-CH2-CH3-VL(B)-VH(B)

[0482] (xiii) VH(A)-VL(B)-CH2-CH3

[0483] (xiv) VH(B)-VL(A)-CH2-CH3

[0484] (xv) VH(A)-VL(B)

[0485] (xvi) VH(B)-VL(A)

[0486] (xvii) VH(A)-VL(A)-VL(B)-VH(B)

[0487] (xviii) VL(A)-VH(A)-VL(B)-VH(B)

[0488] (xix) VH(A)-VL(A)-VH(B)-VL(A)

[0489] (xx) VL(A)-VH(A)-VH(B)-VL(B)

[0490] Also provided by the present disclosure are antigen-binding molecules composed of the polypeptides of the present disclosure. In some embodiments, the antigen-binding molecule of the present disclosure comprises one of the following combinations of polypeptides (A) to (H) or one of the following polypeptides (I) to (L):

[0491] (A) VL(A)-CH1-CH2-CH3 + VH(A)-CL + VH(B)-CH1-CH2-CH3 + VL(B)-CL

[0492] (B) VH(A)-CL-CH2-CH3 + VL(A)-CH1 + VH(B)-CH1-CH2-CH3 + VL(B)-CL

[0493] (C) VH(A)-CH1-CH2-CH3 + VH(B)-VL(B)-CH2-CH3 + VL(A)-CL

[0494] (D) VH(A)-CH1-CH2-CH3 + VL(B)-VH(B)-CH2-CH3 + VL(A)-CL

[0495] (E) VH(A)-CH1-CH2-CH3-VH(B)-VL(B) + VL(A)-CL

[0496] (F) VH(A)-CH1-CH2-CH3-VL(B)-VH(B) + VL(A)-CL

[0497] (G) VH(A)-VL(B)-CH2-CH3 + VH(B)-VL(A)-CH2-CH3

[0498] (H) VH(A)-VL(B) + VH(B)-VL(A)

[0499] (I) VH(A)-VL(A)-VL(B)-VH(B)

[0500] (J) VL(A)-VH(A)-VL(B)-VH(B)

[0501] (K) VH(A)-VL(A)-VH(B)-VL(A)(L) VL(A)-VH(A)-VH(B)-VL(B)

[0502] In some embodiments, the antigen-binding molecule comprises more than one of a polypeptide of the combinations shown in (A) to (H) above. By way of example, with reference to (E) above, in some embodiments, the antigen-binding molecule comprises two polypeptides comprising the structure VH(A)-CH1-CH2-CH3-VH(B)-VL(B), and two polypeptides comprising the structure VL(A)-CL.

[0503] In some embodiments, the antigen-binding molecule comprises a gp130-binding moiety comprising a VH and a VL, and an antagonist of an angiogenic factor which does not comprise a VH and a VL. In some embodiments, the antigen-binding molecule comprises a gp130-binding moiety comprising a VH and a VL, and an antagonist of an angiogenic factor which is a polypeptide e.g. a decoy binding partner molecule e.g. a decoy receptor.

[0504] In the below polypeptides (xxi) to (xxvi) and combinations of polypeptides (M) to (P), VH and VL represent an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specific binding to gp130. In the below polypeptides (xxii) and (xxvi) and combinations of polypeptides (M) to (P), [antagonist of an angiogenic factor] represents a polypeptide e.g. a decoy binding partner molecule e.g. a decoy receptor. In some embodiments, the antagonist of an angiogenic factor is aflibercept.

[0505] In some embodiments, the polypeptide according to the present disclosure comprises a structure from N-to C-terminus according to one of the following:

[0506] (xxi) VH-CH1-CH2-CH3

[0507] (xxii) [antagonist of an angiogenic factor]-CH2-CH3

[0508] (xxiii) VL-CL

[0509] (xxiv) VH-VL-CH2-CH3

[0510] (xxv) VL-VH-CH2-CH3

[0511] (xxvi) VH-CH1-CH2-CH3-[antagonist of an angiogenic factor]

[0512] (xxvii) [antagonist of an angiogenic factor]-VH-CH1-CH2-CH3

[0513] (xxviii) [antagonist of an angiogenic factor]-CH2-CH3-VH-CH1

[0514] Also provided by the present disclosure are antigen-binding molecules composed of the polypeptides of the present disclosure. In some embodiments, the antigen-binding molecule of the present disclosure comprises one of the following combinations of polypeptides:

[0515] (M) VH-CH1-CH2-CH3 + [antagonist of an angiogenic factor]-CH2-CH3 + VL-CL

[0516] (N) VH-VL-CH2-CH3 + [antagonist of an angiogenic factor]-CH2-CH3

[0517] (O) VL-VH-CH2-CH3 + [antagonist of an angiogenic factor]-CH2-CH3

[0518] (P) VH-CH1-CH2-CH3-[antagonist of an angiogenic factor] + VL-CL

[0519] (Q) [antagonist of an angiogenic factor]-VH-CH1-CH2-CH3 + VL-CL

[0520] (R) [antagonist of an angiogenic factor]-CH2-CH3-VH-CH1 + VL-CLIn some embodiments, the antigen-binding molecule comprises more than one of a polypeptide of the combinations shown in (M) to (R) above. By way of example, with reference to (P) above, in some embodiments, the antigen-binding molecule comprises two polypeptides comprising the structure VH-CH1-CH2-CH3-[antagonist of an angiogenic factor], and two polypeptides comprising the structure VL-CL.

[0521] It will be appreciated that any of the polypeptides (i) to (xxviii) may further comprise linker sequences (e.g. linker sequences described herein) between any of the named components. For example, a linker sequence may be provided between a VH sequence and a VL sequence, providing linkage between the VH and VL (e.g. as in an scFv molecule / moiety). By way of further illustration, a linker sequence may be provided between a VH(A) / VL(A) sequence and a VH(B)A / L(B) sequence, providing linkage between a VH(A)A / L(A) scFv moiety and a VH(B)A / L(B) scFv moiety (e.g. as in a tandem scFv molecule). By way of further illustration, a linker sequence may be provided between an Fc component and a VHA / L or antagonist of an angiogenic factor component, providing linkage between the Fc component and the VHA / L or antagonist of an angiogenic factor (e.g. as in polypeptides (xi), (xii), or (xxvi)).

[0522] It will also be appreciated that any of the polypeptides (i) to (xxviii) may further comprise a signal peptide (e.g. a signal peptide as described herein). The signal peptide may be present at the N-terminus of the polypeptide.

[0523] It will also be appreciated that any of the polypeptides (i) to (xxviii) may further comprise an epitope tag (e.g. an epitope tag as described herein). The epitope tag may be present at the N- or C-terminus of the polypeptide.

[0524] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:183, 184, 112, 117, 179, 1, 180, 94, 181, 98, 182, 294, or 174. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:182 or 294.

[0525] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:216, 217, 202, 203, 211, 212, 213, 193, 194, or 17.

[0526] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:190, 191, 121, 126, 186, 9, 187, 295, 188, 189, 102, 106, 109, 147, 148, 143, 144, 145, 146,160, 161 , 156, 157, 158 or 159. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:190, 191, 121, 126, 186, 9, 187, 295, 188, 189, 102, 106, or 109. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:147, 148, 143, 144, 145 or 146. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:160, 161 , 156, 157, 158 or 159. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:187 or 295.

[0527] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:230, 231, 25, 219, 220, or 221.

[0528] In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1, HC-CDR2 and HC-CDR3 as indicated in column A of Table A, and (ii) a VL region comprising LC-CDR1, LC-CDR2 and LC-CDR3 as indicated in column B of Table A, wherein the sequences of columns A and B are selected from the same row of Table A.

[0529] In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-FR1, HC-FR2, HC-FR3 and HC-FR4 as indicated in column A of Table B, and (ii) a VL region comprising LC-FR1, LC-FR2, LC-FR3, and LC-FR4 as indicated in column B of Table B, wherein the sequences of columns A and B are selected from the same row of Table B.

[0530] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising: (i) 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 an amino acid sequence indicated in column A of Table C, and (ii) 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 an amino acid sequence indicated in column B of Table C, wherein the sequences of columns A and B are selected from the same row of Table C. In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) an amino acid sequence indicated in column A of Table C, and (ii) an amino acid sequence indicated in column B of Table C, wherein the sequences of columns A and B are selected from the same row of Table C.In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1 , HC-CDR2 and HC-CDR3 as indicated in column A of Table A of WO 2024 / 121233 A1 , and (ii) a VL region comprising LC-CDR1 , LC-CDR2 and LC-CDR3 as indicated in column B of Table A of WO 2024 / 121233 A1, wherein the sequences of columns A and B are selected from the same row of Table A of WO 2024 / 121233 A1.

[0531] In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-FR1, HC-FR2, HC-FR3 and HC-FR4 as indicated in column A of Table B of WO 2024 / 121233 A1, and (ii) a VL region comprising LC-FR1, LC-FR2, LC-FR3, and LC-FR4 as indicated in column B of Table B of WO 2024 / 121233 A1, wherein the sequences of columns A and B are selected from the same row of Table B of WO 2024 / 121233 A1.

[0532] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising: (i) 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 an amino acid sequence indicated in column A of Table C of WO 2024 / 121233 A1 , and (ii) 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 an amino acid sequence indicated in column B of Table C of WO 2024 / 121233 A1 , wherein the sequences of columns A and B are selected from the same row of Table C of WO 2024 / 121233 A1. In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) an amino acid sequence indicated in column A of Table C of WO 2024 / 121233 A1 , and (ii) an amino acid sequence indicated in column B of Table C of WO 2024 / 121233 A1 , wherein the sequences of columns A and B are selected from the same row of Table C ofWO 2024 / 121233 A1.

[0533] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:265, 273, 280, 288, 290, 292, 384, or 388.

[0534] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:269, 277, 284, 289, 291 , 293, 387 or 389.

[0535] In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1 having the amino acid sequence of SEQ ID NO:266, HC-CDR2 having the amino acid sequence of SEQ ID NO:267, HC-CDR3 having the amino acid sequence of SEQ ID NO:268, and (ii) a LV region comprising LC-CDR1 having the amino acid sequence of SEQ ID NQ:270, LC-CDR2 having the amino acid sequence of SEQ ID NO:271, LC-CDR3 having the amino acidsequence of SEQ ID NO:272. In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1 having the amino acid sequence of SEQ ID NO:274, HC-CDR2 having the amino acid sequence of SEQ ID NO:275, HC-CDR3 having the amino acid sequence of SEQ ID NO:276, and (ii) a LV region comprising LC-CDR1 having the amino acid sequence of SEQ ID NO:278, LC-CDR2 having the amino acid sequence of SEQ ID NO:192, LC-CDR3 having the amino acid sequence of SEQ ID NO:279. In some embodiments, the antigenbinding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1 having the amino acid sequence of SEQ ID NO:281, HC-CDR2 having the amino acid sequence of SEQ ID NO:282, HC-CDR3 having the amino acid sequence of SEQ ID NO:283, and (ii) a VL region comprising LC-CDR1 having the amino acid sequence of SEQ ID NO:285, LC-CDR2 having the amino acid sequence of SEQ ID NO:286, LC-CDR3 having the amino acid sequence of SEQ ID NO:287. In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1 having the amino acid sequence of SEQ ID NO:385, HC-CDR2 having the amino acid sequence of SEQ ID NO:267, HC-CDR3 having the amino acid sequence of SEQ ID NO:386, and (ii) a LV region comprising LC-CDR1 having the amino acid sequence of SEQ ID NQ:270, LC-CDR2 having the amino acid sequence of SEQ ID NO:271, LC-CDR3 having the amino acid sequence of SEQ ID NO:272.

[0536] In some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) an amino acid sequence of SEQ ID NO: 265, 273, 280, 288, 290, 292, 387 or 389 and (ii) an amino acid sequence of SEQ ID NO: 269, 277, 284, 289, 291, 293, 387 or 389 respectively.

[0537] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:297 or 296.

[0538] In some embodiments, the antigen-binding molecule comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to any of SEQ ID NQ:310-381.

[0539] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:310; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:311 ; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:312; and a polypeptide which comprises or consists ofan 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:313.

[0540] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:314; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:315; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:316; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:317.

[0541] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:318; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:319; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:320; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:321.

[0542] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:322; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:323; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:324; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:325.

[0543] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:326; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequenceidentity to SEQ ID NO:327; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:328; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:329.

[0544] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:330; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:331 ; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:332.

[0545] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:333; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:334; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:335.

[0546] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:336; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:337; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:338.

[0547] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:339; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:340; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:341 .In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:342; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:343; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:344.

[0548] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:345; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:346; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:347.

[0549] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:348; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:349.

[0550] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:350; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:351.

[0551] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:352; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:353.In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:354; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:355.

[0552] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:356; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:357.

[0553] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:358: and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:359.

[0554] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:360; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:361.

[0555] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:362; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:363.

[0556] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:364; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:365.In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:366; a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:367; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:368.

[0557] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:369; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:370.

[0558] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:371 ; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:372.

[0559] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:373; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:374.

[0560] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:375; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:376.

[0561] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:377; and apolypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:378.

[0562] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:379.

[0563] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:380.

[0564] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:381.

[0565] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:390; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:391.

[0566] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:392; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:393.

[0567] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:394; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:395.

[0568] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:396; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably oneof 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:397.

[0569] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:398; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:399.

[0570] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:400; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:401.

[0571] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:402; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:403.

[0572] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:404; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:405.

[0573] In some embodiments, the antigen-binding molecule comprises: a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:406; and a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:407.Functional properties of the antigen-binding molecules

[0574] 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:

[0575] binds to gp130 and / or an angiogenic factor;

[0576] binds to cells expressing gp130 and / or an angiogenic factor;

[0577] inhibits signalling mediated by a receptor comprising gp130;

[0578] inhibits signalling mediated by gp130:IL-6Ra, gp130:IL-11Ra, gp130:OSMRp, gp130:LIFRp, gp130:LIFRp:CNTFRa, gp130:IL-27Ra and / or gp130:IL-12Rp2;

[0579] inhibits signalling mediated by a cytokine that binds to a receptor comprising gp130; inhibits IL-6-, IL-11-, OSM-, LIF-, CNTF-, CT-1-, CLC-, IL-27- and / or IL-35-mediated signalling; inhibits signalling mediated by an angiogenic factor;

[0580] inhibits signalling mediated by binding of an angiogenic factor to an interaction partner for the angiogenic factor;

[0581] inhibits a process mediated by an angiogenic factor;

[0582] reduces inflammation and / or fibrosis;

[0583] reduces the pathology of a disease / condition characterised by inflammation and / or fibrosis; reduces or inhibits angiogenesis;

[0584] reduces the pathology of a disease / condition characterised by angiogenesis (e.g. pathological angiogenesis); and / or

[0585] increases killing of cells expressing gp130 and / or an angiogenic factor.

[0586] It will be appreciated that a given antigen-binding molecule may display more than one of the properties recited in the preceding paragraph. A given antigen-binding molecule may be evaluated for the properties recited in the preceding paragraph using suitable assays. For example, the assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays. In some embodiments, the assays may be e.g. in vivo assays, i.e. performed in non-human animals. In some embodiments, the assays may be e.g. ex vivo assays, i.e. performed using cells / tissue / an organ obtained from a subject.

[0587] Where assays are cell-based assays, they may comprise treating cells with a given antigen-binding molecule in order to determine whether the antigen-binding molecule displays one or more of the recited properties. Assays may employ species labelled with detectable entities in order to facilitate their detection. Assays may comprise evaluating the recited properties following treatment of cells separately with a range of quantities / concentrations of a given antigen-binding molecule (e.g. a dilution series).

[0588] Analysis of the results of such assays may comprise determining the concentration at which 50% of the maximal level of the relevant activity is attained. The concentration of a given agent at which 50% of the maximal level of the relevant activity is attained may be referred to as the ‘half-maximal effective concentration’ of the agent in relation to the relevant activity, which may also be referred to as the ‘EC50’. By way of illustration, the EC50 of a given antigen-binding molecule for binding to human gp130 may bethe concentration of the antigen-binding molecule at which 50% of the maximal level of binding to human gp130 is achieved.

[0589] Depending on the property, the EC50 may also be referred to as the ‘half-maximal inhibitory concentration’ or ‘IC50’, this being the concentration of the agent at which 50% of the maximal level of inhibition of a given property is observed.

[0590] The antigen-binding molecule described herein bind to gp130 and / or an angiogenic factor.

[0591] The antigen-binding molecules described herein may bind to gp130. In some embodiments, the antigenbinding molecule binds to human gp130. In some embodiments, the antigen-binding molecule binds to mouse gp130. In some embodiments, the antigen-binding molecule binds to rat gp130. In some embodiments, the antigen-binding molecule binds to rhesus macaque gp130. In some embodiments, the antigen-binding molecule binds to canine gp130.

[0592] In some embodiments, the antigen-binding molecules display cross-reactive binding to human gp130, and to one or more homologues of human gp130 (e.g. selected from rhesus macaque gp130, mouse gp130 and rat gp130). It will be appreciated that cross-reactive binding refers to the ability to bind independently to each antigen, and not simultaneous binding of an antigen-binding domain of the antigenbinding molecule to the two or more antigens.

[0593] In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and rhesus macaque gp130 ( / .e. is capable of binding to human gp130, and is also capable of binding to rhesus macaque gp130). In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and mouse gp130. In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and rat gp130. In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and rhesus macaque gp130 and mouse gp130 and rat gp130.

[0594] In some embodiments, the antigen-binding molecule binds to an angiogenic factor, e.g. a VEGF, an FGF, a PDGF, a VEGF receptor, an FGF receptor or a PDGF receptor.

[0595] The antigen-binding molecules and antigen-binding domains described herein preferably display specific binding to gp130 and or an angiogenic factor. As used herein, ‘specific binding’ refers to binding which is selective for the antigen, and which can be discriminated from non-specific binding to non-target antigen. An antigen-binding molecule / domain that specifically binds to a target molecule preferably binds the target with greater affinity, and / or with greater duration than it binds to other, non-target molecules.

[0596] The ability of a given polypeptide to bind specifically to a given molecule can be determined by analysis according to methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty etal., Methods Mol Biol (2012) 907:411-442), Bio-Layer Interferometry (BLI; see e.g. Lad etal., (2015) J Biomol Screen 20(4): 498-507), flow cytometry, or by a radiolabelled antigen-binding assay (RIA)enzyme-linked immunosorbent assay. Through such analysis binding to a given molecule can be measured and quantified. In some embodiments, the binding may be the response detected in a given assay.

[0597] In some embodiments, the extent of binding of the antigen-binding molecule to a non-target molecule is less than about 10% of the binding of the antibody to the target molecule as measured, e.g. by ELISA, SPR, BLI or by RIA. Alternatively, binding specificity may be reflected in terms of binding affinity where the antigen-binding molecule binds with a dissociation constant (KD) that is at least 0.1 order of magnitude ( / .e. 0.1 x 10n, where n is an integer representing the order of magnitude) greater than the KD of the antigen-binding molecule towards a non-target molecule. This may optionally be one of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0.

[0598] The affinity of binding to a given target antigen for an antigen-binding molecule described herein may be determined by SPR, e.g. as described in the Examples of the present disclosure.

[0599] In some embodiments, the antigen-binding molecule described herein binds to gp130 with an affinity in the micromolar range, i.e. KD = 9.9 x 10-4to 1 x 10-6M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-micromolar affinity, i.e. KD < 1 x 10-6M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with an affinity in the nanomolar range, i.e. KD = 9.9 x 107to 1 x 109M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-nanomolar affinity, i.e. KD < 1 x 109M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with an affinity in the picomolar range, i.e. KD = 9.9 x 1O-1CIto 1 x 10-12M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-picomolar affinity, i.e. KD < 1 x 10-12M.

[0600] In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 10 pM or less, preferably one of <5 pM, <2 pM, <1 pM, <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or<1 pM (e.g. as determined by analysis surface plasmon resonance analysis, e.g. performed as described in Example 2 of WO 2025 / 017127 A1). In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 100 nM or less, preferably one of <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or<1 pM (e.g. as determined by analysis surface plasmon resonance analysis, e.g. performed as described in Example 2 of WO 2025 / 017127 A1). In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 3 nM or less, preferably one of <2.5 nM, <2 nM, <1.5 nM, <1 nM, <750 pM, <500 pM, or <400 pM.

[0601] In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of <200 nM, preferably one of <190 nM, <180 nM, <170 nM, <160 nM, <150 nM, <140 nM, <130nM, <120 nM, <110 nM, <100 nM, <95 nM, <90 nM, <85 nM, <80 nM, <75 nM, <60 nM, <55 nM, <50 nM, <45 nM, <40 nM, <35 nM, <30 nM, <25 nM, <20 nM, <15 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM, <3 nM, <2 nM or <1 nM (e.g. as determined by analysis surface plasmon resonance analysis, e.g. performed as described in Example 2 of WO 2025 / 017127 A1). In some embodiments, the antigenbinding molecule described herein binds to human gp130 isoform 1 with a KD of <166 nM. In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of <2.91 nM.

[0602] In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with an EC50 of 10 pM or less, preferably one of <5 pM, <2 pM, <1 pM, <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM.

[0603] In some embodiments, the antigen-binding molecule described herein binds to an angiogenic factor (e.g. VEGF) with an affinity in the micromolar range, i.e. KD = 9.9 x 10-4to 1 x 10-6M. In some embodiments, the antigen-binding molecule described herein binds to an angiogenic factor (e.g. VEGF) with submicromolar affinity, i.e. KD < 1 x 10-6M. In some embodiments, the antigen-binding molecule described herein binds to an angiogenic factor (e.g. VEGF) with an affinity in the nanomolar range, i.e. KD = 9.9 x 10-7to 1 x IO9M. In some embodiments, the antigen-binding molecule described herein binds to an angiogenic factor (e.g. VEGF) with sub-nanomolar affinity, i.e. KD < 1 x 109M. In some embodiments, the antigen-binding molecule described herein binds to an angiogenic factor (e.g. VEGF) with an affinity in the picomolar range, i.e. KD = 9.9 x IO-10to 1 x 10-12M. In some embodiments, the antigen-binding molecule described herein binds to an angiogenic factor (e.g. VEGF) with sub-picomolar affinity, i.e. KD < 1 x 10-12M.

[0604] In some embodiments, the antigen-binding molecule described herein binds to human VEGF165 with a KD of 10 pM or less, preferably one of <5 pM, <2 pM, <1 pM, <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM (e.g. as determined by analysis surface plasmon resonance analysis, e.g. performed as described in Example 9 herein). In some embodiments, the antigen-binding molecule described herein binds to human VEGF165 with a KD of 100 nM or less, preferably one of <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM (e.g. as determined by analysis surface plasmon resonance analysis, e.g. performed as described in Example 9 herein). In some embodiments, the antigen-binding molecule described herein binds to human VEGF165 with a KD of 20 nM or less, preferably one of <10 nM, <2.5 nM, <2 nM, <1.5 nM, <1 nM, <750 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, or <15 pM.The antigen-binding molecules of the present disclosure may bind to a particular region of interest of gp130. Antigen-binding molecules according to the present disclosure may bind to linear epitope of gp130, consisting of a contiguous sequence of amino acids ( / .e. an amino acid primary sequence). In some embodiments, an antigen-binding molecules may bind to a conformational epitope of gp130, consisting of a discontinuous sequence of amino acids of the amino acid sequence.

[0605] The region of a given target molecule to which an antigen-binding molecule binds can be determined by the skilled person using various methods well known in the art, including X-ray co-crystallography analysis of antibody-antigen complexes, peptide scanning, mutagenesis mapping, hydrogen-deuterium exchange analysis by mass spectrometry, phage display, competition ELISA and proteolysis-based ‘protection’ methods. Such methods are described, for example, in Gershoni etal., BioDrugs, 2007, 21 (3):145-156, which is hereby incorporated by reference in its entirety.

[0606] In some embodiments, the antigen-binding molecule of the present disclosure binds to the extracellular domain of gp130. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:75. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:75.

[0607] In some embodiments, the antigen-binding molecule of the present disclosure binds to the cytokine binding module of gp130. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:85. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:85.

[0608] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:89. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:89. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:89. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:89. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:89.

[0609] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:86. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:86. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:86. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:86. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:87. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:87. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:87. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:87. In some embodiments, theantigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:88. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:88. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:88. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:88.

[0610] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NOs:86, 87 and 88. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NOs:86, 87 and 88. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NOs:86, 87 and 88. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:86, 87 and 88.

[0611] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:93. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:93. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:93. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:93. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:93.

[0612] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NQ:90. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NQ:90. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NQ:90. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NQ:90. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:91. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:91. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:91. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:91. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:92. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:92. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:92. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:92.

[0613] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NQs:90, 91 and 92. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NQs:90, 91 and 92. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NQs:90, 91 and 92. Insome embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:90, 91 and 92.

[0614] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:169. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:169. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:169. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:169. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NQ:170. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NQ:170. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NQ:170. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NQ:170.

[0615] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:171. In some embodiments, the antigen-binding molecule contacts the region ofgp130 shown in SEQ ID NO:171. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:171. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:171. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:172. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:172. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:172. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:172.

[0616] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NOs:169 and 170. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NOs:169 and 170. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NOs:169 and 170. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:169 and 170.

[0617] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NOs:171 and 172. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NOs:171 and 172. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NOs:171 and 172. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:171 and 172.

[0618] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:173. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQID NO:173. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:173. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:173. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:173.

[0619] In some embodiments, the antigen-binding molecule does not bind to the region of gp130 shown in SEQ ID NO:178. In some embodiments, the antigen-binding molecule does not contact the region of gp130 shown in SEQ ID NO:178. In some embodiments, the antigen-binding molecule does not bind to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:178. In some embodiments, the epitope of the antigen-binding molecule does not consist of the amino acid sequence shown in SEQ ID NO:178. In some embodiments, the antigen-binding molecule does not bind to a polypeptide consisting of the amino acid sequence shown in SEQ ID NO:178.

[0620] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in any one of SEQ ID NO:169 to 188 of WO 2024 / 121233 A1.

[0621] The ability of an antigen-binding molecule 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, SPR and BLI.

[0622] In some embodiments, the antigen-binding molecule is capable of binding the same region of gp130, or an overlapping region of gp130, to the region of gp130 which is bound by an antibody comprising the VH and VL regions (see e.g. Table C) of an antibody selected from B035-C03-A3, CSP-S-5H8, A3_3.2 VH I A3_3 VL, A3_3.2 VH I A3_4 VL, A3_3.2 VH I A3_5 VL, A3_4.2 VH I A3_3 VL, A3_4.2 VH I A3_4 VL, A3_4.2 VH I A3_5 VL, A3_6.2 VH I A3_3 VL, A3_6.2 VH I A3_4 VL, A3_6.2 VH I A3_5 VL, A3-derived VH CON I A3-derived VL CON, A3-Hum VH CON I A3-Hum VL CON, B035-C03-A3_D50X, A3_3.2 VH I A3_3_D50X VL, A3_3.2 VH I A3_4_D50X VL, A3_3.2 VH I A3_5_D50X VL, A3_4.2 VH I A3_3_D50X VL, A3_4.2 VH I A3_4_D50X VL, A3_4.2 VH I A3_5_D50X VL, A3_6.2 VH I A3_3_D50X VL, A3_6.2 VH I A3_4_D50X VL, A3_6.2 VH I A3_5_D50X VL, A3-derived VH CON I A3-derived VL_D50X CON, A3-Hum VH CON I A3-Hum VL_D50X CON, B035-C03-A3_D50A, A3_3.2 VH I A3_3_D50A VL, A3_3.2 VH I A3_4_D50A VL, A3_3.2 VH I A3_5_D50A VL, A3_4.2 VH I A3_3_D50A VL, A3_4.2 VH I A3_4_D50A VL, A3_4.2 VH I A3_5_D50A VL, A3_6.2 VH I A3_3_D50A VL, A3_6.2 VH I A3_4_D50A VL, A3_6.2 VH I A35D50A VL, A3-derived VH CON I A3-derived VLD50A CON and A3-Hum VH CON I A3-Hum

[0623]

[0624] A3_5_G51A VL, A3_6.2_I1OOT VH / A3_3_G51A VL, A3_6.2_I1OOT VH / A3_4_G51A VL, A3_6.2_I1OOT VH I A3_5_G51 A VL, A3_6.2_I1 OOT VH I A3_3 VL, A3_6.2_I1OOT VH I A3_4 VL, A3_6.2_I1OOT VH I A3_5 VL, A3_6.2 VH I A3_3_G51 A VL, A3_6.2 VH I A3_4_G51 A VL, A3_6.2 VH I A3_5_G51 A VL, A3-derivedJWOT VH CON / A3-derived_G51 A VL CON, A3-derived_l100T VH CON / A3-derived VL CON, A3-derived VH CON / A3-derived_G51A VL CON, A3-Hum_l100T VH CON / A3-Hum_G51A VL CON, A3-Hum_l100T VH CON I A3-Hum VL CON, A3-Hum VH CON I A3-Hum_G51 A VL CON, 5H8CVH4 VH I 5H8CVL3 VL, 5H8CVH4 VH I 5H8CVL4 VL, 5H8CVH4 VH I 5H8GVL3 VL, 5H8GVH4 VH I 5H8CVL3 VL, 5H8GVH4 VH I 5H8CVL4 VL, 5H8GVH4 VH I 5H8GVL3 VL, 5H8-derived VH CON I 5H8-derived VL CON, 5H8-Hum VH CON I 5H8-Hum VL CON, CSP-S-5H8_D98G VH I CSP-S-5H8 VL, 5H8CVH4_D98G VH I 5H8CVL3 VL, 5H8CVH4_D98G VH I 5H8CVL4 VL, 5H8CVH4_D98G VH I 5H8GVL3 VL, 5H8GVH4_D98G VH I 5H8CVL3 VL, 5H8GVH4_D98G VH I 5H8CVL4 VL, 5H8GVH4_D98G VH I 5H8GVL3 VL, 5H8-derived_D98G VH CON 15H8-derived VL CON, or 5H8-Hum_D98G VH CON 15H8-Hum VL CON.

[0625] In some embodiments, the antigen-binding molecule is capable of binding the same region of gp130, or an overlapping region of gp130, to the region of gp130 which is bound by an antibody comprising the VH and VL regions of an antibody as described in WO 2024 / 121233 A1 (e.g. comprising the VH and VL as included in Table C of WO 2024 / 121233 A1).

[0626] Whether a test antigen-binding molecule binds to the same or an overlapping region of a given target as a reference antigen-binding molecule can be evaluated, for example, by analysis of (i) interaction between the test antigen-binding molecule and the target in the absence of the reference binding molecule, and (ii) interaction between the test antigen-binding molecule in the presence of the reference antigen-binding molecule, or following incubation of the target with the reference antigen-binding molecule. Determination of a reduced level of interaction between the test antigen-binding molecule and the target following analysis according to (ii) as compared to (i) might support an inference that the test and reference antigen-binding molecule bind to the same or an overlapping region of the target. Suitable assays for such analysis include e.g. competition ELISA assays and epitope binning assays.

[0627] In some embodiments, the antigen-binding molecule of the present disclosure binds to gp130 in a region which is accessible to an antigen-binding molecule ( / .e., an extracellular antigen-binding molecule) when gp130 is expressed at the cell surface ( / .e. in or at the cell membrane). In some embodiments, the antigen-binding molecule binds to gp130 expressed at the cell surface of a cell expressing gp130. In some embodiments, the antigen-binding molecule binds to gp130-expressing cells (e.g. fibroblasts). In some embodiments, the antigen-binding molecule does not bind ( / .e. does not substantially bind) to cells lacking surface expression of gp130.

[0628] The ability of an antigen-binding molecule to bind to a given cell type (e.g. cells expressing gp130 and / or an angiogenic factor, or cells not expressing gp130 and / or an angiogenic factor) can be analysed by contacting cells with the antigen-binding molecule, and detecting antigen-binding molecule bound to the cells, e.g. after a washing step to remove unbound antigen-binding molecule. The ability of an antigen-binding molecule to bind to a given cell type can be analysed by methods such as flow cytometry and immunofluorescence microscopy.

[0629] In some embodiments, the antigen-binding molecule of the present disclosure inhibits signalling mediated by a receptor comprising gp130. In some embodiments, the antigen-binding molecule inhibits gp130-mediated signalling (e.g. gp130-mediated signalling as described hereinabove). Signalling mediated by gp130 and / or by receptors comprising gp130 can be analysed using cells expressing gp130 / the relevant receptor, e.g. using an assay for detecting and / or quantifying gp130-mediated signalling. Suitable assays include e.g. assays for detecting the phosphorylation / activity / expression of factors which are phosphorylated / activated / expressed as a consequence of signalling though gp130 / receptors comprising gp130.

[0630] Such assays may comprise contacting cells expressing a given cytokine receptor comprising gp130 with an antigen-binding molecule according to the present disclosure, e.g. in the presence of a ligand for the cytokine receptor. By way of illustration, an assay for investigating the ability of an antigen-binding molecule to inhibit IL-6-mediated signalling and / or the ability of an antigen-binding molecule to inhibit signalling mediated by gp130:IL-6Ra may comprise contacting cells expressing gp130:IL-6Ra complexes with an antigen-binding molecule according to the present disclosure, e.g. in the presence of IL-6. By way of further illustration, an assay for investigating the ability of an antigen-binding molecule to inhibit IL-11 -mediated signalling and / or the ability of an antigen-binding molecule to inhibit signalling mediated by gp130:l L-11Ra may comprise contacting cells expressing gp130:IL-11Ra complexes with an antigenbinding molecule according to the present disclosure, e.g. in the presence of IL-11.

[0631] For example, gp130-mediated signalling can be investigated by evaluating phosphorylation of one or more signal transduction molecules of a signal transduction pathway triggered by signalling through gp130 / cytokine receptors comprising gp130 (e.g. the JAK / STAT, MAPK / ERK or PI3K / AKT pathways). For example, the level of gp130-mediated signalling can be analysed by detection and / or quantification of the level of phosphorylation of JAK1 , JAK2, STAT1 , STAT3, STAT5 and / or ERK (e.g. STAT3 and / or ERK). By way of illustration, in the experimental examples of the present disclosure, gp130-mediated signalling (particularly gp130-mediated signalling in response to stimulation with IL-6, IL-11, OSM, LIF, CT-1 or CNTF) is analysed by evaluating phosphorylation of STAT3 or ERK1 / 2 by western blot.

[0632] The level of gp130-mediated signalling can also be evaluated by analysing one or more correlates of gp130-mediated signalling. For example, gp130-mediated signalling may be investigated by detecting and / or quantifying the expression or activity of a factor whose expression / activity is upregulated or downregulated as a consequence of gp130-mediated signalling. In some embodiments, gp130-mediated signalling may be investigated by detecting and / or quantifying the expression of a factor whose expression is upregulated as a consequence of gp130-mediated signalling, e.g. a proinflammatory / profibrotic / profibroinflammatory factor. By way of illustration, in the experimental examples of the present disclosure, gp130-mediated signalling is analysed by evaluating the expression of aSMA and MMP2.The level of gp130-mediated signalling can also be analysed using reporter-based methods. For example, gp130-mediated signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by gp130-mediated signalling. By way of illustration, in the experimental examples of the present disclosure, gp130-mediated signalling is investigated using a HEK293 reporter cell line comprising a luciferase gene under the control of STAT3 response elements (STAT3 Reporter (Luc)-HEK293 cell line (puromycin), BPS Bioscience).

[0633] In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130 and / or signalling by a receptor comprising gp130 to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence signalling mediated by gp130 and / or signalling by a receptor comprising gp130).

[0634] In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-11 -mediated signalling. In some embodiments, the antigen-binding molecule inhibits OSM-mediated signalling. In some embodiments, the antigen-binding molecule inhibits LIF-mediated signalling. In some embodiments, the antigen-binding molecule inhibits CNTF-mediated signalling. In some embodiments, the antigen-binding molecule inhibits CT-1 -mediated signalling. In some embodiments, the antigen-binding molecule inhibits CLC-mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-27-mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-35-mediated signalling.

[0635] In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling and inhibits IL-11 -mediated signalling and inhibits OSM-mediated signalling and inhibits LIF-mediated signalling and inhibits CNTF-mediated signalling and inhibits CT-1 -mediated signalling.

[0636] In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling and inhibits IL-11 -mediated signalling and inhibits OSM-mediated signalling and inhibits LIF-mediated signalling and inhibits CNTF-mediated signalling and inhibits CT-1 -mediated signalling and inhibits CLC-mediated signalling and inhibits IL-27-mediated signalling and inhibits IL-35-mediated signalling.

[0637] In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-11Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:OSMRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:LIFRp:CNTFRa. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-27Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-12Rp2.In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra and inhibits signalling mediated by gp130:IL-11Ra and inhibits signalling mediated by gp130:OSMRp and inhibits signalling mediated by gp130:LIFRp and inhibits signalling mediated by gp130:LIFRp:CNTFRa.

[0638] In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra and inhibits signalling mediated by gp130:IL-11Ra and inhibits signalling mediated by gp130:OSMRp and inhibits signalling mediated by gp130:LIFRp and inhibits signalling mediated by gp130:LIFRp:CNTFRa and inhibits signalling mediated by gp130:IL-27Ra and inhibits signalling mediated by gp130:IL-12Rp2.

[0639] In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra. In some embodiments, the antigenbinding molecule inhibits signalling mediated by binding of OSM to cells expressing gp130:OSMRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of OSM to cells expressing gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of LIF to cells expressing gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2.

[0640] In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra and inhibits signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra and inhibits signalling mediated by binding of OSM to cells expressing gp130:OSMRp and inhibits signalling mediated by binding of OSM to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of LIF to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa.

[0641] In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra and inhibits signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra and inhibits signalling mediated by binding of OSM to cells expressing gp130:OSMRp and inhibits signalling mediated by binding of OSM to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of LIF to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa and inhibits signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa and inhibits signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra and inhibits signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2.In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra). In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0642] In some embodiments, the antigen-binding molecule inhibits IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra). In some embodiments, the antigen-binding molecule inhibits IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM,<12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigenbinding molecule to inhibit such signalling.

[0643] In some embodiments, the antigen-binding molecule inhibits OSM-mediated signalling / sig nailing mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by

[0644] gp130:LI FRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp). In some embodiments, the antigenbinding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by

[0645] gp130:LI FRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp). In some embodiments, the antigenbinding molecule inhibits OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigenbinding molecule to inhibit such signalling.

[0646] In some embodiments, the antigen-binding molecule inhibits LIF-mediated signalling / signalling mediated by gp130:LI FR / signalling mediated by binding of LIF to cells expressing gp130:LIFRp to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence LIF-mediated signalling / signallingmediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or<1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0647] In some embodiments, the antigen-binding molecule inhibits CT-1 -mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence CT-1-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the CT-1-mediated signalling / signalling mediated by gp130:LI FRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence CT-1-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits CT-1 -mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0648] In some embodiments, the antigen-binding molecule inhibits CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times,<0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0649] In some embodiments, the antigen-binding molecule inhibits CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM,<300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0650] In some embodiments, the antigen-binding molecule inhibits IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra). In some embodiments, the antigen-binding molecule inhibits IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigenbinding molecule to inhibit such signalling.

[0651] In some embodiments, the antigen-binding molecule inhibits IL-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-35-mediated signalling / signalling mediated by gp130:l L-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2). In some embodiments, the antigen-binding molecule inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2). In some embodiments, the antigen-binding molecule inhibits IL-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 with an IC50 of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0652] In some embodiments, the antigen-binding molecule: (i) inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra); (ii) inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-11 -mediated signalling / signalling mediated by gp130:IL-11Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-11 -mediated signalling / signalling mediated by gp130:IL- 11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:l L-11Ra); (iii) inhibits more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence OSM-mediated signallin...

Claims

Claims:

1. An antigen-binding molecule that binds to gp130, comprising (i) a gp130-binding moiety, and (ii) an antagonist of an angiogenic factor.

2. The antigen-binding molecule according to claim 1, wherein the gp130-binding moiety inhibits IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1 -mediated signalling, and LIF-mediated signalling.

3. The antigen-binding molecule according to claim 1 or claim 2, wherein the gp130-binding moiety contacts the region ofgp130 shown in SEQ ID NO:89.

4. The antigen-binding molecule according to any one of claims 1 to 3, wherein the gp130-binding moiety comprises:(a) (i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:2HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10LC-CDR2 having the amino acid sequence of SEQ ID NO:11LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or(b)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:2HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-CDR3 having the amino acid sequence of SEQ ID NO:185; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10LC-CDR2 having the amino acid sequence of SEQ ID NO:192LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or(c)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:2HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-CDR3 having the amino acid sequence of SEQ ID NO:185; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10LC-CDR2 having the amino acid sequence of SEQ ID NO:11LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or(d)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:2HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10LC-CDR2 having the amino acid sequence of SEQ ID NO:192LC-CDR3 having the amino acid sequence of SEQ ID NO:12.

5. The antigen-binding molecule according to any one of claims 1 to 4, wherein the gp130-binding moiety comprises:(i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 68, 71, 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, and(ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 68, 71, 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C,wherein the VH and VL sequences are selected from the same row of Table C.

6. The antigen-binding molecule according to any one of claims 1 to 3, wherein the gp130-binding moiety comprises:(a)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NO:218; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(b)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NQ:204; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(c)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NO:20; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(d)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NO:195; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(e)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NO:214; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(f)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NO:215; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28.

7. The antigen-binding molecule according to any one of claims 1 to 3 or 6, wherein the gp130-binding moiety comprises:(i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 89, 90, 80-88, 74-79 or 2 of Table C, and(ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 89, 90, 80-88, 74-79 or 2 of Table C,wherein the VH and VL sequences are selected from the same row of Table C.

8. The antigen-binding molecule according to any one of claims 1 to 7, wherein the angiogenic factor is selected from vascular endothelial growth factor (VEGF), a fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).

9. The antigen-binding molecule according to any one of claims 1 to 8, wherein the angiogenic factor is VEGF.

10. The antigen-binding molecule according to any one of claims 1 to 9, wherein the antagonist of an angiogenic factor is selected from: a VEGF decoy receptor, an antigen-binding moiety that binds to VEGF, and an antigen-binding moiety that binds to a VEGF receptor.

11. The antigen-binding molecule according to any one of claims 1 to 10, wherein the antigen-binding molecule is a bispecific antigen-binding molecule.

12. The antigen-binding molecule according to any one of claims 1 to 11 , wherein the antagonist of an angiogenic factor is an antigen-binding moiety that binds to VEGF, or an antigen-binding moiety that binds to a VEGF receptor.

13. The antigen-binding molecule according to any one of claims 1 to 12, wherein the antagonist of an angiogenic factor comprises:(a)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:266HC-CDR2 having the amino acid sequence of SEQ ID NO:267HC-CDR3 having the amino acid sequence of SEQ ID NO:268; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:270LC-CDR2 having the amino acid sequence of SEQ ID NO:271LC-CDR3 having the amino acid sequence of SEQ ID NO:272; or(b)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:274HC-CDR2 having the amino acid sequence of SEQ ID NO:275HC-CDR3 having the amino acid sequence of SEQ ID NO:276; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:278LC-CDR2 having the amino acid sequence of SEQ ID NO:192LC-CDR3 having the amino acid sequence of SEQ ID NO:279; or(c)(i) a heavy chain variable (VH) region incorporating the following CDRs:217HC-CDR1 having the amino acid sequence of SEQ ID NO:281HC-CDR2 having the amino acid sequence of SEQ ID NO:282HC-CDR3 having the amino acid sequence of SEQ ID NO:283; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:285LC-CDR2 having the amino acid sequence of SEQ ID NO:286LC-CDR3 having the amino acid sequence of SEQ ID NO:287; or(d)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:385HC-CDR2 having the amino acid sequence of SEQ ID NO:267HC-CDR3 having the amino acid sequence of SEQ ID NO:386; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:270LC-CDR2 having the amino acid sequence of SEQ ID NO:271LC-CDR3 having the amino acid sequence of SEQ ID NO:272.

14. The antigen-binding molecule according to any one of claims 1 to 11 , wherein the antagonist of an angiogenic factor is a decoy receptor.

15. The antigen-binding molecule according to claim 14, wherein the antagonist of an angiogenic factor is aflibercept.

16. The antigen-binding molecule according to claim 14 or claim 15, wherein the antagonist of an angiogenic factor comprises or consists of SEQ ID NO:296 or 297.

17. A nucleic acid, or a plurality of nucleic acids, encoding an antigen-binding molecule according to any one of claims 1 to 16.

18. An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 17.

19. A cell comprising an antigen-binding molecule according to any one of claims 1 to 16, a nucleic acid or a plurality of nucleic acids according to claim 17, or an expression vector or a plurality of expression vectors according to claim 18.

20. A method comprising culturing a cell according to claim 19 under conditions suitable for expression of an antigen-binding molecule by the cell.

21. A composition comprising an antigen-binding molecule according to any one of claims 1 to 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of218expression vectors according to claim 18, or a cell according to claim 19, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

22. An antigen-binding molecule according to any one of claims 1 to 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, a cell according to claim 19, or a composition according to claim 21, for use in a method of medical treatment or prophylaxis.

23. An antigen-binding molecule according to any one of claims 1 to 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, a cell according to claim 19, or a composition according to claim 21, for use in a method of treating or preventing fibrosis, a disease / condition characterised by fibrosis, pathological angiogenesis, a disease / condition characterised by angiogenesis, pathological inflammation and / or a disease / condition characterised by inflammation.

24. Use of an antigen-binding molecule according to any one of claims 1 to 16, a nucleic acid ora plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, a cell according to claim 19, or a composition according to claim 21, in the manufacture of a medicament for use in a method of treating or preventing fibrosis, a disease / condition characterised by fibrosis, pathological angiogenesis, a disease / condition characterised by angiogenesis, pathological inflammation and / or a disease / condition characterised by inflammation.

25. A method of treating or preventing fibrosis, a disease / condition characterised by fibrosis, pathological angiogenesis, a disease / condition characterised by angiogenesis, pathological inflammation and / or a disease / condition characterised by inflammation comprising administering to a subject a therapeutically-or prophylactically-effective amount of an antigen-binding molecule according to any one of claims 1 to 16, a nucleic acid or a plurality of nucleic acids according to claim 17, an expression vector or a plurality of expression vectors according to claim 18, a cell according to claim 19, or a composition according to claim 21.

26. The antigen-binding molecule, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell, or composition for use according to claim 23, the use according to claim 24, or the method according to claim 25, wherein the fibrosis, disease / condition characterised by fibrosis, pathological angiogenesis, disease / condition characterised by angiogenesis, pathological inflammation and / or disease / condition characterised by inflammation, affects tissue of the eye.

27. The antigen-binding molecule, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell, or composition for use according to claim 23 or claim 26, the use according to claim 24 or claim 26, or the method according to claim 25 or claim 26, wherein the fibrosis, disease / condition characterised by fibrosis, pathological angiogenesis, disease / condition characterised by angiogenesis, pathological inflammation and / or disease / condition characterised by inflammation is219selected from: choroidal neovascularization, retinal fibrosis, epiretinal fibrosis, idiopathic pre-macular fibrosis, retinal detachment, macular degeneration, subretinal fibrosis associated with wet age-related macular degeneration, diabetic retinopathy, glaucoma, geographic atrophy, corneal fibrosis, post-surgical fibrosis, post-surgical fibrosis of the posterior capsule following cataract surgery, post-surgical fibrosis of the bleb following trabeculectomy for glaucoma, conjunctival fibrosis, subconjunctival fibrosis, proliferative retinal vasculopathy, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, autoimmune uveitis, infectious uveitis, Bechet’s disease, cataracts, keratic precipitates, conjunctival ulcers, corneal immune ring opacities, post-surgical inflammation, dry eye disease, retinitis pigmentosa, glaucoma, toxic anterior segment syndrome (TASS), Eales’ disease, diabetic retinopathy, retinal dystrophy (e.g. retinitis pigmentosa) and Sjogrens syndrome.

28. The antigen-binding molecule, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell, or composition for use according to any one of claims 23, 26 or 27, the use according to any one of claims 24, 26 or 27, or the method according to any one of claims 25, 26 or 27, wherein the fibrosis, disease / condition characterised by fibrosis, pathological angiogenesis, disease / condition characterised by angiogenesis, pathological inflammation and / or disease / condition characterised by inflammation is selected from: choroidal neovascularization, retinal fibrosis, epiretinal fibrosis, subretinal fibrosis, dacryoadenitis, uveitis, autoimmune uveitis, infectious uveitis, Bechet’s disease, and dry eye disease.

29. An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 16 bound to gp130 and / or an angiogenic factor.

30. A method for detecting gp130 and / or an angiogenic factor in a sample, comprising contacting a sample containing, or suspected to contain, gp130 and / or an angiogenic factor with an antigen-binding molecule according to any one of claims 1 to 16, and detecting the formation of a complex of the antigenbinding molecule with gp130 and / or an angiogenic factor.

31. Use of an antigen-binding molecule according to any one of claims 1 to 16 as an in vitro or in vivo diagnostic or prognostic agent.220

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