Il-13 antigen binding proteins

Abstract

The present disclosure relates to antigen binding proteins that bind to one or more cytokines. In particular, the present disclosure provides interleukin 13 (IL-13) binding proteins as well as multispecific antigen binding proteins comprising an IL-13 binding domain. The present disclosure further relates to the use of said binding proteins in medicine.

Description

[0001] 70541FF

[0002] ANTIGEN BINDING PROTEINS

[0003] SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0004] This application contains a sequence listing, which is provided in XML format with a file name “70541FF.xml”. The XML file has a size of about 102,778 bytes and was created on or about 17thNovember 2025. The sequence listing submitted electronically is part of the specification and is incorporated herein by reference in its entirety.

[0005] FIELD OF THE INVENTION

[0006] The present disclosure relates to antigen binding proteins. In particular, the present disclosure relates to interleukin 13 (IL- 13) binding proteins as well as multispecific antigen binding proteins that comprise an IL- 13 binding domain. The present disclosure further relates to the use of said antigen binding proteins in medicine.

[0007] BACKGROUND TO THE INVENTION

[0008] Atopic dermatitis (AD) is a heterogeneous chronic relapsing inflammatory skin disorder caused by skin barrier dysfunction and dysregulation of the immune response. Clinically, AD is characterized by xerosis, erythematous crusting rash, lichenification, an impaired skin barrier, and intense pruritus (Bieber T., N Engl J Med 2008;358: 1483-94) but is also often associated with other inflammatory disorders such as allergic rhinitis and asthma. Patients with AD have a high disease burden, and their quality of life is significantly impacted leading to high socioeconomic burden. Patients with moderate to severe AD have a higher prevalence of social dysfunction and sleep impairment, which is related to severity of disease (Williams H, et al., J Allergy Clin Immunol 2008; 121 :947-54.el5).

[0009] Typical treatments for AD include topical lotions and moisturizers, topical corticosteroid ointments, creams or injections. Most treatment options, however, offer only temporary, incomplete, symptom relief. Moreover, many patients become resistant to treatment by topical corticosteroids or by calcineurin inhibitors. More recently, systemically administered biologic therapies have extended treatment options for patients with moderate to severe AD. However, significant residual unmet need remains owing to the fact that most patients fail to achieve prolonged remission with therapies with a safe side-effect profile (Trzeciak et al. Front Med (Lausanne). 2024 Jun 19, PMID: 38962737). There remains a need for effective therapies for AD.

[0010] SUMMARY OF THE INVENTION

[0011] The present disclosure provides IL- 13 binding proteins that bind to IL- 13 with high affinity, as well as multispecific antigen binding proteins that bind to both IL- 13 and IL- 18 with high affinity. 70541FF

[0012] The inventors surprisingly discovered that said IL- 13 binding proteins (or multispecific antigen binding proteins, notably bispecific antibodies, comprising the variable domains of said IL- 13 binding proteins) had significantly improved potency for inhibiting IL- 13 induced upregulation of vascular cell adhesion molecule 1 (VCAM-1) compared to Tralokinumab. VCAM-1 is a membrane protein which mediates adhesion of different immune cells (e.g. lymphocytes, monocytes, eosinophils and basophils) to endothelial cells and has been shown to be upregulated in patients with AD (Jung et al Allergy. 1996 Jul;51(7):452-60 and Chun et al British Journal of Dermatology. 1997 Jan; 136(1): pg 136).

[0013] In a first aspect there is provided an IL- 13 binding protein comprising the following 6 CDRs : a) CDRH 1 of SEQ ID NO : 3 ; CDRH2 of SEQ ID NO : 4 and CDRH3 of SEQ ID NO : 5 ; and CDRL1 of SEQ ID NO: 8; CDRL2 of SEQ ID NO: 9; and CDRL3 of SEQ ID NO: 10; b) CDRH 1 of SEQ ID NO: 13; CDRH2 of SEQ ID NO: 14 and CDRH3 of SEQ ID NO: 15; and CDRL1 of SEQ ID NO: 18; CDRL2 of SEQ ID NO: 19; and CDRL3 of SEQ ID NO: 20; or c) CDRH1 of SEQ ID NO: 23; CDRH2 of SEQ ID NO: 24 and CDRH3 of SEQ ID NO: 25; and CDRL1 of SEQ ID NO: 28; CDRL2 of SEQ ID NO: 29; and CDRL3 of SEQ ID NO: 30.

[0014] In a further aspect there is provided a multispecific antigen binding protein comprising the IL- 13 binding protein of the disclosure, optionally wherein said multispecific antigen binding protein is a bispecific antibody. In a particular embodiment, said multispecific antigen binding protein further comprises an IL- 18 binding domain, optionally wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36.

[0015] In a further aspect there is provided a multispecific antigen binding protein comprising an interleukin 18 (IL- 18) binding domain and an interleukin 13 (IL- 13) binding domain. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0016] In a further aspect there is provided an anti-IL-18 and anti-IL-13 bispecific antibody comprising anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33 , CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. 70541FF

[0017] In a further aspect there is provided a nucleic acid sequence encoding the IL- 13 binding protein, the multispecific antigen binding protein or the bispecific antibody of the disclosure. Further provided is a nucleic acid sequence encoding any one, two, three or all four of the following amino acid sequences: a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98.

[0018] In a further aspect there is provided an expression vector comprising the nucleic acid sequence(s) of the disclosure. In a further aspect there is provided a recombinant host cell comprising the nucleic acid sequence(s) or the expression vector(s) of the disclosure.

[0019] In a further aspect there is provided a method for the production of an IL- 13 binding protein, a multispecific antigen binding protein or a bispecific antibody said method comprising culturing the recombinant host cells of the disclosure under conditions suitable for expression of said nucleic acid sequence(s) or vector(s), whereby said IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody is produced. IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibodies produced by said method are further provided.

[0020] In a further aspect there is provided a cell line engineered to express the IL- 13 binding proteins, the multispecific antigen binding proteins or the bispecific antibodies of the disclosure.

[0021] In a further aspect there is provided a pharmaceutical composition comprising the IL- 13 binding proteins, the multispecific antigen binding proteins or the bispecific antibodies of the disclosure in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0022] In a further aspect there is provided a method for the prevention or treatment of a disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the IL- 13 binding proteins, the multispecific antigen binding proteins or the bispecific antibodies or the pharmaceutical compositions of the disclosure. In an embodiment the disease is an immunoinflammatory disease such as atopic dermatitis.

[0023] DESCRIPTION OF FIGURES

[0024] FIG 1.: Neutralization of human IL-13 induced VCAM-1 upregulation by TPP-16674 (black squares), Tralokinumab (grey triangles) and anti-IL-13 control 3 (grey circles) in HUVEC cells (n=2).

[0025] FIG 2.: TPP-16674 (aIL-13xIL-18 Het-mAb) and anti-IL-13 control restore Filaggrin (FLG) gene expression in differentiated neonatal primary human epidermal keratinocytes (neo- NHEK) following IL- 13 and / or IL- 18 treatment. The differentiated primary neo-NHEK were stimulated with IL- 13 and IL- 18 in the absence or presence of TPP-16674, anti-IL-13 control, anti- IL-18 control or anti-RSV control antibodies for 120hrs, prior to gene expression analysis by RT- qPCR. The sample from differentiated neo-NHEK cultured without cytokines or antibody (referred to as Media) was used as the control sample for calculating fold change in gene expression. All 70541FF samples were normalised to housekeeping genes (HRPT1 and UBC). Data corresponds n=5 donors and error = SEM. *p<0.05, **p< 0.01, ***p<0.001.

[0026] FIG 3.: TPP- 16674 and anti-IL-13 control restore Loricrin (LOR) gene expression in differentiated neonatal primary human epidermal keratinocytes (neo-NHEK) following IL- 13 and IL- 18 treatment. Differentiated primary neo-NHEK were stimulated with 406pM IL- 13 and 406pM IL-18 in absence or presence of 30 nM TPP-16674, 30 nM anti-IL-13 control, 30 nM anti- IL-18 control or 30 nM anti-RSV control antibodies for 120 hrs, prior to gene expression analysis by RT-qPCR. The sample from differentiated neo-NHEK cultured without cytokines or antibody (referred to as Media) and was used as the control sample for calculating fold change in gene expression. All samples were normalised to housekeeping genes (HRPT1 and UBC). Data corresponds n=5 donors and error = SEM. Statistical significance represents as *p<0.05, **p< 0.01, ***p<0.001.

[0027] FIG 4.: Impact of anti-IL-13 control (anti-IL-13), anti-IL-18 control (anti-IL-18), and TPP- 16674 (Het-mAb) on IFNy (INFg), GM-CSF, IL-22, CCL17 (TARC) and CCL22 (MDC) secretion from IL-13 and IL-18 stimulated CD4+ T cells. Samples where CD4+ T cells were stimulated with cytokine but no antibody correspond to the maximum response. The percentage change in cytokine secretion from the maximum response (% change from Ctrl) was calculated and is represented as a heatmap.

[0028] FIG 5.: Dose-dependent inhibition by TPP-16674, anti-IL-18 control, anti-IL-13 control, and anti-RSV control of IFNy (IFNg), CCL17 (TARC), IL-22, and CCL22 (MDC) secretions from IL- 13 and IL- 18 stimulated CD4+ T cells. Cytokine concentrations (% response) were normalised to the geometric mean of the maximum response where CD4+ T cells were stimulated with cytokines but no antibody. Four-parameter logistic curves with a sigmoidal dose response relationship were fit to the data. All dots represent the mean and standard error of mean (SEM) from 11 donors.

[0029] FIG 6.: The final peptide coverage map of cleaved IL- 13 following processing and curation of HDX-MS data. The horizontal bars indicate the location and length of the individual peptides that were used in the evaluation of this experiment. Residues G35 to N146 use the numbering scheme from entry P35225 in the Uniprot sequence database. Two residues (asterisked) at the N-terminus are non-canonical residues present from a cleaved protein tag.

[0030] FIG 7.: Volcano plot of HDX protection across all timepoints of IL13-TPP-16674-IL18 complex compared to apo IL13. Horizontal error bars indicate the spread of differential deuterium uptake across replicates. Significant protection effects are indicated in the dashed box. Certain data points are selected to represent the IL- 13 protein sequence in which protection effects were observed.

[0031] FIG 8.: HDX protection patterns plotted along the IL- 13 primary sequence (Uniprot code: P35225). IL-13 regions that are significantly protected in complex with TPP-16674 and IL-18 as 70541FF indicated by the HDX data are underlined in black. Data from overlapping peptides (Fig. 6) was used to resolve the positions of significant protection patterns where available.

[0032] FIG 9.: HDX protection patterns plotted onto a crystal structure of the IL13-IL4R- IL13Ral ternary complex (PDB code: 3BPO).

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0035] “Affinity”, also referred to as “binding affinity”, as used herein is the strength of binding at a single interaction site, i.e., of one molecule, e.g., a binding domain (such as an IL-18 or IL-13 binding domain or an IL-18 or IL-13 binding protein), to another molecule, e.g., its target antigen, at a single binding site. Binding affinity may be determined by equilibrium methods (e.g., enzyme- linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g., surface plasmon resonance analysis using a BIACORE instrument or equivalent).

[0036] The term “antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136). The term, full, whole or intact antibody, used interchangeably herein, refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons. An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment. The Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CHI (heavy) and CL (light). The Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding Clq, the first component of the classical complement pathway. The five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, a and 5 respectively, each heavy chain can pair with either a K or / , light chain. The majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (IgGl, IgG2, IgG3 and IgG4), the sequences of which differ mainly in their hinge region. 70541FF

[0037] The term “antigen binding protein” refers to antibodies and other protein constructs, such as domains, that are capable of binding to said antigen(s). This does not include the natural cognate ligand or receptor. The term “multispecific antigen binding protein” refers to antibodies and other protein constructs that bind two or more different epitopes (for example, two, three, four or more different epitopes). As used herein, the term “multispecific antigen binding protein” refers to antibodies and other protein constructs that are capable of binding to and neutralizing at least two antigens (for example IL-18 and IL-13). Accordingly, “IL-18 and IL-13 binding protein” and “multispecific antigen binding protein” may be used interchangeably herein. An example of a multispecific antibody is a “bispecific antibody” which binds two different epitopes.

[0038] As used herein, a “bispecific antibody” is an antibody capable of binding to, and neutralizing, two antigens: IL- 18 and IL-13. Accordingly, “anti-IL-18 and anti-IL-13 bispecific antibody” and “bispecific antibody” are used interchangeably herein.

[0039] The term “derived” is intended to define not only the source in the sense of it being the physical origin for the material but also to define material, which is structurally identical to the material, but which does not originate from the reference source.

[0040] The term “domain” refers to a folded polypeptide structure which retains its tertiary structure independent of the rest of the polypeptide. Generally, domains are responsible for discrete functional properties of polypeptides and in many cases may be added, removed, or transferred to other polypeptides without loss of function of the remainder of the protein and / or of the domain.

[0041] The term “Effector Function” as used herein refers to one or more of antibody-mediated effects including but not limited to antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated complement activation including complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated phagocytosis (CDCP), antibody dependent complement- mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP). The interaction between the Fc region of an antigen binding protein comprising an Fc region, such as an antibody, and various Fc receptors (FcR), including FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), FcRn, Clq, and type II Fc receptors can mediate the effector functions of the antigen binding protein. Significant biological effects can be a consequence of effector functionality. An antigen binding protein can mediate one of, a plurality of, or each effector function. Effector function can be assessed in a number of ways including, for example, evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcyRIII, or monocytes / macrophages via FcyRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via Clq. For example, an antigen binding protein of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay. Examples of such assays can be found in Shields et al, 2001, The Journal of Biological Chemistry, Vol. 276, p. 6591-6604; Chappel et al, 1993, The Journal of Biological Chemistry, Vol 268, p. 25124-25131; Lazar et al, 2006, PNAS, 103; 4005-4010. Examples of 70541FF assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38. The effects of mutations on effector functions (e.g., FcRn binding, FcyRs and Clq binding, CDC, ADCML, ADCC, ADCP) can be assessed, e.g., as described in Grevys et al., J Immunol. 2015 Jun 1; 194(11): 5497-5508, or Tam et al., Antibodies 2017, 6(3); Monnet et al., 2014 mAbs, 6:2, 422- 436.

[0042] The term "epitope" as used herein refers to that portion of the antigen (i.e., IL-18 or IL-13) that makes contact with a particular binding domain of a binding protein provided herein (i.e., a paratope). An epitope may be linear, conformational, or discontinuous. A conformational or discontinuous epitope comprises amino acid residues that are separated, for example, by one or more other amino acids, i.e., not in a continuous sequence in the antigen's primary sequence when assembled by tertiary folding of the polypeptide chain. Although the residues may be from different regions of the polypeptide chain, they can be in close proximity in the three-dimensional structure of the antigen (i.e., IL-13 or IL-18). Particular residues comprised within an epitope can be determined via a computer modelling program or via one or more three-dimensional structures obtained through a structural method such as X-ray crystallography. An epitope can be determined using epitope mapping, such as by one or more techniques, for example, peptide-based approaches such as pepscan, whereby a series of overlapping peptides can be screened for binding using one or more techniques such as ELISA or by in vitro display of large libraries of peptides or protein mutants, e.g., on phage. Detailed epitope information can be determined by structural techniques, for example, X-ray crystallography, solution nuclear magnetic resonance (NMR) spectroscopy, and cryogenic-electron microscopy (cryo-EM). Another method is hydrogen / deuterium exchange (HDX) combined with proteolysis and liquid-chromatography mass spectrometry (LC-MS) analysis to characterize discontinuous or conformational epitopes.

[0043] “Half-life” or “t' / z” refers to the time required for the serum concentration of an antigen binding protein to reach half of its original value. The serum half-life of proteins can be measured by pharmacokinetic studies according to the method described by Kim et al., 1994, Eur. J. of Immuno. 24: 542-548. According to this method, radio-labelled protein is injected intravenously into mice and its plasma concentration is periodically measured as a function of time, for example, at about 3 minutes to about 72 hours after the injection. Other methods for pharmacokinetic analysis and determination of the half-life of a molecule will be familiar to those skilled in the art.

[0044] A “Het mAb” is an IgG-like molecule that targets two different epitopes, either on the same or different targets. A “Het mAb” is an example of a bispecific antibody. As used herein, a “Het mAb” binds to two different targets: IL- 18 and IL-13. A Het mAb has four distinct chains: two non-identical heavy chains and two non-identical light chains. These chains contain a set of mutations in the Fc portion of the molecule that drive heavy chain dimerization and a set of mutations on the Fab portion that drive correct heavy / light chain pairing, e.g., kappa / kappa or lambda / kappa subtype bispecific mAbs. Suitable mutations for driving heavy chain dimerization 70541FF are disclosed in WO2012 / 058768 and W02013 / 063702. Suitable mutations for driving HC / LC pairing are disclosed in WO2014 / 082179, WO2015 / 181805, and WO2017 / 059551.

[0045] As used herein the term “immunoinflammatory disease” or “immunoinflammatory disorder” encompasses a variety of conditions, including autoimmune diseases. Immunoinflammatory diseases are characterized by dysregulation of the immune system more particularly by inappropriate activation of the immune response which damages the body's own tissues.

[0046] “Interleukin 18 (IL- 18)” is a proinflammatory, context-dependent cytokine involved in epithelial barrier repair, polarized T-helper 1 (Thl) and Th2 cell and natural killer (NK) cell immune responses. The sequence of human IL-18 is set out in SEQ ID NO: 101 (see also UniProt #Q14116). Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. IL- 18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity.

[0047] “IL- 18 binding domain” or “domain that binds to IL- 18” as used herein refers to a domain capable of binding to and neutralizing IL-18.

[0048] “Interleukin- 13 (IL- 13)” is a pleiotropic cytokine produced by Th2 cells and ILC2 but also by mast cells, basophils, eosinophils, NK cells, macrophages, monocytes and dendritic cells. Free IL-13 binds to the al subunit of the IL-13 receptor (IL-13Ral) which in turn favors the recruitment of IL-4Ra which induces (by dimerization) the formation of a signal transducer that actives JAK1 and TYK2 and a downstream signaling cascade that leads to Th2 differentiation and classswitching to IgE.

[0049] “IL- 13 binding domain” “or domain that binds IL- 13” as used herein refers to a domain capable of binding to and neutralizing IL-13.

[0050] The term “neutralizes” as used herein means that the biological activity of a particular target is reduced in the presence of a binding molecule that binds to said target. In terms of the present disclosure therefore, neutralizes may mean that the biological activity of IL- 13 is reduced in the presence of an IL- 13 binding protein or IL- 13 binding domain as described herein in comparison to the activity of IL- 13 in the absence of the IL- 13 binding protein or IL- 13 binding domain, in vitro or in vivo; or that the biological activity of IL- 18 is reduced in the presence of an IL- 18 binding domain as described herein in comparison to the activity of IL- 18 in the absence of the IL- 18 binding domain, in vitro or in vivo, as appropriate. In both cases, neutralization may be due to one or more of blocking the target (e.g., IL-18 and / or IL-13) binding to its receptor(s), preventing the target (e.g., IL- 18 and / or IL- 13) from activating its receptor, down-regulating the target (e.g., IL-18 and / or IL-13) or its receptor, or affecting effector functionality. The reduction or inhibition in biological activity may be partial or total. 70541FF

[0051] “Percent identity” or “% identity” between a query sequence and a subject sequence is the “Identities” value, expressed as a percentage, that is calculated using a suitable algorithm or software, such as BLASTP, FASTA, DNASTAR Lasergene, GeneDoc, Bioedit, EMBOSS needle or EMBOSS infoalign, over the entire length of the query sequence after a pair-wise global sequence alignment has been performed using a suitable algorithm / software such as BLASTP, FASTA, ClustalW, MUSCLE, MAFFT, EMBOSS Needle, T-Coffee, and DNASTAR Lasergene. Importantly, a query sequence may be described by a sequence disclosed herein, e.g., an amino acid sequence identified in one or more of the claims. The query sequence may be 100% identical to the subject sequence, or it may include up to a certain integer number of amino acid or nucleotide alterations as compared to the subject sequence such that the % identity is less than 100%. For example, the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. Such alterations include at least one amino acid deletion, substitution (including conservative and non-conservative substitution), or insertion, and wherein said alterations may occur at the amino- or carboxy-terminal positions of the query sequence or anywhere between those terminal positions, interspersed either individually among the amino acids or nucleotides in the query sequence or in one or more contiguous groups within the query sequence. The % identity may be determined across the entire length of the query sequence, including the CDRs. Alternatively, the % identity may exclude one or more or all of the CDRs, for example all of the CDRs are 100% identical to the subject sequence and the % identity variation is in the remaining portion of the query sequence, e.g., the framework sequence, so that the CDR sequences are fixed and intact.

[0052] The term “therapeutically effective amount” refers to the quantity of an IL- 13 binding protein, a multispecific antigen binding protein or a bispecific antibody disclosed herein that will elicit the desired biological response in a subject. It may vary depending on the disease and its severity and the age and weight of the subject to be treated, as well as the multispecific antigen binding protein or bispecific antibody used.

[0053] The term "therapy" encompasses alleviation, reduction, or prevention of at least one aspect or symptom of a disease.

[0054] IL- 13 Binding Proteins

[0055] The disclosure provides interleukin 13 (IL- 13) binding proteins, notably wherein said IL- 13 binding proteins are antibodies that are capable of specifically binding to IL-13.

[0056] The IL- 13 binding proteins disclosed herein comprise complementarity determining region (CDR) amino acid sequences. These are the hypervariable regions of IL- 13 binding proteins disclosed herein, such as immunoglobulin heavy and light chains. Typically, there are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an IL- 13 binding protein such as an immunoglobulin. Thus, "CDRs" as used herein can refer to three heavy chain 70541FF

[0057] CDRs of an IL- 13 binding protein, three light chain CDRs of an IL- 13 binding protein, all heavy and light chain CDRs of an IL- 13 binding protein, or at least two CDRs of an IL- 13 binding protein. However, the present disclosure does foresee IL- 13 binding proteins having heavy and / or light chains with less than three CDR’s for example when it is discovered using appropriate structural methods (e.g., Cryo-EM) that a region identified as being a CDR region does not in fact bind to the antigen. Throughout this specification, amino acid residues in variable domain sequences and variable domain regions within full-length IL- 13 binding sequences, e.g., within an antibody heavy chain sequence or antibody light chain sequence, are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, and “CDRH3” used in the Examples follow the Kabat numbering convention. For further information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).

[0058] There are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. Throughout this specification, amino acid residues in Fc regions, in antibody sequences or full-length IL-13 binding protein sequences, are numbered according to the EU index numbering convention.

[0059] There are also alternative numbering conventions for CDR sequences, for example, those set out in Chothia et al. (1989) Nature 342: 877-883. The structure and protein folding of the IL-13 binding protein may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person. Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods. The CDR regions for SEQ ID NOs: 2, 12 or 22 and SEQ ID NOs: 7, 17 or 27 can be defined by any numbering convention, for example, the Kabat, Chothia, AbM, and contact conventions. Table 1 below represents one definition using each numbering convention for CDRs, or binding unit, provided herein. The Kabat numbering scheme is used in Table 1 to number the variable domain amino acid sequence. It should be noted that CDR definitions can vary depending on the individual publication used.

[0060] Table 1: CDR Numbering 70541FF

[0061] CDRs of an IL- 13 binding protein provided herein can be modified by one or by more than one amino acid substitution, deletion, or addition, wherein the variant IL- 13 binding protein substantially retains the biological characteristics of the unmodified protein. It will be appreciated that each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, or CDRL3 may be modified alone or in combination with any other CDR, in any permutation or combination. A CDR may be modified by the substitution, deletion, or addition of up to 3 amino acids. Each modification of a CDR, VH, VL, or other protein provided herein can be a conservative substitution. A modification can be a conservative substitution, for example, as shown in Table 2a or in Table 2b below.

[0062] Table 2a: Examples of conservative substitutions by side chain type

[0063] Table 2b: Examples of conservative substitutions by amino acid For example, in a variant CDR, one or more flanking residues that comprise the CDR as part of alternative defmition(s), e.g., Kabat or Chhoti, may be substituted with a conservative amino acid 70541FF residue. Such IL-13 binding proteins comprising variant CDRs as described above may be referred to herein as “functional CDR variants”.

[0064] In a first aspect there is provided an interleukin 13 (IL-13) binding protein comprising: (i) any one or a combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 2, 12 or 22 and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 7, 17 or 27; or (ii) a CDR variant of (i), wherein the variant has 1, 2, or 3 amino acid modifications; or a VH region comprising a sequence at least 80%, at least 85%, at least 90% or at least 95% identical to the sequence of SEQ ID NO: 2, 12 or 22; and / or a VL region comprising a sequence at least 80%, at least 85%, at least 90% or at least 95% identical to the sequence of SEQ ID NO: 7, 17 or 27. In an embodiment, the CDR of (a) (i) is: a CDRH1 selected from SEQ ID NOs: 3, 13 or 23; a CDRH2 selected from SEQ ID NOs: 4, 14 or 24 ; and / or a CDRH3 selected from SEQ ID NOs: 5, 15 or 25 ; a CDRL1 selected from SEQ ID NOs: 8, 18 or 28; a CDRL2 selected from SEQ ID NOs: 9, 19 or 29; and / or CDRL3 selected from SEQ ID NOs: 10, 20 or 30. In an embodiment said IL-13 binding protein comprises: a CDRH1 that is 100% identical to SEQ ID NOs: 3, 13 or 23; a CDRH2 that is 100% identical to SEQ ID NOs: 4, 14 or 24; and / or a CDRH3 that is 100% identical to SEQ ID NOs: 5, 15 or 25; a CDRL1 that is 100% identical to SEQ ID NOs: 8, 18 or 28; a CDRL2 that is 100% identical to SEQ ID NOs: 9, 19 or 29; and / or a CDRL3 that is 100% identical to SEQ ID NOs: 10, 20 or 30. In an embodiment all six CDRs are present in the IL- 13 binding protein. In an embodiment said IL- 13 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 2, 12 or 22 and / or a VL region that is 100% identical to SEQ ID NO: 7, 17 or 27.

[0065] In a further aspect of the disclosure there is provided an IL- 13 binding protein comprising the following 6 CDRs: a) CDRH1 of SEQ ID NO: 3; CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5; and CDRL1 of SEQ ID NO: 8; CDRL2 of SEQ ID NO: 9; and CDRL3 of SEQ ID NO: 10; b) CDRHl of SEQ ID NO: 13; CDRH2 of SEQ ID NO: 14 and CDRH3 of SEQ ID NO: 15; and CDRL1 of SEQ ID NO: 18; CDRL2 of SEQ ID NO: 19; and CDRL3 of SEQ ID NO: 20; or c) CDRH1 of SEQ ID NO: 23; CDRH2 of SEQ ID NO: 24 and CDRH3 of SEQ ID NO: 25; and CDRL1 of SEQ ID NO: 28; CDRL2 of SEQ ID NO: 29; and CDRL3 of SEQ ID NO: 30. In a particular embodiment, the IL- 13 binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5; and CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0066] In an embodiment said IL- 13 binding protein comprises a) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 2 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 7; b) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 12 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 17; or c) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 22 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 27. In a particular embodiment, the IL-13 70541FF binding protein comprises a) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 2 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 7

[0067] In an embodiment said IL- 13 binding protein comprises a) a VH region that is 100% identical to SEQ ID NO: 2 and / or a VL region that is 100% identical to SEQ ID NO: 7; b) a VH region that is 100% identical to SEQ ID NO: 12 and / or a VL region that is 100% identical to SEQ ID NO: 17; or c) a VH region that is 100% identical to SEQ ID NO: 22 and / or a VL region that is 100% identical to SEQ ID NO: 27. In a particular embodiment said IL-13 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 2 and a VL region that is 100% identical to SEQ ID NO:7.

[0068] In an embodiment said IL- 13 binding protein comprises a heavy chain constant region as shown in SEQ ID NO: 99 and a light chain constant region as shown in SEQ ID NO: 100.

[0069] In an embodiment said IL- 13 binding protein comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 1 and the amino acid sequence of the light chain is shown in SEQ ID NO: 6.

[0070] There is further provided an IL- 13 binding protein that binds to human IL- 13 and competes for binding to said human IL- 13 with a reference IL- 13 binding protein, wherein said reference IL- 13 binding protein comprises a variable heavy chain sequence of SEQ ID NO: 2, 12 or 22, and a variable light chain sequence of SEQ ID NO: 7, 17 or 27. Competition between an IL-13 binding protein described herein and a reference IL- 13 binding protein, e.g., a reference antibody, may be determined by one or more techniques known to the skilled person such as ELISA, FMAT, Surface Plasmon Resonance (SPR) or FORTEBIO OCTET Bio-Layer Interferometry (BLI). Such techniques can be referred to as epitope binning. A competition assay may be carried out, for example, using flow cytometry-based epitope binning. Competition can occur, for example, when two proteins bind to the same or overlapping epitopes, when there is steric inhibition of binding, or in a case wherein binding of the first protein induces a conformational change in the antigen that can prevent or reduce binding of the second protein.

[0071] In an embodiment the IL- 13 binding proteins disclosed herein are derived from a mammal. In an embodiment, the IL- 13 binding proteins disclosed herein are human IL- 13 binding proteins.

[0072] In a particular embodiment the IL- 13 binding proteins disclosed herein may be an antibody (i.e. an anti-IL-13 antibody) or an antigen binding fragment thereof. Antibodies provided herein can be fully human antibodies, and can be obtained using a variety of methods, for example, using a library of human antibodies or fragments in conjunction with an antibody display system like phage or yeast display or immunizing transgenic animals (e.g., mice) that are capable of producing repertoires of human antibodies. In some cases, transgenic animals that have been modified to express human immunoglobulin genes can be immunised with an antigen of interest and antigen specific human antibodies can be isolated using a variety of antibody discovery techniques 70541FF including B-cell cloning, hybridoma, and repertoire sequencing. Human antibodies produced using these techniques can then be screened for desired properties such as activity, affinity, developability, and selectivity.

[0073] An antibody provided herein can be a “humanized antibody,” which refers to a type of engineered antibody having CDRs derived from a non-human donor immunoglobulin, the remaining immunoglobulin-derived parts of the molecule being derived from one or more human immunoglobulin(s). In addition, framework support residues may be altered to preserve binding affinity. A suitable human acceptor antibody may be one selected from a conventional database (e.g., the KABAT database, Los Alamos database, and Swiss Protein database), or by homology to the nucleotide and / or amino acid sequences of a donor antibody.

[0074] The IL- 13 binding proteins disclosed herein may be engineered into alternative antibody formats in which the one or more CDRs of the antigen binding protein (e.g., IL-13 binding protein) can be arranged onto a suitable non-immunoglobulin protein scaffold. “Protein Scaffold” as used herein includes but is not limited to an immunoglobulin (Ig) scaffold, for example an IgG scaffold, which may be a four chain or two chain antibody, or which may comprise only the Fc region of an antibody, or which may comprise one or more constant regions from an antibody, which constant regions may be of human or primate origin, or which may be an artificial chimera of human and primate constant regions. The protein scaffold may be an Ig scaffold, for example an IgG, or IgA scaffold. The IgG scaffold may comprise some or all the domains of an intact antibody (i.e. CHI, CH2, CH3, VH, VL). The antigen binding protein may comprise an IgG scaffold selected from IgGl, IgG2, IgG3, IgG4 or IgG4PE. For example, the scaffold may be IgGl. The scaffold may consist of, or comprise, the Fc region of an antibody, or is a part thereof. The protein scaffold may be a derivative of a scaffold selected from the group consisting of CTLA-4, lipocalin, Protein A derived molecules such as Z-domain of Protein A (Affibody, SpA), A-domain (Avimer / Maxibody); heat shock proteins such as GroEl and GroES; transferrin (trans-body); ankyrin repeat protein (DARPin); peptide aptamer; C-type lectin domain (Tetranectin); human y-crystallin and human ubiquitin (affilins); PDZ domains; scorpion toxin kunitz type domains of human protease inhibitors; and fibronectin / adnectin; which has been subjected to protein engineering in order to obtain binding to an antigen, such as IL-13, other than the natural ligand.

[0075] With regards to the binding of an IL- 13 binding protein to IL- 13 the terms “bind”, “specific binding”, “specifically binds to”, “selective for” (etc.) means binding that is measurably different from a non-specific or non-selective interaction (e.g. with a non-target molecule). In an embodiment, the IL- 13 binding proteins disclosed herein bind to human IL- 13 with an affinity (KD) of less than 250 pM. In an embodiment, said IL-13 binding protein binds to human IL-13 with an affinity (KD) of less than 150 pM, less than 100 pM or less than 75 pM. In an embodiment, said IL- 13 binding protein binds to human IL- 13 with an affinity (KD) of between 1 pM and 150 pM, such as between 10 pM and 100 pM, between 25 pM and 75 pM or between 40 pM and 60 70541FF pM. In an embodiment, binding affinity is measured using surface plasmon resonance (SPR) at, for example, 37°C. In a particular embodiment binding affinity is measured by SPR at 37°C. For antigen binding proteins herein (i.e., IL-13 binding proteins) a smaller KD numerical value corresponds with stronger binding to an antigen such as IL-13.

[0076] In an embodiment, the IL- 13 binding proteins disclosed herein are capable of inhibiting IL- 13- induced vascular cell adhesion molecule-1 (VCAM-1) upregulation. In an embodiment, inhibition of IL-13 induced VCAM-1 upregulation is measured in HUVEC cells. In an embodiment, said IL- 13 binding protein inhibits VCAM-1 upregulation with an IC50 of less than 200 pM. In an embodiment, said IL- 13 binding protein inhibits VCAM-1 upregulation in HUVEC cells with an IC50 of between 50 pM and 200 pM, between 100 and 180 pM or between 120 pM and 160 pM. A suitable method for determining the capacity of an IL- 13 binding protein to inhibit IL- 13 -induced VCAM-1 upregulation is provided herein, for example (but not limited to) the methodology described in Example 5a.

[0077] In an embodiment the IL- 13 binding proteins disclosed herein bind to IL- 13 and blocks IL- 13 from binding to IL- 13 Rai and IL-13Ra2. In an embodiment said IL- 13 binding protein binds to IL- 13 and inhibits the activation of the IL 13 Rai and IL-13Ra2. Thus in an embodiment there is provided an IL-13 binding protein comprising the following 6 CDRs: a) CDRH1 of SEQ ID NO: 3; CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5; and CDRL1 of SEQ ID NO: 8; CDRL2 of SEQ ID NO: 9; and CDRL3 of SEQ ID NO: 10 wherein said IL-13 binding protein blocks IL-13 from binding to IL- 13 Rai and IL-13Ra2.

[0078] In an embodiment, the IL- 13 binding proteins disclosed herein bind to an epitope comprising residues within both human IL-13 helix A and helix D. In an embodiment, said IL-13 binding protein binds to an epitope comprising one or more amino acids within residues G30 and Q57 and further comprising one or more amino acids within residues K122 to N146 wherein said numbering is in respect of the human IL-13 sequence set forth in SEQ ID NO: 102. In an embodiment said epitope comprises one or more amino acids within residues G35 and V51 and further comprises one or more amino acids within residues L134 and N146, wherein said numbering is in respect of the human IL-13 sequence set forth in SEQ ID NO: 102. In a particular embodiment said epitope further comprises one or more amino acids between residues G75 and N86, more particularly one or more amino acids between residues C78 and L81 wherein said numbering is in respect of the human IL- 13 sequence set forth in SEQ ID NO: 102. In an embodiment said epitope is a conformational epitope.

[0079] The IL- 13 binding proteins disclosed herein (or fragments thereof) may be comprised within multispecific antigen binding proteins i.e. they may provide one arm of a bispecific antibody. Thus, in a particular aspect of the disclosure there is provided a multispecific antigen binding protein comprising the IL- 13 binding protein disclosed herein and optionally wherein said multispecific antigen binding protein is a bispecific antibody. In an embodiment there is provided a 70541FF multispecific antigen binding protein comprising the IL- 13 binding protein disclosed herein and a means for binding to IL-18.

[0080] In a particular embodiment there is provided a multispecific antigen binding protein comprising the IL- 13 binding protein disclosed herein wherein said IL- 13 binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 3; CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5; and CDRL1 of SEQ ID NO: 8; CDRL2 of SEQ ID NO: 9; and CDRL3 of SEQ ID NO: 10 and a means for binding to IL-18, optionally wherein said multispecific antigen binding protein is a bispecific antibody. In a particular embodiment there is provided a multispecific antigen binding protein comprising the IL- 13 binding protein disclosed herein wherein said IL- 13 binding protein comprises a VH domain of SEQ ID NO 2 and a VL domain of SEQ ID NO: 7 and a means for binding to IL-18, optionally wherein said multispecific antigen binding protein is a bispecific antibody. Thus, said multispecific antigen binding protein is further capable of binding to human IL-18. In an embodiment the multispecific antigen binding protein further comprises an IL- 18 binding domain, optionally wherein said IL- 18 binding domain comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36.

[0081] Specific multispecific antigen binding proteins and bispecific antibodies are disclosed below.

[0082] Multispecific Antigen Binding Proteins

[0083] The present disclosure provides multispecific antigen binding proteins, in particular bispecific antibodies, that are capable of binding to interleukin 18 (IL- 18) and interleukin 13 (IL- 13).

[0084] Thus, in one aspect there is provided a multispecific antigen binding protein comprising an interleukin 18 (IL- 18) binding domain and an interleukin 13 (IL- 13) binding domain. In a particular embodiment, said multispecific antigen binding protein comprises an IL- 13 binding domain wherein said IL- 13 binding domain blocks IL- 13 from binding to IL- 13 Rai and IL-13Ra2. Thus, in an embodiment there is provided a multispecific antigen binding protein comprising an interleukin 18 (IL- 18) binding domain and an interleukin 13 (IL- 13) binding domain wherein said IL-13 binding domain blocks IL-13 from binding to IL-13Ral and IL-13Ra2. It is within the remit of the person skilled in the art to assess whether an IL- 13 binding domain is capable of inhibiting binding to neither of, one of, or both of IL- 13 Rai and IL-13Ra2 for example by using biochemical receptor-ligand interaction assays such as that described in Popovic et al lQYl (Journal of Molecular Biology, 429(2): pages 208-219 /

[0085] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain binds to human IL- 18 70541FF and said IL- 13 binding domain binds to human IL-13. In an embodiment the multispecific antigen binding proteins of the present disclosure show cross-reactivity between human IL- 18 and human IL- 13 and both IL- 18 and IL- 13 from another species such as cynomolgus macaque IL- 18 and cynomolgus macaque IL-13. This is particularly useful, since drug development typically requires testing of lead drug candidates in non-human systems before the drug is tested in humans. In an embodiment, the binding affinity of the multispecific antigen binding protein for cynomolgus macaque IL- 18 and cynomolgus macaque IL- 13 and the binding affinity for human IL- 18 and human IL- 13 differ by no more than a factor of 2, 5, 10, 50, 100 or 250.

[0086] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: a) CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36; b) CDRH 1 of SEQ ID NO : 39, CDRH2 of SEQ ID NO : 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO: 42, CDRL2 of SEQ ID NO: 43 and CDRL3 of SEQ ID NO: 44; or c) CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL 1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108.

[0087] In particular said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36.

[0088] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises the following CDRs: a. CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10; b . CDRH 1 of SEQ ID NO : 13 , CDRH2 of SEQ ID NO : 14, CDRH3 of SEQ ID NO: 15, CDRL1 of SEQ ID NO: 18, CDRL2 of SEQ ID NO: 19 and CDRL3 of SEQ ID NO: 20; c. CDRH1 of SEQ ID NO: 23, CDRH2 of SEQ ID NO: 24, CDRH3 of SEQ ID NO: 25, CDRL1 of SEQ ID NO: 28, CDRL2 of SEQ ID NO: 29 and CDRL3 of SEQ ID NO: 30; d. CDRH1 of SEQ ID NO: 47, CDRH2 of SEQ ID NO: 48, CDRH3 of SEQ ID NO: 49, CDRL1 of SEQ ID NO: 50, CDRL2 of SEQ ID NO: 51 and CDRL3 of SEQ ID NO: 52; 70541FF e . CDRH 1 of SEQ ID NO : 55 , CDRH2 of SEQ ID NO : 56, CDRH3 of SEQ ID NO: 57, CDRL1 of SEQ ID NO: 58, CDRL2 of SEQ ID NO: 59 and CDRL3 of SEQ ID NO: 60; f. CDRH 1 of SEQ ID NO : 63 , CDRH2 of SEQ ID NO : 64, CDRH3 of SEQ ID NO: 65, CDRL1 of SEQ ID NO: 66, CDRL2 of SEQ ID NO: 67 and CDRL3 of SEQ ID NO: 68; g . CDRH 1 of SEQ ID NO : 71 , CDRH2 of SEQ ID NO : 72, CDRH3 of SEQ ID NO: 73, CDRL1 of SEQ ID NO: 74, CDRL2 of SEQ ID NO: 75 and CDRL3 of SEQ ID NO: 76; h. CDRH1 of SEQ ID NO: 79, CDRH2 of SEQ ID NO: 80, CDRH3 of SEQ ID NO: 81, CDRL1 of SEQ ID NO: 82, CDRL2 of SEQ ID NO: 83 and CDRL3 of SEQ ID NO: 84; or i. CDRH 1 of SEQ ID NO: 87, CDRH2 of SEQ ID NO: 88, CDRH3 of SEQ ID NO: 89, CDRL1 of SEQ ID NO: 90, CDRL2 of SEQ ID NO: 91 and CDRL3 of SEQ ID NO: 92.

[0089] In particular said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL-13 binding domain wherein said IL-13 binding domain comprises the following CDRs: CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0090] Provided herein are multispecific antigen binding proteins comprising any combination of the above-mentioned IL- 18 binding domains and IL- 13 binding domains (each combination being provided below as follows): i. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO : 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. ii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 13, CDRH2 of SEQ ID NO: 14, CDRH3 of SEQ ID NO: 15, CDRL1 of SEQ ID NO: 18, CDRL2 of SEQ ID NO: 19 and CDRL3 of SEQ ID NO: 20. 70541FF iii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 23 , CDRH2 of SEQ ID NO : 24, CDRH3 of SEQ ID NO : 25 , CDRL 1 of SEQ ID NO: 28, CDRL2 of SEQ ID NO: 29 and CDRL3 of SEQ ID NO: 30. iv. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 47, CDRH2 of SEQ ID NO: 48, CDRH3 of SEQ ID NO: 49, CDRL1 of SEQ ID NO: 50, CDRL2 of SEQ ID NO: 51 and CDRL3 of SEQ ID NO: 52. v. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 55 , CDRH2 of SEQ ID NO : 56, CDRH3 of SEQ ID NO : 57, CDRL 1 of SEQ ID NO: 58, CDRL2 of SEQ ID NO: 59 and CDRL3 of SEQ ID NO: 60. vi. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 63 , CDRH2 of SEQ ID NO : 64, CDRH3 of SEQ ID NO : 65 , CDRL 1 of SEQ ID NO: 66, CDRL2 of SEQ ID NO: 67 and CDRL3 of SEQ ID NO: 68. vii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 71 , CDRH2 of SEQ ID NO : 72, CDRH3 of SEQ ID NO : 73 , CDRL 1 of SEQ ID NO: 74, CDRL2 of SEQ ID NO: 75 and CDRL3 of SEQ ID NO: 76. viii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the 70541FF following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 79, CDRH2 of SEQ ID NO: 80, CDRH3 of SEQ ID NO: 81, CDRL1 of SEQ ID NO: 82, CDRL2 of SEQ ID NO: 83 and CDRL3 of SEQ ID NO: 84. ix. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 87, CDRH2 of SEQ ID NO: 88, CDRH3 of SEQ ID NO: 89, CDRL1 of SEQ ID NO: 90, CDRL2 of SEQ ID NO: 91 and CDRL3 of SEQ ID NO: 92. x. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO: 41, CDRL1 of SEQ ID NO: 42, CDRL2 of SEQ ID NO: 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO : 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. xi. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 13, CDRH2 of SEQ ID NO: 14, CDRH3 of SEQ ID NO: 15, CDRL 1 of SEQ ID NO: 18, CDRL2 of SEQ ID NO: 19 and CDRL3 of SEQ ID NO: 20. xii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 23 , CDRH2 of SEQ ID NO : 24, CDRH3 of SEQ ID NO : 25 , CDRL 1 of SEQ ID NO: 28, CDRL2 of SEQ ID NO: 29 and CDRL3 of SEQ ID NO: 30. xiii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ 70541FF

[0091] ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 47, CDRH2 of SEQ ID NO: 48, CDRH3 of SEQ ID NO: 49, CDRL1 of SEQ ID NO: 50, CDRL2 of SEQ ID NO: 51 and CDRL3 of SEQ ID NO: 52. xiv. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 55 , CDRH2 of SEQ ID NO : 56, CDRH3 of SEQ ID NO : 57, CDRL 1 of SEQ ID NO: 58, CDRL2 of SEQ ID NO: 59 and CDRL3 of SEQ ID NO: 60. xv. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 63 , CDRH2 of SEQ ID NO : 64, CDRH3 of SEQ ID NO : 65 , CDRL 1 of SEQ ID NO: 66, CDRL2 of SEQ ID NO: 67 and CDRL3 of SEQ ID NO: 68. xvi. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO : 71 , CDRH2 of SEQ ID NO : 72, CDRH3 of SEQ ID NO : 73 , CDRL 1 of SEQ ID NO: 74, CDRL2 of SEQ ID NO: 75 and CDRL3 of SEQ ID NO: 76. xvii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 79, CDRH2 of SEQ ID NO: 80, CDRH3 of SEQ ID NO: 81, CDRL1 of SEQ ID NO: 82, CDRL2 of SEQ ID NO: 83 and CDRL3 of SEQ ID NO: 84. xviii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO : 41 , CDRL 1 of SEQ ID NO : 42, CDRL2 of SEQ ID NO : 43 and CDRL3 of SEQ ID NO: 44 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ 70541FF

[0092] ID NO: 87, CDRH2 of SEQ ID NO: 88, CDRH3 of SEQ ID NO: 89, CDRL1 of SEQ ID NO : 90, CDRL2 of SEQ ID NO : 91 and CDRL3 of SEQ ID NO : 92. xix. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. xx. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 13, CDRH2 of SEQ ID NO: 14, CDRH3 of SEQ ID NO: 15, CDRL 1 of SEQ ID NO: 18, CDRL2 of SEQ ID NO: 19 and CDRL3 of SEQ ID NO: 20. xxi. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH 1 of SEQ ID NO : 23 , CDRH2 of SEQ ID NO : 24, CDRH3 of SEQ ID NO : 25 , CDRL1 of SEQ ID NO: 28, CDRL2 of SEQ ID NO: 29 and CDRL3 of SEQ ID NO: 30. xxii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 47, CDRH2 of SEQ ID NO: 48, CDRH3 of SEQ ID NO: 49, CDRL1 of SEQ ID NO: 50, CDRL2 of SEQ ID NO: 51 and CDRL3 of SEQ ID NO: 52. xxiii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 55, CDRH2 of SEQ ID NO: 56, CDRH3 of SEQ ID NO: 57, CDRL1 of SEQ ID NO: 58, CDRL2 of SEQ ID NO: 59 and CDRL3 of SEQ ID NO: 60. 70541FF xxiv. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH 1 of SEQ ID NO : 63 , CDRH2 of SEQ ID NO : 64, CDRH3 of SEQ ID NO : 65 , CDRL1 of SEQ ID NO: 66, CDRL2 of SEQ ID NO: 67 and CDRL3 of SEQ ID NO: 68. xxv. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH 1 of SEQ ID NO : 71 , CDRH2 of SEQ ID NO : 72, CDRH3 of SEQ ID NO : 73 , CDRL1 of SEQ ID NO: 74, CDRL2 of SEQ ID NO: 75 and CDRL3 of SEQ ID NO: 76. xxvi. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 79, CDRH2 of SEQ ID NO: 80, CDRH3 of SEQ ID NO: 81, CDRL1 of SEQ ID NO: 82, CDRL2 of SEQ ID NO: 83 and CDRL3 of SEQ ID NO: 84. xxvii. In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108 and said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 87, CDRH2 of SEQ ID NO: 88, CDRH3 of SEQ ID NO: 89, CDRL 1 of SEQ ID NO : 90, CDRL2 of SEQ ID NO : 91 and CDRL3 of SEQ ID NO : 92.

[0093] However, in a most particular embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5 , CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. In a particular embodiment said multispecific antigen binding protein is a bispecific antibody, thus there is provided a bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 70541FF binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and said IL-13 binding domain comprises the following CDRs: CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. In an embodiment there is provided an anti-IL-18 and anti-IL-13 bispecific antibody comprising anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and comprising anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0094] In an embodiment, there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises: a) a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 37 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 38, b) a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 45 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 46; or c) a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 109 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 110.

[0095] In a particular embodiment the multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 37 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 38.

[0096] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises: a. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 2 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 7; b. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 12 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 17; 70541FF c. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 22 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 27; d. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 53 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:54; e. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 61 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 62; f. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 69 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 70; g. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 77 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 78; h. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 85 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 86; or i. a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 93 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:94.

[0097] In a particular embodiment the multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL-13 binding domain comprises a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 2 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 7.

[0098] Provided herein are multispecific antigen binding proteins comprising any combination of the above-mentioned IL- 18 binding domains and IL- 13 binding domains (as defined by their VH / VL sequences), however, in a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain, wherein said IL- 18 binding domain comprises a VH domain comprising a sequence at least 90%, 70541FF

[0099] 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 37 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 38 and wherein said IL-13 binding domain comprises a VH domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 2 and / or a VL domain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 7. In an embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 37 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 38 and wherein said IL- 13 binding domain comprises a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 2 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 7.

[0100] As well as providing VH and / or VL sequences with varying degrees of sequence identity to defined SEQ ID NOs, the VH or VL (or HC or LC sequences) disclosed herein may be a variant VH / VL sequence with up to 10 amino acid substitutions, additions, or deletions. For example, the variant sequence may have up to 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitution(s), addition(s), or deletion(s). Sequence variation (both in terms of percentage identity or in terms of amino acid substitutions, addition or deletion variant) may exclude one or more or all of the CDRs, for example the CDRs are the same as the VH or VL (or HC or LC) sequence and the variation is in the remaining portion of the VH or VL (or HC or LC) sequence, so that the CDR sequences are fixed and intact. In the case of multispecific antigen binding proteins that comprise a constant region, the sequence variation may also exclude sequences that increase binding to FcRn and thus increase half-life of the antigen binding protein, e.g., YTE (M252Y / S254T / T256E). The sequence variation may also exclude sequences that decrease effector function of the antigen binding protein, e.g., LAGA (L235A and G237A) and may also exclude sequences that promote heavy chain dimerization or that drive correct heavy / light chain pairing. Typically, the modification is a substitution, particularly a conservative substitution.

[0101] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL-13 binding domain wherein said IL-18 binding domain comprises: a) a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 37 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 38 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions, b) a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 45 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 46 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; or c) a VH domain that is a variant of the amino acid 70541FF sequence set forth in SEQ ID NO: 109 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 110 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0102] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises: a. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 2 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 7 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; b. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 12 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 17 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; c. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 22 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 27 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; d. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 53 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 54 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; e. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 61 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 62 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; f. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 69 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 70 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; g. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 77 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 78 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; h. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 85 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 70541FF

[0103] 86 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; or i. a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 93 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 94 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0104] However, in a particular embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein: said IL- 18 binding domain comprises a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 37 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 38 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; and wherein said IL- 13 binding domain comprises a VH domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 2 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions and / or a VL domain that is a variant of the amino acid sequence set forth in SEQ ID NO: 7 containing 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0105] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a) a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38, b) a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46; or c) a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110. However, in a most particular embodiment, there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38.

[0106] In an embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL-13 binding domain wherein said IL- 13 binding domain comprises: a. a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7; b. a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 17; c. a VH domain of SEQ ID NO: 22 and a VL domain of SEQ ID NO: 27; d. a VH domain of SEQ ID NO: 53 and a VL domain of SEQ ID NO: 54; e. a VH domain of SEQ ID NO: 61 and a VL domain of SEQ ID NO: 62; f. a VH domain of SEQ ID NO: 69 and a VL domain of SEQ ID NO: 70; g. a VH domain of SEQ ID NO: 77 and a VL domain of SEQ ID NO: 78; h. a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86; or i. a VH domain of SEQ ID NO: 93 and a VL domain of SEQ ID NO: 94. 70541FF

[0107] However, in a most particular embodiment, there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

[0108] Provided herein are multispecific antigen binding proteins comprising any combination of the above-mentioned IL- 18 binding domains and IL- 13 binding domains (as defined by their VH / VL sequences), each combination being provided below as follows: i. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL- 13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7. ii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 17. iii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 22 and a VL domain of SEQ ID NO: 27. iv. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 53 and a VL domain of SEQ ID NO: 54. v. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 61 and a VL domain of SEQ ID NO: 62. vi. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 69 and a VL domain of SEQ ID NO: 70. 70541FF vii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 77 and a VL domain of SEQ ID NO: 78. viii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86. ix. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 93 and a VL domain of SEQ ID NO: 94. x. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7. xi. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 17. xii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 22 and a VL domain of SEQ ID NO: 27. xiii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 53 and a VL domain of SEQ ID NO: 54. xiv. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain 70541FF comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 61 and a VL domain of SEQ ID NO: 62. xv. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 69 and a VL domain of SEQ ID NO: 70. xvi. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 77 and a VL domain of SEQ ID NO: 78. xvii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86. xviii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 93 and a VL domain of SEQ ID NO: 94. xix. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7. xx. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 17. xxi. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 70541FF and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 22 and a VL domain of SEQ ID NO: 27. xxii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 53 and a VL domain of SEQ ID NO: 54. xxiii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 61 and a VL domain of SEQ ID NO: 62. xxiv. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 69 and a VL domain of SEQ ID NO: 70. xxv. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 77 and a VL domain of SEQ ID NO: 78. xxvi. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86. xxvii. In an embodiment, said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 93 and a VL domain of SEQ ID NO: 94.

[0109] However, in a particular embodiment said multispecific antigen binding protein comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7. In an embodiment said multispecific antigen binding protein is a bispecific antibody, thus there is 70541FF provided a bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL-18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7. In an embodiment, there is provided an anti-IL-18 and anti-IL-13 bispecific antibody wherein said anti-IL-18 comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and wherein said anti-IL-13 comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

[0110] The multispecific antigen binding proteins disclosed herein may be bispecific antigen binding proteins. Even more particularly said multispecific antigen binding proteins (e.g. bispecific antigen binding proteins) are bispecific antibodies.

[0111] Classification and formats of bispecific antibodies are comprehensively described in reviews by Labrijn et al 2019 and Brinkmann and Kontermann 2017. Bispecifics may be generally classified as having a symmetric or asymmetric architecture. Bispecifics may have an Fc or may be fragment-based (lacking an Fc). Fragment based bispecifics combine multiple antigen-binding antibody fragments in one molecule without an Fc region e.g., Fab-scFv, Fab-scFv2, orthoganol Fab-Fab, Fab-Fv, tandem scFc (e.g., BiTE and BiKE molecules), Diabody, DART, TandAb, scDiabody, tandem dAb etc. Symmetric formats combine multiple binding specificities in a single polypeptide chain or single HC / LC pair including Fc-fiision proteins of fragment-based formats and formats whereby antibody fragments are fused to regular antibody molecules. Examples of symmetric formats may include DVD-Ig, TVD-Ig, CODV-Ig, (scFv)4-Fc, IgG-(scFv)2, Tetravalent DART-Fc, F(ab)4CrossMab, IgG-HC-scFv, IgG-LC-scFv, mAb-dAb etc. Asymmetric formats retain as closely as possible the native architecture of natural antibodies by forcing correct HL chain pairing and / or promoting H chain heterodimerization during the co-expression of three (if common heavy or light chains are used) or four polypeptide chains e.g., Triomab, asymmetric reengineering technology immunoglobulin (ART-Ig), CrossMab, Biclonics common light chain, ZW 1 common light chain, DuoBody and knobs into holes (KiH), DuetMab, KZ body, Xmab, YBODY, Het mAb, HET-Fab, DART-Fc, SEEDbody, mouse / rat chimeric IgG. Bispecific formats also include an antibody fused to a non-Ig scaffold such as Affimabs, Fynomabs, Zybodies, and Anticalin-IgG fusions, ImmTAC.

[0112] In an embodiment, the bispecific antibody is selected from the group consisting of: duobody, L-body, common light chain antibody, an antibody with a modified cysteine bridging between the heavy and light chains, a chimeric heavy / light chain antibody, cross-mab, mAb pair, and Het mAb. However, in a particular embodiment, the multispecific antigen binding proteins disclosed herein are bispecific antibodies are Het-mAbs.

[0113] As previously described, Het mAbs target two different epitopes, in the present case, said epitopes being on two different targets: IL-18 and IL-13. A “Het mAb” is an example of a bispecific antibody. Het mAb’s have four distinct chains: two non-identical heavy chains (in the 70541FF present case one anti-IL-18 heavy chain and one anti-IL-13 heavy chain) and two non-identical light chains (in the present case one anti-IL-18 light chain and one anti-IL-13 light chain). These chains contain a set of mutations in the Fc portion of the molecule that drive heavy chain dimerization, optionally wherein a first heavy chain contains the mutations T350V, L351Y, F405A, Y407V and a second heavy chain contains the mutations T350V, T366L, K392L, T394W (EU Index Numbering). Other suitable mutations for driving heavy chain dimerization are disclosed in WO2012 / 058768 and W02013 / 063702. These mutations may be described herein as “Azymetric Fc mutations”. Thus, in an embodiment, the multispecific antigen binding proteins disclosed herein comprise an Fc domain, wherein the Fc domain comprises Azymetric Fc mutations. These chains further contain a set of mutations on the Fab portion that drive correct heavy / light chain pairing, e.g., kappa / kappa or lambda / kappa subtype bispecific mAbs. Suitable mutations for driving heavy / light chain pairing are disclosed in WO2014 / 082179, W02015 / 181805, and WO2017 / 059551.

[0114] Multispecific antigen binding proteins (e.g., bispecific antigen binding proteins) and bispecific antibodies of the disclosure may be derived from rat, mouse, primate (e.g., cynomolgus, Old World monkey or Great Ape) or human. In an embodiment, the multispecific antigen binding proteins (e.g., bispecific antigen binding proteins) or bispecific antibody of the disclosure is derived from a human, humanized or chimeric antibody. The multispecific antigen binding protein (e.g., bispecific antigen binding protein) may comprise a constant region, which may be of any isotype or subclass. The constant region of the multispecific antigen binding protein (e.g., bispecific antigen binding protein) or bispecific antibody may be of the IgG isotype, for example IgGl, IgG2, IgG3, IgG4 or variants thereof. In an embodiment, the multispecific antigen binding protein (e.g., bispecific antigen binding protein) or bispecific antibody comprises an IgGl constant region. In an embodiment, the bispecific antibody is an IgGl antibody.

[0115] In an embodiment, the multispecific antigen binding protein (e.g., bispecific antigen binding protein) or bispecific antibody comprises an IgGlx constant region. In an embodiment, the bispecific antibody is an IgG I K antibody.

[0116] In an embodiment, the multispecific antigen binding protein (e.g., bispecific antigen binding protein) or the bispecific antibody is a disulfide-linked a2p2 tetramer. In an embodiment, the multispecific antigen binding protein (e.g., bispecific antigen binding protein) or bispecific antibody comprises two light (kappa, K) and two heavy (IgGl) chains.

[0117] The present disclosure provides multispecific antigen binding proteins, in particular bispecific antibodies, that are capable of binding to IL- 18 and IL-13. In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a heavy chain and a light chain and wherein said IL- 13 binding domain comprises a heavy chain and a light chain. 70541FF

[0118] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises: a heavy chain having 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 95; and a light chain having 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 97.

[0119] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises: a heavy chain wherein said heavy chain is a variant of the amino acid sequence set forth in SEQ ID NO: 95 that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; and a light chain wherein said light chain is a variant of the amino acid sequence set forth in SEQ ID NO: 97 that contains that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0120] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises: a heavy chain comprising SEQ ID NO: 95; and a light chain comprising SEQ ID NO: 97.

[0121] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises: a heavy chain having 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 96; and a light chain having 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 98.

[0122] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises: 70541FF a heavy chain wherein said heavy chain is a variant of the amino acid sequence set forth in SEQ ID NO: 96 that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; and a light chain wherein said light chain is a variant of the amino acid sequence set forth in SEQ ID NO: 98 that contains that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0123] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 13 binding domain comprises: a heavy chain comprising SEQ ID NO: 96; and a light chain comprising SEQ ID NO: 98.

[0124] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a heavy chain (IL-18-HC) and a light chain (IL-18-LC) and wherein said IL- 13 binding domain comprises a heavy chain (IL-13-HC) and a light chain (IL-13-LC), wherein: said IL-18-HC has 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 95; said IL-18-LC has 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 97; said IL-13-HC has 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 96; and said IL-13-LC has 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater or 100% identity to the amino acid sequence set forth in SEQ ID NO: 98.

[0125] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a heavy chain (IL-18-HC) and a light chain (IL-18-LC) and wherein said IL- 13 binding domain comprises a heavy chain (IL-13-HC) and a light chain (IL-13-LC), wherein: said IL-18-HC is a variant of the amino acid sequence set forth in SEQ ID NO: 95 that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; said IL-18-LC is a variant of the amino acid sequence set forth in SEQ ID NO: 97 that contains that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; 70541FF said IL-13-HC is a variant of the amino acid sequence set forth in SEQ ID NO: 96 that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions; and said IL-13-LC is a variant of the amino acid sequence set forth in SEQ ID NO: 98 that contains that contains 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0126] In an embodiment said multispecific antigen binding protein or bispecific antibody comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a heavy chain (IL-18-HC) and a light chain (IL-18-LC) and wherein said IL- 13 binding domain comprises a heavy chain (IL-13-HC) and a light chain (IL-13-LC), wherein: said IL-18-HC comprises or consists of SEQ ID NO: 95; said IL-18-LC comprises or consists of SEQ ID NO: 97; said IL-13-HC comprises or consists of SEQ ID NO: 96; and said IL-13-LC comprises or consists of SEQ ID NO: 98.

[0127] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the present disclosure comprises two heavy chains and two light chains. Thus, in an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said multispecific antigen binding protein or bispecific antibody comprises: a heavy chain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 95, a light chain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 97, a heavy chain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 96, and a light chain comprising a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:98.

[0128] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said multispecific antigen binding protein comprises: a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 95, a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 97, a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 96, and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO:98; wherein each variant may contain 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, insertions, or deletions.

[0129] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said multispecific antigen binding protein comprises: a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98. 70541FF

[0130] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the present disclosure comprises an IL- 18 binding domain and an IL- 13 binding domain wherein said multispecific antigen binding protein or bispecific antibody comprises: an IL- 18 binding domain having a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO: 97 and an IL-13 binding domain having a heavy chain of SEQ ID NO: 96 , a light chain of SEQ ID NO: 98.

[0131] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the disclosure comprises an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 95 that contains up to 10 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO:97 that contains up to 10 amino acid substitutions, insertions, or deletions; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 96 that contains up to 10 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 98 that contains up to 10 amino acid substitutions, insertions, or deletions; wherein none of the amino acid substitutions, insertions, or deletions are within any of the CDRs.

[0132] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the disclosure comprises an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 95 that contains up to 5 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO:97 that contains up to 5 amino acid substitutions, insertions, or deletions; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 96 that contains up to 5 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 98 that contains up to 5 amino acid substitutions, insertions, or deletions; wherein none of the amino acid substitutions, insertions, or deletions are within any of the CDRs.

[0133] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the disclosure comprises an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 95 that contains up to 10 amino acid 70541FF substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO:97 that contains up to 10 amino acid substitutions, insertions, or deletions; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 96 that contains up to 10 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 98 that contains up to 10 amino acid substitutions, insertions, or deletions; wherein none of the amino acid substitutions, insertions, or deletions are within any of the CDRs and none of the amino acid substitutions, insertions, or deletions are within YTE (M252Y / S254T / T256E).

[0134] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the disclosure comprises an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 95 that contains up to 5 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO:97 that contains up to 5 amino acid substitutions, insertions, or deletions; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 96 that contains up to 5 amino acid substitutions, insertions, or deletions; and a light chain comprising a variant of the amino acid sequence set forth in SEQ ID NO: 98 that contains up to 5 amino acid substitutions, insertions, or deletions; wherein none of the amino acid substitutions, insertions, or deletions are within any of the CDRs and none of the amino acid substitutions, insertions, or deletions are within YTE (M252Y / S254T / T256E).

[0135] In an embodiment, the multispecific antigen binding protein or bispecific antibody of the disclosure comprises an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NO:31), CDRH2 (SEQ ID NO:32), and CDRH3 (SEQ ID NO:33), and having 95% or greater identity to SEQ ID NO: 95 and a light chain comprising CDRL1 (SEQ ID NO:34), CDRL2 (SEQ ID NO:35), and CDRL3 (SEQ ID NO:36), and having 95% or greater identity to SEQ ID NO: 97; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NO:3), CDRH2 (SEQ ID NO: 4), and CDRH3 (SEQ ID NO: 5), and having 95% or greater identity to SEQ ID NO: 96 and a light chain comprising CDRL1 (SEQ ID 70541FF

[0136] NO: 8), CDRL2 (SEQ ID NO: 9), and CDRL3 (SEQ ID NO: 10), and having 95% or greater identity to SEQ ID NO: 98.

[0137] Further provided within the present disclosure are anti-IL-18 and anti-IL-13 bispecific antibodies. In an embodiment said anti-IL-18 and anti-IL-13 bispecific antibody comprises anti-IL- 18 (or an anti-IL-18 arm) having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and anti-IL-13 (or an anti-IL-13 arm) having the following CDRs: CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. In an embodiment, said anti- IL-18 and anti-IL-13 bispecific antibody comprises anti-IL-18 (or an anti-IL-18 arm) comprising a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and wherein said anti-IL-13 (or anti-IL-13 arm) comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

[0138] In a further aspect there is provided an anti-IL-18 and anti-IL-13 bispecific antibody, comprising: anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36; anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10 wherein the anti-IL-18 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 95 and a light chain having a sequence at least 95% identical to SEQ ID NO: 97 and the anti-IL13 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 96, and a light chain having a sequence at least 95% identical to SEQ ID NO: 98.

[0139] In an embodiment said bispecific antibody comprises anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36, anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, an Fc region comprising M252Y, S254T and T256E (EU index numbering); and wherein the anti-IL-18 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 95 and a light chain having a sequence at least 95% identical to SEQ ID NO: 97 and the anti-IL-13 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 96, and a light chain having a sequence at least 95% identical to SEQ ID NO: 98. In an embodiment, said Fc region further comprises the amino acid substitutions L235A and G237A (EU index numbering). In an embodiment there is provided an anti-IL-18 and anti-IL-13 bispecific antibody wherein anti-IL-18 comprises the heavy chain of SEQ ID NO: 95 and the light chain of SEQ ID NO: 97 and wherein anti-IL-13 comprises the heavy chain of SEQ ID NO: 96 and the light chain of SEQ ID NO: 98. 70541FF

[0140] A multispecific antigen binding protein or bispecific antibody of the disclosure may neutralize the activity of IL-18 by at least 20%, 30% 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100% relative to IL-18 activity in the absence of the IL- 18 binding domain (or relative to IL- 18 activity in the presence of a control antibody). Neutralization may be determined or measured using one or more assays known to the skilled person or as described herein, for example (but by no means limited to) the IFNy assay (for example see Example 6). A multispecific antigen binding protein or bispecific antibody of the disclosure may neutralize the activity of IL-13 by at least 20%, 30% 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100% relative to IL- 13 activity in the absence of the IL- 13 binding domain (or relative to the IL- 13 activity in the presence of a control antibody). Neutralization may be determined or measured using one or more assays known to the skilled person or as described herein, for example (but by no means limited to) the VCAM-1 HUVEC cell assay (for example see Example 5a)

[0141] In an embodiment, the equilibrium dissociation constant (KD) of the multispecific antigen binding protein - IL- 18 interaction and / or of the multispecific antigen binding protein - IL- 13 interaction is about 1 nM or less, 500 pM or less, 250 pM or less, 150 pM or less, 100 pM or less or 75 pM or less. Alternatively, the KD may be between about 1 pM and about 250 pM, between about 10 pM and about 100 pM, between about 20 pM and about 100 pM; between about 20 pM and about 75 pM, or between about 20 pM and about 60 pM. A skilled person will appreciate that the smaller the KD numerical value, the strongerthe binding. The reciprocal of KD (i.e., 1 / KD) is the equilibrium association constant (KA) having units M1. A skilled person will appreciate that the larger the KA numerical value, the strongerthe binding. The KD values provided herein are all provided in respect of binding to human IL- 18 and human IL-13. A skilled person will appreciate that surface plasmon resonance (SPR) is a suitable method to measure binding affinity and also determine binding kinetics, see, e.g., Day etal., Protein Science (2002), 11: 1017-1025; and Hearty et al, Methods Mol Biol (2012) 907:411-4.

[0142] The skilled person will appreciate that upon production of any of the IL- 13 binding proteins or multispecific antigen binding proteins disclosed herein post-translational modifications may occur. For example, this may include the cleavage of certain leader sequences, the addition of various sugar moieties in various glycosylation patterns, non-enzymatic glycation, deamidation, oxidation, disulfide bond scrambling and other cysteine variants such as free sulfhydryls, racemized disulfides, thioethers and trisulfide bonds, isomerisation, C-terminal lysine clipping, and N-terminal glutamine cyclisation. The present disclosure encompasses the use of IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies that have been subjected to, or have undergone, one or more post-translational modifications. Thus an “IL-13 binding protein”, “multispecific antigen binding protein” or “bispecific antibody” of the disclosure includes those that have undergone a post-translational modification such as those described herein. For 70541FF example, C-terminal lysine clipping is an enzymatic reaction catalyzed by carboxypeptidases and is commonly observed in recombinant and natural human antibodies. Variants of this process include removal of lysine from one or both heavy chains due to cellular enzymes from the recombinant host cell. Thus, the C- terminal lysine of the heavy chain Fc region may be removed, for example, during production or purification of any of the IL- 13 binding proteins, multispecific antibodies or bispecific antibodies disclosed herein. Accordingly, a composition of the disclosure may comprise IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibody populations with all C-terminal lysine residues removed, IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibody populations with no C-terminal lysine residues removed, and IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibody populations having a mixture of antibodies with and without the C-terminal lysine residue.

[0143] Fc Modification

[0144] As described in the sections above (under the headings “IL- 13 Binding Protein” and “Multispecific Antigen Binding Protein”) the IL- 13 binding proteins and multispecific antigen binding proteins disclosed herein are, in particular embodiments, antibodies and bispecific antibodies respectively. Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to Clq or Fey receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc to the FcRn (Neonatal Fc Receptor).

[0145] Some isotypes of human constant regions, in particular IgG4 and IgG2 isotypes, essentially lack the functions of a) activation of complement by the classical pathway; and b) ADCC. Various modifications to the heavy chain constant region of antigen binding proteins may be carried out to alter effector function depending on the desired effector property. IgGl constant regions containing specific mutations that reduce binding to Fc receptors and reduce an effector function, such as ADCC and CDC, have been described (Duncan et al. Nature 1988, 332; 563-564; Lund et al. J. Immunol. 1991, 147; 2657-2662; Chappel et al. PNAS 1991, 88; 9036-9040; Burton and Woof, Adv. Immunol. 1992, 51 ; 1-84; Morgan et al., Immunology 1995, 86; 319-324; Hezareh et al., J. Virol. 2001, 75 (24); 12161-12168).

[0146] Thus, provided herein are IL-13 binding proteins (e.g. antibodies or antigen binding fragments thereof) and multispecific antigen binding proteins (e.g. bispecific antibodies) comprising an Fc domain having reduced effector function. In an embodiment there are herein provided IL- 13 binding proteins (e.g. antibodies or antigen binding fragments thereof) and multispecific antigen binding proteins (e.g. bispecific antibodies) comprising an Fc domain such 70541FF that said IL- 13 binding protein or multispecific antigen binding protein has reduced effector function, such as reduced ADCC and / or CDC.

[0147] The heavy chain constant region may comprise a naturally disabled constant region of an IgG2 or IgG4 isotype or a mutated IgGl constant region. Non-limiting examples of suitable modifications are described in EP0307434. In an embodiment, the IL-13 binding proteins, multispecific antigen binding proteins and bispecific antibodies disclosed herein comprise a modified Fc region and said modification comprises substitution with alanine at positions 235 and 237 (EU index numbering), i.e., L235A and G237A (commonly referred to as “LAGA” mutations). Other examples can comprise substitution with alanine at positions 234 and 235 (EU index numbering), i.e., L234A and L235A (commonly referred to as “LALA” mutations). Additional examples can comprise substitution with alanine at positions 234, 235 and 237 (EU index numbering), i.e., L234A, L235A, and G237A (referred to as “LALAGA” mutations). Further examples, described in EP2691417 and US8969526, comprise P329G or P329R, in combination with the LALA mutations (EU index numbering) for IgGl Fes and P329G or P329R in combination with S228P and L235E for IgG4 Fes (EU index numbering).

[0148] In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO : 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain and wherein said Fc domain comprises amino acid modifications that reduce effector function compared to an Fc domain without said modifications. In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL-18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7 wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain and wherein said Fc domain comprises amino acid modifications that reduce effector function compared to an Fc domain without said modifications.

[0149] In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ 70541FF

[0150] ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO : 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain wherein said Fc domain comprises the amino acid substitutions L235A and G237A (EU index numbering). In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7 wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain wherein said Fc domain comprises the amino acid substitutions L235A and G237A (EU index numbering).

[0151] Additional alterations and mutations to decrease effector function include: (with reference to IgGl unless otherwise noted): aglycosylated N297A orN297Q orN297G; L235E; IgG4:F234A / L235A; and chimeric IgG2 / IgG4. IgG2: H268Q / V309L / A330S / P331S, and IgG2: V234A / G237A / P238S / H268A / V309L / A330S / P331S can reduce FcyR and Clq binding (Wang et al. 2018 and US8961967).

[0152] Other mutations that decrease effector function include L234F / L235E / P331S; a chimeric antibody created using the CHI and hinge region from human IgG2 and the CH2 and CH3 regions from human IgG4; IgG2m4, based on the IgG2 isotype with four key amino acid residue changes derived from IgG4 (H268Q, V309L, A330S and P33 IS); IgG2o that contains V234A / G237A / P238S / H268A / V309L / A330S / P33 IS substitutions to eliminate affinity for Fey receptors and Clq complement protein; IgG2m4 (H268Q / V309L / A330S / P33 I S. changes to IgG4); IgG4 (S228P / L234A / L235A); huIgGl L234A / L235A (AA); huIgG4 S228P / L234A / L235A; IgGlc (L234A / L235A / G237A / P238S / H268A / A330S / P33 IS); IgG4c I (S228P / F234A / L235A / G237A / P238S); and IgG4c2 (S228P / F234A / L235A / AG236 / G237A / P238S, wherein A denotes a deletion) (Tam et al., Antibodies 2017, 6(3)).

[0153] The long half-life of IgG antibodies is reported to be dependent on their binding to FcRn. Therefore, substitutions that increase the binding affinity of IgG to FcRn at pH 6.0 while maintaining the pH dependence of the interaction with target, by engineering the constant region, have been extensively studied (Ghetie et al., Nature Biotech. 15: 637-640, 1997; Hinton et al., JBC 279: 6213-6216, 2004; Dall'Acqua et al., 10 J Immunol 117: 1129-1138, 2006). The in vivo halflife of IL- 13 binding proteins or multispecific antigen binding proteins of the present invention may be altered by modification of a heavy chain constant domain or an FcRn binding domain therein.

[0154] In adult mammals, FcRn, also known as the neonatal Fc receptor, plays a key role in maintaining serum antibody levels by acting as a protective receptor that binds and salvages antibodies of the IgG isotype from degradation. IgG molecules are endocytosed by endothelial cells 70541FF and, if they bind to FcRn, are recycled out of the cells back into circulation. In contrast, IgG molecules that enter the cells and do not bind to FcRn and are targeted to the lysosomal pathway where they are degraded.

[0155] FcRn is believed to be involved in both antibody clearance and the transcytosis across tissues (see Junghans R.P (1997) Immunol. Res 16. 29-57 and Ghetie et al (2000) Annu.Rev.Immunol. 18, 739-766). Human IgGl residues determined to interact directly with human FcRn include Ile253, Ser254, Lys288, Thr307, Gln311, Asn434 and His435. Mutations at any of these positions may enable increased serum half-life and / or altered effector properties of IL- 13 binding proteins or multispecific antigen binding proteins of the disclosure.

[0156] IL 13 -binding proteins or multispecific antigen binding proteins of the present disclosure may have amino acid modifications that increase the affinity of the constant domain or fragment thereof for FcRn. Increasing the half-life (i.e., serum half-life) of therapeutic and diagnostic IgG antibodies and other bioactive molecules has many benefits including reducing the amount and / or frequency of dosing of these molecules. In one embodiment an IL13-binding protein or multispecific antigen binding protein of the present disclosure comprises all or a portion (an FcRn binding portion) of an IgG constant domain having one or more of the following amino acid modifications.

[0157] For example, with reference to IgGl, M252Y / S254T / T256E (commonly referred to as “YTE” mutations) and M428L / N434S (commonly referred to as “LS” mutations) increase FcRn binding at pH 6.0 (Wang et al. 2018).

[0158] In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO : 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain and wherein said Fc domain comprises amino acid modifications that increase the affinity of the Fc domain for FcRn compared to an Fc domain without said modifications. In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL-18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7 wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain and wherein said Fc domain comprises amino acid modifications that increase the affinity of the Fc domain for FcRn compared to an Fc domain without said modifications . 70541FF

[0159] In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO : 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain wherein said Fc domain comprises the amino acid substitutions M252Y / S254T / T256E (EU Index Numbering). In a particular embodiment there is provided a multispecific antigen binding protein comprising an IL- 18 binding domain and an IL- 13 binding domain wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL- 13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7 wherein said multispecific antigen binding protein is a bispecific antibody, said bispecific antibody having an Fc domain wherein said Fc domain comprises the amino acid substitutions M252Y / S254T / T256E (EU Index Numbering).

[0160] Half-life can also be enhanced by T250Q / M428L, V259I / V308F / M428L, N434A, and T307A / E380A / N434A mutations (with reference to IgGl and Kabat numbering) (Monnet et al.).

[0161] Half-life and FcRn binding can also be extended by introducing H433K and N434F mutations (commonly referred to as “HN” or “NHance” mutations) (with reference to IgGl) (W02006 / 130834).

[0162] WO00 / 42072 discloses a polypeptide comprising a variant Fc region with altered FcRn binding affinity, which polypeptide comprises an amino acid modification at any one or more of amino acid positions 238, 252, 253, 254, 255, 256, 265, 272, 286, 288, 303, 305, 307, 309, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 386,388, 400, 413, 415, 424, 433, 434, 435, 436, 439, and 447 of the Fc region (EU index numbering).

[0163] W002 / 060919 discloses a modified IgG comprising an IgG constant domain comprising one or more amino acid modifications relative to a wild-type IgG constant domain, wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type IgG constant domain, and wherein the one or more amino acid modifications are at one or more of positions 251, 253, 255, 285-290, 308-314, 385-389, and 428-435.

[0164] Shields et al. (2001, J Biol Chem; 276:6591-604) used alanine scanning mutagenesis to alter residues in the Fc region of a human IgGl antibody and then assessed the binding to human FcRn. Positions that effectively abrogated binding to FcRn when changed to alanine include 1253, S254, H435, and Y436. Other positions showed a less pronounced reduction in binding as follows: E233-G236, R255, K288, L309, S415, and H433. Several amino acid positions exhibited an improvement in FcRn binding when changed to alanine; notable among these are P238, T256, 70541FF

[0165] E272, V305, T307, Q311, D312, K317, D376, E380, E382, S424, and N434. Many other amino acid positions exhibited a slight improvement (D265, N286, V303, K360, Q362, and A378) or no change (S239, K246, K248, D249, M252, E258, T260, S267, H268, S269, D270, K274, N276, Y278, D280, V282, E283, H285, T289, K290, R292, E293, E294, Q295, Y296, N297, S298, R301, N315, E318, K320, K322, S324, K326, A327, P329, P331, E333, K334, T335, S337, K338, K340, Q342, R344, E345, Q345, Q347, R356, M358, T359, K360, N361, Y373, S375, S383, N384, Q386, E388, N389, N390, K392, L398, S400, D401, K414, R416, Q418, Q419, N421, V422, E430, T437, K439, S440, S442, S444, and K447) in FcRn binding.

[0166] The most pronounced effect with respect to improved FcRn binding was found for combination variants. At pH 6.0, the E380A / N434A variant showed over 8-fold better binding to FcRn, relative to native IgGl, compared with 2-fold for E380A and 3.5-fold for N434A. Adding T307A to this resulted in a 12-fold improvement in binding relative to native IgGl. In one embodiment the IL 13 -binding proteins or multispecific antigen binding proteins of the present disclosure comprises the E380A / N434A mutations and has increased binding to FcRn.

[0167] Dall’Acqua et al. (2002, J Immunol. ; 169:5171 -80) describes random mutagenesis and screening of human IgGl hinge-Fc fragment phage display libraries against mouse FcRn. They disclosed random mutagenesis of positions 251, 252, 254-256, 308, 309, 311, 312, 314, 385-387, 389, 428, 433, 434, and 436. The major improvements in IgGl-human FcRn complex stability occur when substituting residues located in a band across the Fc-FcRn interface (M252, S254, T256, H433, N434, and Y436) and to lesser extent substitutions of residues at the periphery, such as V308, L309, Q311, G385, Q386, P387, and N389. The variant with the highest affinity to human FcRn was obtained by combining the M252Y / S254T / T256E (“YTE”) and H433K / N434F / Y436H mutations and exhibited a 57-fold increase in affinity relative to the wild-type IgGl. The in vivo behaviour of such a mutated human IgGl exhibited a nearly 4-fold increase in serum half-life in cynomolgus monkey as compared to wild-type IgGl.

[0168] The present disclosure therefore provides IL- 13 binding proteins and multispecific antigen binding proteins with optimized binding to FcRn. In an embodiment, the IL 13 -binding proteins or multispecific antigen binding proteins of the present disclosure comprise an Fc region wherein said Fc region comprises at least one amino acid modification, wherein said modification is at an amino acid position selected from the group consisting of 226, 227, 228, 230, 231, 233, 234, 239, 241, 243, 246, 250, 252, 256, 259, 264, 265, 267, 269, 270, 276, 284, 285, 288, 289, 290, 291, 292, 294,

[0169] 297, 298, 299, 301, 302, 303, 305, 307, 308, 309, 311, 315, 317, 320, 322, 325, 327, 330, 332, 334,

[0170] 335, 338, 340, 342, 343, 345, 347, 350, 352, 354, 355, 356, 359, 360, 361, 362, 369, 370, 371, 375,

[0171] 378, 380, 382, 384, 385, 386, 387, 389, 390, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401 403,

[0172] 404, 408, 411, 412, 414, 415, 416, 418, 419, 420, 421, 422, 424, 426, 428, 433, 434, 438, 439, 440,

[0173] 443, 444, 445, 446 and 447 of the Fc region. 70541FF

[0174] Additionally, various publications describe methods for obtaining physiologically active molecules with modified half-lives, either by introducing an FcRn-binding polypeptide into the molecules (WO97 / 43316, US5869046, US5747035, WO96 / 32478 and WO91 / 14438) or by fusing the molecules with antibodies whose FcRn-binding affinities are preserved, but affinities for other Fc receptors have been greatly reduced (WO99 / 43713), or fusing with FcRn binding domains of antibodies (WO00 / 09560, US4703039).

[0175] FcRn affinity enhanced Fc variants to improve both antibody cytotoxicity and half-life were identified in screens at pH 6.0. The selected IgG variants can be produced as low fucosylated molecules. The resulting variants show increased serum persistence in hFcRn mice, as well as conserved enhanced ADCC (Monnet et al.) Exemplary variants include (with reference to IgGl and Kabat numbering): P230T / V303A / K322R / N389T / F404L / N434S; P228R / N434S; Q311R / K334R / Q342E / N434Y; C226G / Q386R / N434Y; T307P / N389T / N434Y; P230S / N434S;P230T / V305A / T307A / A378V / L398P / N434S; P23OT / P387S / N434S; P230Q / E269D / N434S; N276S / A378V / N434S; T307A / N315D / A330V / 382V / N389T / N434Y; T256N / A378V / S383N / N434Y;

[0176] N315D / A330V / N361D / A387V / N434Y;V259I / N315D / M428L / N434Y; P230S / N315D / M428L / N434Y; F241L / V264E / T307P / A378V / H433R; T250A / N389K / N434Y; V305A / N315D / A330V / P395A / N434Y; V264E / Q386R / P396L / N434S / K439R;

[0177] E294del / T307P / N434Y (wherein ‘del’ indicates a deletion).

[0178] Production:

[0179] IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies of the disclosure may be prepared by any of a number of conventional techniques. For example, IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibodies may either be purified from cells that naturally express them (e.g., an antibody can be purified from a hybridoma that produces it) or produced in recombinant expression systems. A number of different expression systems and purification regimes can be used to generate the IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies of the disclosure. Generally, host cells are transformed with a recombinant expression vector encoding the desired IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody. The expression vector may be maintained by the host as a separate genetic element or integrated into the host chromosome depending on the expression system.

[0180] In an aspect of the disclosure, there is provided a nucleic acid sequence encoding an IL- 13 binding protein, a multispecific antigen binding protein or a bispecific antibody of the disclosure. In a first specific embodiment the nucleic acid sequence may encode either or both of the following amino acid sequences: a heavy comprising the VH domain of SEQ ID NO: 2 and a light chain comprising the VL domain of SEQ ID NO: 7. In a second specific embodiment the nucleic acid 70541FF sequence encodes any one, two, three or all four of the following amino acid sequences: a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO: 96 and a light chain of SEQ ID NO:98.

[0181] Thus, further provided herein are nucleic acid sequences that encode the IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies as disclosed herein. In an embodiment said nucleic acid sequences are isolated nucleic acid sequences. The nucleic acids coding for the IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies may comprise at least one chemical modification. Nucleic acids (e.g., mRNAs) can be modified to enhance stability by including one or more chemical modifications. Such chemical modifications include, but are not limited to, a modified nucleotide, a modified sugar backbone, and the like.

[0182] In an aspect of the disclosure, an expression vector comprising the nucleic acid sequence(s) of the disclosure is provided. In an embodiment, the vector comprises a nucleic acid sequence encoding any one, two, three or all four of the following amino acid sequences: a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO:96 and a light chain of SEQ ID NO:98. In an embodiment, the vector comprises the following nucleic acid sequences: a nucleic acid sequence encoding a heavy chain of SEQ ID NO: 95, a nucleic acid sequence encoding a light chain of SEQ ID NO:97, a nucleic acid sequence encoding a heavy chain of SEQ ID NO:96, and a nucleic acid sequence encoding a light chain of SEQ ID NO: 98. In an embodiment, the vector comprises a nucleic acid sequence encoding a heavy chain of SEQ ID NO: 95 and a nucleic acid sequence encoding a light chain of SEQ ID NO: 97. In an embodiment, the vector comprises a nucleic acid sequence encoding a heavy chain of SEQ ID NO: 96 and a nucleic acid sequence encoding a light chain of SEQ ID NO: 98. In an embodiment, the vector comprises a nucleic acid sequence encoding a heavy chain of SEQ ID NO: 95. In an embodiment, the vector comprises a nucleic acid sequence encoding a light chain of SEQ ID NO: 97. In an embodiment, the vector comprises a nucleic acid sequence encoding a heavy chain of SEQ ID NO: 96. In an embodiment, the vector comprises a nucleic acid sequence encoding a nucleic acid sequence encoding a light chain of SEQ ID NO: 98.

[0183] In a further aspect of the disclosure there is provided a recombinant host cell comprising the nucleic acid sequence(s) or the expression vector(s) of the disclosure. A wide range of host cells can be employed, including Prokaryotes (including Gram negative or Gram-positive bacteria, for example Escherichia coli. Bacilli sp., Pseudomonas sp., Corynehacterium sp.), Eukaryotes including yeast (for example Saccharomyces cerevisiae, Pichia pasioris). fungi (for example Aspergilus sp.), or higher Eukaryotes including insect cells and cell lines of mammalian origin (for example, CHO, NSO, PER.C6, HEK293, HeLa).

[0184] The host cell may be an isolated host cell. The host cell is usually not part of a multicellular organism (e.g., plant or animal). The host cell may be a non-human host cell. 70541FF

[0185] Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian host cells are known in the art.

[0186] The cells can be cultured under conditions that promote expression of the multispecific antigen binding protein or bispecific antibody using a variety of equipment such as shake flasks, spinner flasks, and bioreactors. The polypeptide is (or polypeptides are) recovered by conventional protein purification procedures. Protein purification procedures typically consist of a series of unit operations comprised of various filtration and chromatographic processes developed to selectively concentrate and isolate the antigen binding protein. The purified multispecific antigen binding protein or bispecific antibody may be formulated in a pharmaceutically acceptable composition.

[0187] Further provided are cell lines engineered to express the multispecific antigen binding proteins or the bispecific antibodies of the disclosure. In an embodiment, the multispecific antigen binding protein or bispecific antibody of the disclosure is produced in CHO cells.

[0188] Further provided are methods for the production of a multispecific antigen binding protein or bispecific antibody said method comprising culturing the recombinant host cell of the disclosure under conditions suitable for expression of said nucleic acid sequence(s) or vector(s), whereby said multispecific antigen binding protein or bispecific antibody is produced. Multispecific antigen binding proteins and bispecific antibodies produced by this method are furthermore provided.

[0189] Pharmaceutical Compositions and Methods of Use:

[0190] IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies as described herein may be incorporated into pharmaceutical compositions for use in the treatment of diseases (e.g., human diseases) as described herein. Thus, in a further aspect there is provided a pharmaceutical composition comprising any of the IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibodies disclosed herein in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0191] In an embodiment the pharmaceutical composition comprises an IL- 13 binding protein comprising the following 6 CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5; and CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, in combination with one or more pharmaceutically acceptable excipients, diluents or carriers. In an embodiment the pharmaceutical composition comprises an IL- 13 binding protein comprising a VH domain that is 100% identical to SEQ ID NO: 2 and a VL domain that is 100% identical to SEQ ID NO: 7 in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0192] In an embodiment the pharmaceutical composition comprises a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein, said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, 70541FF

[0193] CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and wherein said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, in combination with one or more pharmaceutically acceptable excipients, diluents or carriers. In an embodiment the pharmaceutical composition comprises a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein, said IL-18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and said IL-13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7 in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0194] In an embodiment the pharmaceutical composition comprises a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NO: 31), CDRH2 (SEQ ID NO:32), and CDRH3 (SEQ ID NO:33), and having 95% or greater identity to SEQ ID NO: 95 and a light chain comprising CDRL1 (SEQ ID NO:34), CDRL2 (SEQ ID NO: 35), and CDRL3 (SEQ ID NO: 36), and having 95% or greater identity to SEQ ID NO: 97; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NO: 3), CDRH2 (SEQ ID NO: 4), and CDRH3 (SEQ ID NO:5), and having 95% or greater identity to SEQ ID NO: 96 and a light chain comprising CDRL1 (SEQ ID NO: 8), CDRL2 (SEQ ID NO: 9), and CDRL3 (SEQ ID NO: 10), and having 95% or greater identity to SEQ ID NO: 98, in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0195] In an embodiment the pharmaceutical composition comprises a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein: said IL-18 binding domain comprises a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO: 97 and said IL-13 binding domain comprises a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98 in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0196] Pharmaceutical compositions may be administered by injection or continuous infusion (examples include, but are not limited to, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intraocular, and intraportal). In one embodiment, the pharmaceutical composition is suitable for intravenous or subcutaneous administration.

[0197] The pharmaceutical compositions of the present disclosure may be included in a kit containing the IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody together with instructions for use. For convenience, the kit may comprise the reagents in predetermined amounts. 70541FF

[0198] The kit may also include devices used for administration of the pharmaceutical composition. In an embodiment, said kit further comprises additional medicaments.

[0199] In an embodiment, each unit dose of the IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody of the disclosure is in a prefilled syringe. In an embodiment, the prefilled syringe is for subcutaneous injection. In an embodiment, each unit dose of the multispecific antigen binding protein or bispecific antibody of the disclosure is in an autoinjector. In an embodiment, the autoinjector is for subcutaneous injection.

[0200] The IL- 13 binding proteins, multispecific antigen binding proteins and bispecific antibodies described herein may be used in methods of treatment. It will be appreciated by those skilled in the art that references herein to treatment refer to the treatment of established conditions. However, the IL- 13 binding proteins multispecific antigen binding proteins and bispecific antibodies described herein may, depending on the condition, also be useful in the prevention of certain diseases. The IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibodies described herein may be used in an effective amount for therapeutic, prophylactic or preventative treatment. A therapeutically effective amount of the IL- 13 binding proteins, multispecific antigen binding proteins or bispecific antibodies described herein is an amount effective to ameliorate or reduce one or more symptoms of, or to prevent or cure, the disease. The terms “individual”, “subject” and “patient” are used herein interchangeably. In one embodiment, the subject is an animal. In another embodiment, the subject is a mammal, such as a primate, for example a marmoset or monkey. In another embodiment, the subject is a human. It is preferred that the subject is a human.

[0201] In an embodiment an IL- 13 binding protein, multispecific antigen binding protein or a bispecific antibody described herein, can be used for prophylactic or preventative treatment. In this case, the IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody is administered to an individual in order to prevent or delay the onset of one or more aspects or symptoms of a disease. The subject may have a genetic predisposition to the disease. In some embodiments, a prophylactically effective amount of the multispecific antigen binding protein or bispecific antibody is administered to such an individual. In some embodiments, a prophylactically effective amount is an amount which prevents or delays the onset of one or more aspects or symptoms of a disease described herein.

[0202] Those in need of treatment may include individuals already suffering from a medical disease in addition to those who may develop the disease in the future. In an embodiment, the subjects have inadequately responded to prior treatment with biologic therapies for the same disease.

[0203] The use of an IL- 13 binding protein, multispecific antigen binding protein, in particular a bispecific antibody, described herein need not affect a complete cure or eradicate every symptom or manifestation of the disease to constitute a viable therapeutic treatment. As is recognized in the pertinent field, therapeutic agents may reduce the severity of a given disease state but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents. Similarly, a 70541FF prophylactically administered treatment need not be completely effective in preventing the onset of a disease in order to constitute a viable prophylactic agent. Simply reducing the impact of a disease (for example, by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reducing the likelihood that the disease will occur (for example by delaying the onset of the disease) or worsen in a subject, is sufficient. In an embodiment, a treatment may comprise further monitoring of a disease or condition of a subject. A treatment may comprise a single treatment or may comprise a recurring treatment.

[0204] The present disclosure further provides a method for the treatment of disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an IL- 13 binding protein multispecific antigen binding protein, a bispecific antibody or a pharmaceutical composition as disclosed herein.

[0205] The IL- 13 binding proteins, multispecific antigen binding proteins, bispecific antibodies or pharmaceutical compositions disclosed herein may find therapeutic uses for treating various diseases, but most especially pathological disorders mediated by IL- 13 and / or IL-18. In the case of the multispecific antigen binding proteins or bispecific antibodies disclosed herein (and pharmaceutical compositions comprising said multispecific antigen binding proteins or bispecifics) these may find therapeutic use for treating disorders mediated by both IL- 13 and IL- 18 e.g. autoimmune disease and immunoinflammatory disease or conditions that involve IL- 13 and IL- 18 dysregulation.

[0206] In an aspect there is provided a method for the treatment of an immunoinflammatory disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an IL- 13 binding protein, multispecific antigen binding protein, a bispecific antibody or a pharmaceutical composition as disclosed herein. In an embodiment the immunoinflammatory disease is a disease selected from the group consisting of multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), chronic obstructive pulmonary disease (COPD), fibrosis, alopecia areata, prurigo nodularis (PN) and eczema (such as chronic hand eczema (CHE).

[0207] In a particular embodiment, the immunoinflammatory disease is an immunoinflammatory skin disease or skin condition. In a particular embodiment, the immunoinflammatory skin disease or skin condition is atopic dermatitis.

[0208] The term "Atopic dermatitis" (AD) or "eczema", as used herein, means an immunoinflammatory skin disease characterized by intense pruritus (e.g., severe itch) and by scaly and dry eczematous lesions. The term "Atopic dermatitis" or "eczema" includes, but is not limited to, AD (eczema) caused by or associated with epidermal barrier dysfunction, allergy (e.g., skin allergy, allergy to certain foods, pollen, mold, dust mite, animals, etc.), radiation exposure, and / or asthma. The present disclosure encompasses methods to treat patients with mild, moderate-to- 70541FF severe or severe AD. As used herein, "moderate-to-severe AD", is characterized widespread skin lesions that are often complicated by persistent bacterial, viral or fungal infections. Moderate-to- severe AD also includes chronic AD in patients. In many cases, the chronic lesions include thickened plaques of skin, lichenification and fibrous papules. Patients affected by moderate-to- severe AD also, in general, have an Investigator's Global Assessment (IGA) score of 3 or 4, and / or an Eczema Area and Severity Index (EASI) score of at least 7.1 or at least 10, but generally at least 15 or 16. Moderate-to-severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids. A patient may also be said to have moderate-to-severe AD when the patient is resistant or refractory to treatment by either a topical corticosteroid or a calcineurin inhibitor or any other commonly used therapeutic agent known in the art.

[0209] In an aspect there is provided a method for the treatment of atopic dermatitis (optionally moderate-to-severe AD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody or a pharmaceutical composition as disclosed herein.

[0210] In a further aspect, there is provided an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody or a pharmaceutical composition of the present disclosure for use in the treatment of disease. In an aspect there is provided an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody or a pharmaceutical composition of the present disclosure for use in the treatment of an immunoinflammatory disease, optionally wherein said immunoinflammatory disease is a disease selected from the group consisting of multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), chronic obstructive pulmonary disease (COPD), fibrosis, alopecia areata, prurigo nodularis (PN) and eczema (such as chronic hand eczema (CHE). In a particular embodiment the immunoinflammatory disease is an immunoinflammatory skin disease or skin condition. In a particular embodiment the immunoinflammatory skin disease or skin condition is atopic dermatitis.

[0211] In a further aspect there is provided an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody or a pharmaceutical composition of the present disclosure for use in the treatment of atopic dermatitis (optionally moderate-to-severe AD).

[0212] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein, said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and wherein said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, for use in the treatment of an immunoinflammatory disease, particularly an immunoinflammatory skin disease. 70541FF

[0213] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NO:31), CDRH2 (SEQ ID NO:32), and CDRH3 (SEQ ID NO:33), and having 95% or greater identity to SEQ ID NO: 95 and a light chain comprising CDRL1 (SEQ ID NON), CDRL2 (SEQ ID NON), and CDRL3 (SEQ ID NO:5), and having 95% or greater identity to SEQ ID NO: 97; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NON), CDRH2 (SEQ ID NON), and CDRH3 (SEQ ID NON), and having 95% or greater identity to SEQ ID NO: 96 and a light chain comprising CDRL1 (SEQ ID NO: 8), CDRL2 (SEQ ID NON), and CDRL3 (SEQ ID NO: 10), and having 95% or greater identity to SEQ ID NO: 98; for use in the treatment of an immunoinflammatory disease, particularly an immunoinflammatory skin disease.

[0214] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein: said IL- 18 binding domain comprises a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO:97 and said IL- 13 binding domain comprises a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98 for use in the treatment of an immunoinflammatory disease, particularly an immunoinflammatory skin disease.

[0215] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein, said IL- 18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and wherein said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, for use in the treatment of atopic dermatitis.

[0216] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein: i) said IL- 18 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NO:31), CDRH2 (SEQ ID NO:32), and CDRH3 (SEQ ID NO:33), and having 95% or greater identity to SEQ ID NO: 95 and a light chain comprising CDRL1 (SEQ ID NO:34), CDRL2 (SEQ ID NO:35), and CDRL3 (SEQ ID NO: 36), and having 95% or greater identity to SEQ ID NO: 97; and wherein ii) said IL- 13 binding domain comprises a heavy chain comprising CDRH1 (SEQ ID NON), CDRH2 (SEQ ID NON), and CDRH3 (SEQ ID NON), and having 95% or greater identity to SEQ ID NO: 96 and a light chain comprising CDRL1 (SEQ ID 70541FF

[0217] NO: 8), CDRL2 (SEQ ID NO: 9), and CDRL3 (SEQ ID NO: 10), and having 95% or greater identity to SEQ ID NO: 98; for use in the treatment of atopic dermatitis.

[0218] In an embodiment there is provided a multispecific antigen binding protein or bispecific antibody comprising an IL- 18 binding domain and an IL- 13 binding domain wherein: said IL- 18 binding domain comprises a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO:97 and said IL-13 binding domain comprises a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98 for use in the treatment of atopic dermatitis.

[0219] Alternatively, a subject in need may be delivered one or more nucleic acids (e.g. mRNA) encoding an IL- 13 binding protein, a multispecific antigen binding protein or bispecific antibody provided herein. The nucleic acids encoding the IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody may be delivered to the subject naked (i.e., without an encapsulating particle) or packaged (i.e., encapsulated in liposomes or polymer-based vehicles). The nucleic acid may include elements such as a poly-A tail, and a 5’ and / or 3’ untranslated region (UTR).

[0220] Further provided is the use of an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for use in the treatment of a disease, optionally wherein the disease is an immunoinflammatory disease. Further provided is the use of an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for use in the treatment of an immunoinflammatory skin disease. Further provided is the use of an IL- 13 binding protein, a multispecific antigen binding protein, a bispecific antibody, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for use in the treatment of atopic dermatitis.

[0221] Embodiments are further described in the subsequent numbered clauses:

[0222] 1. An interleukin 13 (IL-13) binding protein comprising: a. (i) any one or a combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 2, 12 or 22 and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 7, 17 or 27; or

[0223] (ii) a CDR variant of (i), wherein the variant has 1, 2, or 3 amino acid modifications; or b. a VH region comprising a sequence at least 80%, at least 85%, at least 90% or at least 95% identical to the sequence of SEQ ID NO: 2, 12 or 22; and / or a VL region comprising a sequence at least 80%, at least 85%, at least 90% or at least 95% identical to the sequence of SEQ ID NO: 7, 17 or 27.

[0224] 2. The IL- 13 binding protein of clause 1 wherein the CDR of (a) (i) is: a CDRH1 selected from SEQ ID NOs: 3, 13 or 23; a CDRH2 selected from SEQ ID NOs: 4, 14 or 24 ; and / or a CDRH3 selected from SEQ ID NOs: 5, 15 or 25 ; a CDRL1 selected from SEQ 70541FF

[0225] ID NOs: 8, 18 or 28; a CDRL2 selected from SEQ ID NOs: 9, 19 or 29; and / or CDRL3 selected from SEQ ID NOs: 10, 20 or 30.

[0226] 3. The IL- 13 binding protein of clause 1 or clause 2 wherein said IL- 13 binding protein comprises: a CDRH1 that is 100% identical to SEQ ID NOs: 3, 13 or 23; a CDRH2 that is 100% identical to SEQ ID NOs: 4, 14 or 24; and / or a CDRH3 that is 100% identical to SEQ ID NOs: 5, 15 or 25; a CDRL1 that is 100% identical to SEQ ID NOs: 8, 18 or 28; a CDRL2 that is 100% identical to SEQ ID NOs: 9, 19 or 29; and / or a CDRL3 that is 100% identical to SEQ ID NOs: 10, 20 or 30.

[0227] 4. The IL-13 binding protein of clauses 1-3 wherein all six CDRs are present in the IL-13 binding protein.

[0228] 5. The IL- 13 binding protein according to clauses 1-4 wherein said IL- 13 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 2, 12 or 22 and / or a VL region that is 100% identical to SEQ ID NO: 7, 17 or 27.

[0229] 6. An IL- 13 binding protein comprising the following 6 CDRs: a) CDRH1 of SEQ ID NO: 3 ; CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5 ; and CDRL1 of SEQ ID NO: 8 ; CDRL2 of SEQ ID NO: 9; and CDRL3 of SEQ ID NO: 10; b) CDRH1 of SEQ ID NO: 13 ; CDRH2 of SEQ ID NO: 14 and CDRH3 of SEQ ID NO: 15 ; and CDRL1 of SEQ ID NO: 18 ; CDRL2 of SEQ ID NO: 19; and CDRL3 of SEQ ID NO: 20; or c) CDRH1 of SEQ ID NO: 23 ; CDRH2 of SEQ ID NO: 24 and CDRH3 of SEQ ID NO: 25 ; and CDRL1 of SEQ ID NO: 28 ; CDRL2 of SEQ ID NO: 29; and CDRL3 of SEQ ID NO: 30.

[0230] 7. The IL- 13 binding protein according to clause 6 comprising the following 6 CDRs: CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4 and CDRH3 of SEQ ID NO : 5 ; and CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0231] 8. The IL- 13 binding protein according to clause 6 wherein said IL- 13 binding protein comprises a) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 2 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 7; b) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 12 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 17; or c) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 22 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 27.

[0232] 9. The IL- 13 binding protein according to clause 8 wherein said IL- 13 binding protein comprises a) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 2 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 7. 70541FF

[0233] 10. The IL- 13 binding protein according to clause 6 wherein said IL- 13 binding protein comprises a) a VH region that is 100% identical to SEQ ID NO: 2 and / or a VL region that is 100% identical to SEQ ID NO: 7, b) a VH region that is 100% identical to SEQ ID NO: 12 and / or a VL region that is 100% identical to SEQ ID NO: 17, or c) a VH region that is 100% identical to SEQ ID NO: 22 and / or a VL region that is 100% identical to SEQ ID NO: 27.

[0234] 11. The IL- 13 binding protein according to clause 10 wherein said IL- 13 binding protein comprises a) a VH region that is 100% identical to SEQ ID NO: 2 and / or a VL region that is 100% identical to SEQ ID NO:7.

[0235] 12. The IL-13 binding protein according to clauses 6-11 wherein said IL-13 binding protein comprises a heavy chain constant region as shown in SEQ ID NO: 99 and a light chain constant region as shown in SEQ ID NO: 100.

[0236] 13. The IL-13 binding protein according to clauses 6-12 wherein said binding protein comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 1; and the amino acid sequence of the light chain is shown in SEQ ID NO: 6.

[0237] 14. The IL-13 binding protein of clauses 1-13 wherein said IL-13 binding protein binds to human IL-13 with an affinity (KD) of less than 250 pM.

[0238] 15. The IL- 13 binding protein according to clause 14 wherein said IL- 13 binding protein binds to human IL-13 with an affinity (KD) of less than 150 pM, less than 100 pM or less than 75 pM.

[0239] 16. The IL- 13 binding protein according to any preceding clause wherein said IL- 13 binding protein inhibits IL- 13 -induced VCAM-1 upregulation in HUVEC cells.

[0240] 17. The IL- 13 binding protein according to clause 16 wherein said IL- 13 binding protein inhibits VCAM-1 upregulation with an IC50 of less than 200 pM.

[0241] 18. The IL- 13 binding protein according to any preceding clause wherein said IL- 13 binding protein blocks IL- 13 from binding to IL- 13 Rai and IL-13Ra2.

[0242] 19. The IL- 13 binding protein according to any preceding clause wherein said IL- 13 binding protein binds to an epitope comprising residues within both human IL- 13 helix A and helix D, optionally further comprising residues within human IL- 13 helix B.

[0243] 20. The IL- 13 binding protein according to any preceding clause wherein said IL- 13 binding protein binds to an epitope comprising one or more amino acids between residues G30 and Q57 wherein said numbering is in respect of the human IL-13 amino acid sequence set forth in SEQ ID NO: 102.

[0244] 21. The IL- 13 binding protein according to clause 20 wherein said epitope further comprises one or more amino acids between residues K122 and N146 wherein said 70541FF numbering is in respect of the human IL- 13 amino acid sequence set forth in SEQ ID NO: 102.

[0245] 22. The IL- 13 binding protein according to clause 20 or clause 21 wherein said epitope comprises one or more amino acids between residues G35-V51 and one or more amino acids between residues L134-N146 wherein said numbering is in respect of the human IL-13 amino acid sequence set forth in SEQ ID NO: 102, optionally wherein said epitope further comprises one or more amino acids between residues G75-N86, optionally one or more amino acids between residues C78-L81.

[0246] 23. The IL- 13 binding protein of any preceding clause wherein said IL- 13 binding protein is a human or humanized IL- 13 binding protein.

[0247] 24. The IL- 13 binding protein of any preceding clause wherein said IL- 13 binding protein is an antibody or an antigen binding fragment thereof.

[0248] 25. The IL- 13 binding protein of clause 24 wherein said antibody or antigen binding fragment thereof comprises an Fc region, said Fc region being a modified Fc region.

[0249] 26. The IL- 13 binding protein of clause 24 or clause 25 wherein said antibody or antigen binding fragment thereof has reduced effector function, such as reduced ADCC and / or CDC.

[0250] 27. The IL- 13 binding protein of clause 25 or clause 26 wherein said modified Fc region comprises the amino acid substitutions L235A and G237A (EU index numbering).

[0251] 28. A multispecific antigen binding protein comprising the IL- 13 binding protein of clauses 1-27, optionally wherein said multispecific antigen binding protein is a bispecific antibody.

[0252] 29. A multispecific antigen binding protein comprising an interleukin 18 (IL- 18) binding domain and an interleukin 18 (IL- 13) binding domain.

[0253] 30. The multispecific antigen binding protein of clause 29 wherein said IL- 13 binding domain blocks IL- 13 from binding to IL- 13 Rai and IL-13Ra2.

[0254] 31. The multispecific antigen binding protein of clause 29 or clause 30 wherein said IL- 13 binding domain binds to human IL- 13 and said IL- 18 binding domain binds to human IL-18.

[0255] 32. The multispecific antigen binding protein of clauses 29-31 wherein said IL- 18 binding domain comprises the following CDRs: a) CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36; b) CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO: 41, CDRL1 of SEQ ID NO: 42, CDRL2 of SEQ ID NO: 43 and CDRL3 of SEQ ID NO: 44; or c) CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108. 70541FF

[0256] 33. The multispecific antigen binding protein of clause 32 wherein said IL-18 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36.

[0257] 34. The multispecific antigen binding protein of clauses 29-33 wherein said IL-13 binding domain comprises the following CDRs: a. CDRH 1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10; b. CDRH 1 of SEQ ID NO: 13, CDRH2 of SEQ ID NO: 14, CDRH3 of SEQ ID NO: 15, CDRL1 of SEQ ID NO: 18, CDRL2 of SEQ ID NO: 19 and CDRL3 of SEQ ID NO: 20; c. CDRH1 of SEQ ID NO: 23, CDRH2 of SEQ ID NO: 24, CDRH3 of SEQ ID NO: 25, CDRL1 of SEQ ID NO: 28, CDRL2 of SEQ ID NO: 29 and CDRL3 of SEQ ID NO: 30; d. CDRH1 of SEQ ID NO: 47, CDRH2 of SEQ ID NO: 48, CDRH3 of SEQ ID NO: 49, CDRL1 of SEQ ID NO: 50, CDRL2 of SEQ ID NO: 51 and CDRL3 of SEQ ID NO: 52; e . CDRH 1 of SEQ ID NO : 55 , CDRH2 of SEQ ID NO : 56, CDRH3 of SEQ ID NO: 57, CDRL1 of SEQ ID NO: 58, CDRL2 of SEQ ID NO: 59 and CDRL3 of SEQ ID NO: 60; f. CDRH1 of SEQ ID NO: 63, CDRH2 of SEQ ID NO: 64, CDRH3 of SEQ ID NO: 65, CDRL1 of SEQ ID NO: 66, CDRL2 of SEQ ID NO: 67 and CDRL3 of SEQ ID NO: 68; g . CDRH 1 of SEQ ID NO : 71 , CDRH2 of SEQ ID NO : 72, CDRH3 of SEQ ID NO : 73, CDRL1 of SEQ ID NO: 74, CDRL2 of SEQ ID NO: 75 and CDRL3 of SEQ ID NO: 76; h. CDRH1 of SEQ ID NO: 79, CDRH2 of SEQ ID NO: 80, CDRH3 of SEQ ID NO: 81, CDRL1 of SEQ ID NO: 82, CDRL2 of SEQ ID NO: 83 and CDRL3 of SEQ ID NO: 84; or i. CDRH1 of SEQ ID NO: 87, CDRH2 of SEQ ID NO: 88, CDRH3 of SEQ ID NO: 89, CDRL1 of SEQ ID NO: 90, CDRL2 of SEQ ID NO: 91 and CDRL3 of SEQ ID NO: 92.

[0258] 35. The multispecific antigen binding protein of clause 34 wherein said IL-13 binding domain comprises the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10. 70541FF

[0259] 36. The multispecific antigen binding protein of clauses 29-35 wherein said multispecific antigen binding protein comprises an IL- 18 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL-13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO : 3 , CDRH2 of SEQ ID NO : 4, CDRH3 of SEQ ID NO : 5 , CDRL 1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0260] 37. The multispecific antigen binding protein of clauses 29-36 wherein said IL-18 binding domain comprises a) a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 37 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 38, b) a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 45 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 46; or c) a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 109 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 110.

[0261] 38. The multispecific antigen binding protein of clauses 29-37 wherein said IL-18 binding domain comprises a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 37 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 38.

[0262] 39. The multispecific antigen binding protein of clauses 25-32 wherein said IL-13 binding domain comprises: a. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 2 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 7; b. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 12 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 17; c. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 22 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 27; d. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 53 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO:54; e. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 61 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 62; 70541FF f. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 69 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 70; g. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 77 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 78; h. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 85 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 86; or i. a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 93 and / or a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 94

[0263] 40. The multispecific antigen binding protein of clause 39 wherein said IL- 13 binding domain comprises a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 2 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 7.

[0264] 41. The multispecific antigen binding protein of clauses 29-40 wherein said multispecific antigen binding protein comprises: i. an IL- 18 binding domain comprising a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 37 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 38; and ii. an IL- 13 binding domain comprising a VH domain comprising a sequence at least 90% identical to SEQ ID NO: 2 and a VL domain comprising a sequence at least 90% identical to SEQ ID NO: 7.

[0265] 42. The multispecific antigen binding protein of any clauses 29-41 wherein said IL- 18 binding domain comprises a) a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38, b) a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46; or c) a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110.

[0266] 43. The multispecific antigen binding protein of any clauses 29-42 wherein said IL- 18 binding domain comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38.

[0267] 44. The multispecific antigen binding protein of any of clauses 29-43 wherein said IL- 13 binding domain comprises: a. a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7; b. a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 17; c. a VH domain of SEQ ID NO: 22 and a VL domain of SEQ ID NO: 27; d. a VH domain of SEQ ID NO: 53 and a VL domain of SEQ ID NO: 54; 70541FF e. a VH domain of SEQ ID NO: 61 and a VL domain of SEQ ID NO: 62; f. a VH domain of SEQ ID NO: 69 and a VL domain of SEQ ID NO: 70; g. a VH domain of SEQ ID NO: 77 and a VL domain of SEQ ID NO: 78; h. a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86; or i. a VH domain of SEQ ID NO: 93 and a VL domain of SEQ ID NO: 94.

[0268] 45. The multispecific antigen binding protein of clause 44 wherein said IL- 13 binding domain comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

[0269] 46. The multispecific antigen binding protein of clauses 29-45 wherein said multispecific antigen binding protein comprises: i. an IL-18 binding domain comprising a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38; and ii. an IL- 13 binding domain comprising a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

[0270] 47. The multispecific antigen binding protein of clauses 29-46 comprising an Fc domain.

[0271] 48. The multispecific antigen binding protein of clause 47 wherein the Fc domain comprises a half-life extending mutation of set of mutations.

[0272] 49. The multispecific antigen binding protein of clause 47 or clause 48 wherein the Fc domain comprises M252Y, S254T and T256E (EU index numbering).

[0273] 50. The multispecific antigen binding protein of clause 47 wherein the Fc domain has reduced effector function.

[0274] 51. The multispecific antigen binding protein of clause 50 wherein said Fc domain comprises the amino acid substitutions L235A and G237A (EU index numbering).

[0275] 52. The multispecific antigen binding protein of clause 47 wherein the Fc domain comprises Azymetric Fc mutations.

[0276] 53. The multispecific antigen binding protein according to clauses 29-52 wherein said multispecific antigen binding protein comprises a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98.

[0277] 54. The multispecific antigen binding protein according to clause 29-53 wherein said multispecific antigen binding protein comprises an IL- 18 binding domain having a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO: 97 and an IL-13 binding domain having a heavy chain of SEQ ID NO: 96 and a light chain of SEQ ID NO: 98.

[0278] 55. The multispecific antigen binding protein clauses 29-54 wherein said multispecific antigen binding protein is a bispecific antigen binding protein.

[0279] 56. The multispecific antigen binding protein of clause 55 wherein said bispecific antigen binding protein is a bispecific antibody. 70541FF

[0280] 57. An anti-IL-18 and anti-IL-13 bispecific antibody comprising anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33 , CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

[0281] 58. The bispecific antibody of clause 57 wherein said anti-IL-18 comprises a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38 and wherein said anti-IL-13 comprises a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

[0282] 59. An anti-IL-18 and anti-IL-13 bispecific antibody, comprising: anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36; anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, wherein the anti-IL-18 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 95 and a light chain having a sequence at least 95% identical to SEQ ID NO: 97 and the anti-IL13 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 96, and a light chain having a sequence at least 95% identical to SEQ ID NO: 98.

[0283] 60. The bispecific antibody according to clause 59 comprising: anti-IL-18 having the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, an Fc region comprising M252Y, S254T and T256E (EU index numbering); and wherein the anti-IL-18 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 95 and a light chain having a sequence at least 95% identical to SEQ ID NO : 97 and the anti-IL13 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 96, and a light chain having a sequence at least 95% identical to SEQ ID NO: 98.

[0284] 61. The anti-IL-18 and anti-IL-13 bispecific antibody according to clause 60 wherein said Fc region further comprises the amino acid substitutions L235A and G237A (EU index numbering). 70541FF

[0285] 62. The anti-IL-18 and anti-IL-13 bispecific antibody according to clauses 59-61, wherein anti-IL-18 comprises the heavy chain of SEQ ID NO: 95 and the light chain of SEQ ID NO: 97 and wherein anti-IL-13 comprises the heavy chain of SEQ ID NO: 96 and the light chain of SEQ ID NO: 98.

[0286] 63. A nucleic acid sequence encoding the IL- 13 binding protein of clauses 1-27, the multispecific antigen binding protein of clauses 28-56 or the bispecific antibody of clauses 57-62.

[0287] 64. A nucleic acid sequence encoding any one, two, three or all four of the following amino acid sequences: a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98.

[0288] 65. An expression vector comprising the nucleic acid sequence(s) of clause 63 or clause 64.

[0289] 66. A recombinant host cell comprising the nucleic acid sequence(s) according to clause 63 or clause 64 or the expression vector(s) according to clause 65.

[0290] 67. A method for the production of an IL- 13 binding protein, a multispecific antigen binding protein or a bispecific antibody said method comprising culturing the recombinant host cell according to clause 66 under conditions suitable for expression of said nucleic acid sequence(s) or vector(s), whereby said IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody is produced.

[0291] 68. A multispecific antigen binding protein produced by the method of clause 67.

[0292] 69. A cell line engineered to express the IL- 13 binding protein according to any of clauses 1-27, the multispecific antigen binding protein according to any one of clauses 28-56 or the bispecific antibody according to any one of clauses 57-62.

[0293] 70. A pharmaceutical composition comprising the IL-13 binding protein of clauses 1-27, the multispecific antigen binding protein according to any one of clauses 28-56 or the bispecific antibody according to any one of clauses 57-62 in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0294] 71. A method for the prevention or treatment of a disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the IL- 13 binding protein of clauses 1-27, the multispecific antigen binding protein according to any one of clause 28-56, the bispecific antibody according to any one of clauses 57-62, or the pharmaceutical composition according to clause 70.

[0295] 72. A method for the prevention or treatment of an immunoinflammatory disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the IL- 13 binding protein of clauses 1-27, the multispecific antigen binding protein according to any one of clause 28-56, the bispecific antibody according to any one of clauses 57-62, or the pharmaceutical composition according to clause 70. 70541FF

[0296] 73. The method of clause 72 wherein the immunoinflammatory disease is an immunoinflammatory skin condition.

[0297] 74. The method of clause 73 wherein the immunoinflammatory skin condition is atopic dermatitis.

[0298] 75. The IL-13 binding protein of clauses 1-27, the multispecific antigen binding protein according to any one of clauses 28-56, the bispecific antibody according to any one of clauses 57-62, or the pharmaceutical composition according to clause 70 for use in the prevention or treatment of disease.

[0299] 76. The IL-13 binding protein of clauses 1-27, the multispecific antigen binding protein according to any one of clause 28-56, the bispecific antibody according to any one of clauses 57-62, or the pharmaceutical composition according to clause 70 for use in the prevention or treatment of an immunoinflammatory disease.

[0300] 77. The IL-13 binding protein, multispecific antigen binding protein, bispecific antibody or pharmaceutical composition for use according to clause 76 wherein the immunoinflammatory disease is an immunoinflammatory skin condition.

[0301] 78. The IL 13 binding protein, multispecific antigen binding protein, bispecific antibody or pharmaceutical composition for use according to clause 77 wherein the immunoinflammatory skin condition is atopic dermatitis.

[0302] 79. Use of an IL-13 binding protein according to clauses 1-27, a multispecific antigen binding protein according to any one of clauses 28-56, a bispecific antibody according to any one of clauses 57-62, or a pharmaceutical composition according to clause 70 in the manufacture of a medicament for use in the treatment of a disease, optionally wherein the disease is an immunoinflammatory disease.

[0303] 80. Use of an IL-13 binding protein according to clauses 1-27, a multispecific antigen binding protein according to any one of clauses 28-56, a bispecific antibody according to any one of clauses 57-62, or a pharmaceutical composition according to clause 70 in the manufacture of a medicament for use in the treatment of atopic dermatitis.

[0304] The invention is further illustrated by the following non-limiting examples.

[0305] EXAMPLES

[0306] In the Examples section below, the following antibodies are referred to (see Table 3):

[0307] Table 3: Description of Antibodies used throughout Examples 70541FF 70541FF

[0308] Example 1: Generation of IL-13 binding proteins

[0309] Anti-IL-13 antibodies were generated by diversification of anti-IL-13 control 3, in one extended cycle of optimisation utilising antibody library screening using a yeast display platform. The heavy chain and light chain CDRs of Anti-IL-13 control 3 were diversified independently through the introduction of random mutations at a low frequency. During the first cycle of optimisation, three rounds of selections were performed on libraries with diversified HC CDRs paired with parental light chain and diversified LC CDRs paired with parental heavy chain. The selection methods included magnetic cell sorting (MACS) and fluorescence activated cell sorting (FACS) against the human and cynomolgus IL-13 antigens, including parental fAb competition pressuring. The selected heavy chains were then isolated and combined with the diversified light chains, and an additional four selection rounds were performed using MACS, FACS and fAb competition pressuring to isolate IL- 13 binders with improved affinity. 70541FF

[0310] Output sequences from this screen were evaluated in silico for predicted post translational modification (PTM) and immunogenicity risks and based on this and affinity data, three leads (aIL13-l, aIL13-2 and aIL13-3) were selected with improved affinity over the parental antibody.

[0311] Table 4 shows the kinetic rate constants and dissociation constants of the binding of selected leads, parental Anti-IL-13 control 3, an IgGl control with variable domain sequence equivalent to Tralokinumab (Anti-IL13 control 4) and Tralokinumab to CHO-derived human IL-13. Results show KD value for the binding to human IL- 13 of the affinity matured variants were improved 14 - 40-fold as compared to that of anti-IL-13 control 3. All of aIL13-l, -2 and -3 bind to human IL- 13 with significantly greater potency than Tralokinumab.

[0312] Table 4 Assessment of SPR kinetics of human IL-13 binding to affinity matured anti- IL-13 variants at 37°C.

[0313] Example 2: Generation of multispecific binding proteins

[0314] Variants of aIL-13-1 (aIL-13-l-var), aIL13-2 (aIL13-2-var) and aIL13-3 (aIL13-3-var) were generated in silico in which CDR sequences from light chains were grafted onto the human IGKV1D 39 framework, achieved by taking CDRL1-3 loops and replacing them at the equivalent position in the IGKV1D_39 (NCBI Gene ID: 28893) sequence.

[0315] Sequences for aIL-13-l-var (SEQ ID NOs: 1-10), aIL13-2-var (SEQ ID NOs: 11-20) and aIL13-3- var (SEQ ID NOs: 21-30) are provided herein.

[0316] A panel of heterodimeric bi-specific antibodies were generated by pairing each of the anti-IL-13 variable domain sequences with the selected anti-IL-18 arm (variable domains SEQ ID NO: 37 & 38), each expressed with human IgGl / kappa constant domains. Additional engineering mutations were introduced into a subset of the panel to remove potential post-translational modifications (PTM) and immunogenicity risks (identified via in silico sequence analysis).

[0317] The mutations L235A and G237A (EU numbering) and M252Y, S254T and T256E were included in the bispecific antibody heavy chains. 70541FF

[0318] To promote the correct assembly of the bispecific antibody specific CL, CHI and CH3 mutations were introduced into the sequences.

[0319] Variable domains were combined with constant domain sequences containing CL and CHI mutations that selectively favour pairing between either the anti IL- 13 heavy and light chains or anti IL- 18 heavy and light chains and that reduce pairing between either the anti IL- 13 light chain and anti IL- 18 heavy chain or vice versa (three different CL / CH1 pairing mutation sets were tested).

[0320] CH3 mutations that selectively favour heterodimeric heavy-heavy chain pairing were also introduced.

[0321] Bispecific anti-IL-13 x anti-IL-18 antibodies were generated through stable transfection of CHO cells. Expressed material was purified from the culture supernatant by Protein A affinity capture. Expressed molecules were then evaluated for expression yield, proportion of correctly assembled molecules, target binding affinities, IL- 13 neutralization potency and stability.

[0322] Table 5 shows a summary of the variants evaluated, the production run yield and the proportion of molecules that were correctly assembled. Results show that TPP- 16674 had the highest expression yield and one of the highest correct chaining proportions across the panel.

[0323] Table 5 Production yield and correctly assembled molecule proportion of bispecific molecule designs evaluated. All bi-specific molecules contained LAGA / YTE Fc mutations. 70541FF

[0324] *TPP-16664 / -65 / -66 / -67 and TPP-16668 / -69 sequences contained different post-translational modification derisking mutation(s).

[0325] **TPP-16671 / -72 / -73 sequences contained different immunogenicity de-risking mutation(s).

[0326] Table 6 below shows the dissociation constants of binding of selected lead panel molecules and anti-IL13 control 4 to mammalian-derived human IL- 13, E. co / z-derived human IL- 13 Q130R (Q144R in Uniprot sequence shown in SEQ ID NO: 102), mammalian-derived cynomolgus IL-13 and mammalian-derived human IL-18. Results show that TPP- 16674 ranked fifth for affinity to human IL- 13, within 2-fold of the highest affinity variant.

[0327] Table 6 Assessment of binding of TPP-16674 and other IL-13xIL-18 bispecific lead panel molecules to human, human Q130R variant and cynomolgus monkey IL-13 and human IL-18 at 37°C. 70541FF

[0328] For the bispecific antibodies that showed strong binding to both IL- 13 and IL- 18, Table 7 below shows changes in monomer proportion and binding to human IL- 13 and human IL- 18 occurring after a 2-week incubation at 40°C in either acidic or neutral buffer. Results show that TPP- 16674 has a favorable profile as compared to other candidates, remaining monomeric and retaining binding.

[0329] Table 7 Assessment of changes in monomer proportion and proportional target antigen binding of lead anti-IL-13, anti-IL-18 bispecific molecules after 2 week incubation at 40°C in neutral and acidic buffers. 70541FF

[0330] Example 3: IL-13 Neutralization Potency

[0331] The comparative activity of TPP- 16674 to neutralize IL- 13 signaling was evaluated by inhibition of recombinant huIL-13 induced VCAM-1 upregulation in HUVEC cells, using an identical protocol to Example 5 a (n=2).

[0332] The TPP 16674 (“RF mutant”) used in this experiment contained identical variable domains to TPP- 16674 (i.e. VH domain of SEQ ID NO: 2 and VL domain of SEQ ID NO: 7). The only difference was that H435R / Y436F (RF) mutations were included in the CH3 domain of one heavy chain to ablate Protein A binding.

[0333] Table 8 below shows the relative potency of TPP- 16674 (“RF mutant”) in comparison to Tralokinumab and Anti-IL13 control 3.

[0334] Results show that the potency (pICso) of TPP- 16674 at inhibiting IL- 13 induced upregulation of VCAM-1 was approximately 3.4-fold higher than anti-IL13 control 3 and 13.5 -fold higher than Tralokinumab (see Fig. 1).

[0335] Table 8 Relative potency of human IL-13 signalling in HUVEC VCAM-1 upregulation assay.

[0336] *Fc variant of IL-13 control 3 having LAGA / YTE and Het mAb Fc mutations to enable comparison versus TPP- 16674 Het mAb format bispecific.

[0337] ** H435R Y436F present in Fc domain

[0338] The significant improvement in potency of TPP- 16674 (RF) compared to both anti-IL-13 control 3 and Tralokinumab (shown in Table 8 above) was observed despite TPP- 16674 having a monovalent anti-IL-13 arm compared to the bivalent anti-IL13 antibodies, Tralokinumab and anti- IL-13 control 3. 70541FF

[0339] Table 9 below shows (for a different bispecific antibody) that bivalency in terms of anti-IL-13 arms resulted in over double the potency versus Tralokinumab (in terms of pICso) within this VCAM-1 HUVEC assay, compared to an IL- 18 x IL- 13 heterodimeric bispecific antibody having comparable anti-IL13 variable domains (but that is monovalent against IL-13). It is thus inferred that variable domains neutralize IL- 13 independently of each other, as might be predicted for a 1: 1 interaction in solution, and that the observed difference is due to the 2-fold difference in variable domain concentration.

[0340] Table 9 Relative potency of human IL-13 signaling in HUVEC VCAM-1 up-regulation assay.

[0341] *aIL-13-l being one of the three maturation leads described in Example 1 prior to light chain grafting onto the human IGKV1D 39 framework

[0342] Collectively the data presented in Example 2 and 3 demonstrates that TPP- 16674 binds IL- 13 with high affinity, with high proportion of correct molecular assembly and stability. TPP- 16674 also exhibits superior expression. The anti-IL-13 portion of TPP-16674 is based on aIL13-l with the light chain switched to the IGKV1D 39 framework (aIL-13-l-var) but does not contain additional engineering changes.

[0343] Crucially, the anti-IL-13 portion of TPP-16674 (i.e. aIL-13-l-var) demonstrated significantly improved potency to inhibit IL- 13 induced VCAM-1 upregulation compared to Tralokinumab and anti-IL-13 control 3 despite its monovalency for IL-13.

[0344] Example 4: Binding Affinity 70541FF

[0345] Example 4a: Assessment of SPR kinetics of human and cynomolgus monkey IL-13 binding to

[0346] TPP-16674 at 37°C

[0347] Binding of human and cynomolgus monkey IL- 13 to TPP-16674 was assessed using multicycle capture kinetics on the Biacore 8K+ (Cytiva) SPR instrument. Binding was compared to positive controls: anti-IL-13 control and anti-IL-13 control 2 (anti-IL-18 control was used as a negative control).

[0348] The antibodies were diluted in running buffer (HBS-EP+ pH 7.4) to a concentration of 2 pg / ml and were captured on a CM5 sensorchip surface (Cytiva) with immobilized goat anti-human Fc capture antibody, at an injection rate of 10 pl / min. Analytes were injected over the captured antibodies as a concentration series including nine 2-fold serial dilutions with the highest concentration of 32 nM at an injection rate of 50 pl / min. The association phase was 240 seconds, followed by a dissociation phase of 1200 seconds. A buffer only (0 nM analyte) injection was used to double reference the binding curves. Regeneration of the chip surface between cycles was carried out using 10 mM Glycine pH 1.5. The assay was run at 37°C in HBS-EP+ pH 7.4 buffer. Kinetics were analysed in three independently prepared replicate experiments.

[0349] Table 10 shows the kinetic rate constants as well as final KD values. The values shown in the table are geometric mean of n=3 independently prepared and executed measurements. Negative control (anti-IL-18 control) did not bind, as expected.

[0350] Table 10 Assessment of SPR kinetics of human IL-13 (hIL-13) and cynomolgus monkey IL-13 (cIL-13) binding to TPP-16674 at 37°C

[0351] Example 4b: Assessment binding of TPP-16674 to human and rhesus monkey IL-18 at 37°C 70541FF

[0352] Binding of human and rhesus monkey IL- 18 to TPP-16674 was assessed using multicycle capture kinetics on the Biacore 8K+ (Cytiva) SPR instrument. The sequence of cynomolgus monkey and rhesus macaque IL-18 sequence is 100% identical. Binding was compared to anti-IL-18 control used as positive control. Negative controls included were anti-IL-13 control 2 and anti-IL-13 control.

[0353] The antibodies, including controls were diluted in running buffer (HBS-EP+ pH 7.4) to a concentration of 2 pg / ml and were captured on a CM5 sensorchip surface (Cytiva) with immobilized commercial goat anti human Fc capture antibody at an injection rate of 10 pl / min. Analytes were injected over the captured antibodies as a concentration series including eleven 2- fold serial dilutions with the highest concentration of 32 nM at an injection rate of 50 pl / min. The association phase was 240 seconds, followed by a dissociation phase of 1200 seconds. A buffer only (0 nM analyte) injection was used to double reference the binding curves. Regeneration of the chip surface between cycles was carried out using 10 mM Glycine pH 1.5. The assay was run at 37°C in HBS-EP+, pH 7.4 buffer. Kinetics were analysed in three independently prepared replicate experiments.

[0354] Table 11 shows the kinetic rate constants as well as final KD values. The values shown in the table are geometric mean of n=3 independently prepared and executed measurements. Negative controls did not bind, as expected.

[0355] Table 11 Assessment of binding of TPP-16674 to human IL-18 (hIL-18) and rhesus monkey IL-18 (rhIL-18) at 37°C

[0356] Example 4c: Assessment of SPR kinetics of human IL-13 variant binding to TPP-16674 at 37°C 70541FF

[0357] Binding of human IL-13 variant (R130Q) as well as human IL-13 to TPP-16674 was assessed using multicycle capture kinetics on the Biacore 8K+ (Cytiva) SPR instrument. Binding was compared to positive controls: anti-IL-13 control 2 and anti-IL-13 control 1. Anti-IL-18 control was used as a negative control.

[0358] The antibodies were diluted in running buffer (HBS-EP+ pH 7.4) to a concentration of 10 pg / ml and were captured on a CM5 sensorchip surface (Cytiva) with immobilized goat anti-human Fc capture antibody, at an injection rate of 10 pl / min. Analytes were injected over the captured antibodies as a concentration series including thirteen 2-fold serial dilutions with the highest concentration of 256 nM at an injection rate of 50 pl / min. The association phase was 240 seconds, followed by a dissociation phase of 1200 seconds. A buffer only (0 nM analyte) injection was used to double reference the binding curves. Regeneration of the chip surface between cycles was carried out using 10 mM Glycine pH 1.5. The assay was run at 37°C in HBS-EP+ pH 7.4 buffer. Kinetics were analysed in three independently prepared replicate experiments.

[0359] Binding of TPP-16674 to commercial E. coli produced recombinant human IL-13 variant at 37°C was assessed using SPR using the Biacore 8K+ instrument. It was compared to an in-house E. coli produced non-variant recombinant human IL-13. Table 12 shows the kinetic rate constants as well as final KD values. The values shown in the table are geometric mean of n=3 independently prepared and executed measurements. Final KD values were within <3 fold of each other (n=3) between the replicate experiments. Final KD values for variant and non-variant human IL-13 were comparable (within 2-fold of each other).

[0360] Table 12: Assessment of SPR kinetics of human IL-13 variant binding to TPP-16674 at 37°C 70541FF

[0361] Example 4d: Dual engagement of human IL- 13 and human IL- 18 by TPP- 16674

[0362] Dual engagement of human IL-13 and human IL-18 by TPP-16674 was determined using a binding assay on the Sartorius Octet RED384 biolayer interferometry (BLI) instrument. TPP-16674 binding was compared to controls: anti-IL-13 control and Anti-IL-18 control. The antibodies were diluted in PBSF to 50 ug / ml and captured on anti -human Fc biosensors (600s loading time). The sensors were then dipped into PBSF (120s) to establish a baseline, followed by dipping into IL-18 (128 nM, 30s association time) and finally followed by dipping into IL-13 (120 nM, 30s association time). Blank sensors were included to check for nonspecific binding of the proteins to the sensors. The analysis was run at 25 °C, with a plate shaker speed of 1000 rpm. Data were aligned to the baseline but no kinetics model was applied to the data.

[0363] There was no non-specific binding of the human IL- 13 nor the human IL- 18 to the anti -human Fc sensors. Simultaneous binding of TPP-16674 to human IL-13 and IL-18 was successfully confirmed in both orientations (both IL- 13 first followed by IL- 18 as well as IL- 18 first followed by IL-13, results summarized in Table 13).

[0364] Table 13 Dual engagement of human IL-13 and human IL-18 by TPP-16674. 70541FF

[0365] Example 4e: Assessment of binding of TPP-16674 to human and cynomolgus monkey FcRn at pH 6,0 and pH 7,0 using SPR

[0366] TPP-16674 as well as control molecules were analysed for binding to human FcRn at acidic ‘endosomal’ pH6.0 (at 25°C). Biotinylated FcRn receptors were captured on a Biotin CAP series S sensor chip (Cytiva). Ligands were diluted to 0.5 pg / mL before being injected over the sensorchip flow cell 2 from channels 1-6 for 30 seconds. All antibodies were flowed over the immobilised FcRn at 0.122 nM, 0.488 nM, 1.95 nM, 7.81 nM, 31.25 nM, 125 nM, 500 nM and 2000 nM using single cycle kinetics method with association of 180s and dissociation of 1200s. Running buffer was HBS EP+ at pH6.0 with pH adjusted in-house. The regeneration buffer from the biotin capture kit was used, which was a 1:3 mix of IM sodium hydroxide and 8M Guanidine Hydrochloride. The surface activation buffer (CAPture Reagent) was diluted 3 -fold in running buffer and was used as a conditioning step prior to immobilisation / capture of biotinylated proteins.

[0367] TPP-16674 behaved comparatively to the anti-RSV control 2, only a slight reduction in affinity was observed to human (within 2.2 fold) and cynomolgus monkey (within 2.5 fold) FcRn at pH6.0. Table 14 shows the KD values obtained.

[0368] Table 14: Binding of TPP-16674 to human and cynomolgus monkey FcRn at pH 6.0

[0369] Example 4f: Assessment of binding of TPP-16674 to recombinant human and cynomolgus monkey Fc gamma receptors (FcyRs)

[0370] Binding to recombinant human and cynomolgus monkey Fey receptors (FcyR) was assessed using the Biacore 8K+ (Cytiva) SPR instrument. TPP-16674 was compared to a previously assessed positive control antibody containing a wild type human IgGl Fc region (anti-RSV control 3) and anti-RSV control 2 mutations.

[0371] Biotinylated human and cynomolgus monkey FcyR proteins were captured onto flow cell 2 of 8 channels of a Biotin CAP series S sensor chip by capture onto Biotin CAPture reagent. TPP-16674 70541FF and the control antibodies were injected over the FcyR coated chip surface at 4000 nM, 1000 nM, 250 nM, 62.5 nM and 15.62 nM. Antibodies were injected from the lowest concentration to the highest concentration for 180 seconds at 30 pL / min followed by a 1200 second dissociation step. A 0 nM (i.e. buffer only) injection was used to double reference the binding curves. The surface was regenerated with 6M guanidine-HCl, 0.25M NaOH between interactions. The run was carried out at 25°C using HBS-EP+ as the running buffer.

[0372] Following assessment of binding of TPP-16674 to recombinant human and cynomolgus monkey Fc gamma receptors (FcyRs) TPP-16674 showed no measurable binding to Fc gamma receptors. Anti- RSV-LAGA YTE control showed either no binding or signs of a very weak binding, which was not measurable. Binding of anti-RSV WT control antibody to all human proteins tested was measurable and the KD values are included in Table 15 and Table 16. TPP-16674 showed a clear lack of Fc gamma receptors binding.

[0373] Table 15 Assessment of binding of TPP-16674 to recombinant human Fc gamma receptors. NB = No binding, WB = Weak binding

[0374] Table 16 Assessment of binding of TPP-16674 to recombinant cynomolgus monkey Fc gamma receptors. NB = No binding, WB = Weak binding 70541FF

[0375] Example 5: IL-13 inhibition Data

[0376] Example 5a: Neutralisation of human IL-13

[0377] The VCAM-1 MSD assay was used to test the ability of TPP-16674 to neutralise IL-13 induced VCAM-1 upregulation in HUVECs. HUVECs were seeded in a flat-bottom 96 well plate at a density of 4xl05cells / mL in I OOpL growth media (Endothelial Cell Growth Medium 2 Kit) and incubated overnight at 37°C, 5% CO2. After incubation, 2.4 pM - 48000 pM TPP-16674 (or anti- IL-13 control and anti-RSV control) were pre-incubated with 80 pM human IL- 13 in a 1: 1 ratio for 1 hour at room temperature. The HUVECs were then washed with 100 pL PBS and 50 pl growth media was added to each well. 50 pl / well of the antibody-antigen complex was then added to the plate of HUVECs. Additionally, either 50 pl media alone or 50 pl media containing 40 pM human IL- 13 was added to control wells as negative and positive controls, respectively. The cells were returned to the incubator overnight at 37°C, 5% CO2. Final assay concentrations were 0.61 pM - 12000 pM mAb / control mAbs, 20 pM human IL- 13 and a HUVEC cell density of 4xl04cells per well. An MSD custom human 96-well multi -array plate was coated with a VCAM-1 capture antibody. After incubation, the cells were lysed using 75 pL of lysis buffer and the VCAM-1 signal was detected from 50 pl of the cell lysate using a standard MSD immunoassay procedure and a biotinylated VCAM-1 detection antibody. This assay was repeated 3 times for total of 5 plates and 13 replicates of TPP-16674.

[0378] Human IL- 13 induced VCAM-1 upregulation by HUVECs was used to test the neutralisation of human IL-13 by the IL-13xIL-18 HET-mAb TPP-16674. TPP-16674 was found to neutralise human IL-13 with a mean IC50 of 147.13 pM. The negative anti-RSV control antibody anti-RSV control was found to be inactive in this assay. Table 17 summarises the mean and range of the IC50 / PIC50 values for each antibody.

[0379] Table 17 Human IL-13 neutralisation by TPP-16674, parental and control antibodies 70541FF

[0380] Example 5b: Neutralisation of variant IL-13 by TPP-16674

[0381] An identical protocol to Example 5 a was followed for the variant HUVEC assay, with the exception of replacing the human IL-13 cytokine with the variant IL-13 (R130Q) and preincubating the antibodies with 200 pM variant IL- 13 instead of 80 pM of human IL-13. The concentration range of antibodies at the pre-incubation step was 2.4 pM-48000 pM. Final assay concentrations were 50 pM of variant IL- 13 and the concentration ranges of antibodies in the assay were 0.61 pM - 12000 pM.

[0382] TPP-16674 was found to neutralise variant IL-13 with a mean IC50 of 690.06 pM (Error!

[0383] Reference source not found.18). The negative control antibody (anti-RSV control) was found to be inactive in this assay.

[0384] Table 18 Variant IL-13 neutralisation by TPP-16674, parental and control antibodies

[0385] Example 5c: Neutralisation of cynomolgus IL- 13 by TPP-16674

[0386] An identical protocol to Example 5a was followed for the cynomolgus HUVEC assay with the exception of replacing the human IL- 13 cytokine with the cynomolgus IL- 13 and pre-incubating the antibodies with 1264 pM instead of 80 pM human IL-13. The concentration range of antibodies at the pre-incubation step was 2.10 pM-8000 pM. Final assay concentrations were 316 pM of cynomolgus IL-13 and the concentration ranges of antibodies were 0.52 pM-2000 pM.

[0387] TPP-16674 was found to neutralize cynomolgus IL-13 with a mean IC50 of 48.79 pM. The negative anti-RSV control antibody was found to be inactive in this assay. Table 19 summarises the mean and range of the IC50 / PIC50 values for each antibody.

[0388] Table 19 Cynomolgus IL-13 neutralisation by TPP-16674, parental and control antibodies 70541FF

[0389] Example 5d: TPP- 16674 (aIL-13xIL-18 Het-mAb) effectively neutralises IL- 13 induced reduction of Filaggrin (FLG) and Loricrin (LOR) gene expression in differentiated primary neonatal normal human epidermal keratinocytes (neo-NHEK),

[0390] Neo-NHEK were seeded at a density of 1.5 x 105cells per well in 6-well plates, in normal keratinocytes growth medium for 72 hours. After 72-hours the normal keratinocyte growth medium was changed to include 1.3 mM CaCL to induce neo-NHEK differentiation (referred to as 'high CaCL media' hereafter). To evaluate the expression of key barrier genes (FLG & LOR), 72 hours post seeding, media was changed to enable stimulation of the neo-NHEK with 406 pM recombinant human (rh) interleukin (IL)- 13 (rhIL-13, R&D Systems) and 40 6pM of rhIL-18 (R&D Systems) in high CaCL media. These cytokines were added in the presence of 30 nM TPP-16674 (aIL13xIL18 Het-mAb), anti-IL-13 control, anti-IL-18 control, or anti-RSV control, and preincubated for 30 minutes at 37°C in a 5% CO2 before adding to the neo-NHEK. The neo-NHEK were cultured for an additional 120 hours then RNA was extracted. Neo-NHEK cultured in high CaCL media without cytokines and antibodies were treated as “media control”, and neo-NHEK cultured in high CaCL media containing cytokines (IL- 13 and IL- 18) without antibodies were treated as “no mAb control”.

[0391] Neo-NHEK were lysed using 400 pL of RLT lysis buffer (QIAGEN) then RNA was extracted using the QIAsymphony RNA extraction kit (Qiagen). Total RNA was isolated using QIAsymphony SP (QIAGEN) following the manufacturer's guidelines. The quality and quantity of extracted RNA was evaluated using the Nanodrop (ThermoFisher). To obtain complementary DNA (cDNA), reverse transcription reactions were performed using 150 ng of total RNA and Superscript IV first strand reverse transcriptase kit (ThermoFisher) in a 40 pL total volume according to the manufacturer’s instructions. Reverse transcription quantitative polymerase chain reaction (RT- qPCR) were conducted in single plex, in a 20pL total volume containing IpL of diluted cDNA, RNAse-free H2O (Invitrogen), IxTaqMan Fast Advanced Master Mix (ThermoFisher), and IxTaqMan primers / probe (hypoxanthine phosphoribosyl transferase 1 (HPRTl-Hs03929098_ml), ubiquitin C (UBC-Hs00824723-ml), filaggrin (FLG-Hs00856927_g I ) and loricrin (LOR- HsO518719_sI) (ThermoFisher). Real-Time PCR (RT-PCR) was performed using QuantStudio 7 70541FF

[0392] Flex (ThermoFisher) using QuantStudio flex qPCR thermocycling program. Two reference “housekeeping” genes HPRT1 and UBC were used for data normalization.

[0393] Stimulation with 406 pM IL- 13 alone or in combination with 406 pM IL- 18 resulted in a significant reduction in the expression of both FLG and LOR genes when comparing to the media control, with an estimated percentage reduction of approximately 60% in all cases (p<0.001) (Fig. 2, Fig. 3 and Table 20).

[0394] Table 20 IL-13 but not IL-18 reduces the expression of barrier genes (Filaggrin FLG and Loricrin LOR) in differentiated primary neonatal human epidermal keratinocytes relative to the media control

[0395] When comparing FLG and LOR gene expression between IL-13+IL-18 only stimulation (IL- 13+IL-18 no-mAb control) condition and IL- 13+ IL- 18 stimulation in the presence of antibody treatment, an estimated fold increase in FLG gene expression of 1.8-fold (p<0.033) and 2.5-fold (p<0.001) when in the presence of TPP-16674 and anti-IL-13 control treatment respectively was observed. The estimated fold increase in LOR gene expression of 2.67-fold (p<0.0001) or 3.4-fold (p<0.0001) when in the presence of TPP-16674 or anti-IL-13 control treatment respectively was also observed (Table 21).

[0396] Similar trends were observed when comparing the impact of TPP-16674 or anti-IL-13 control on FLG and LOR gene expression relative to the aRSV isotype control (data not shown). 70541FF

[0397] Table 21 TPP-16674 and anti-IL-13 control but not anti-IL-18 control nor anti-RSV control increase barrier gene expression (Filaggrin FLG and Loricrin LOR relative to the no antibody (no mAb) control.

[0398] Comparisons between TPP-16674 (aIL-13xIL-18 Het-mAb) or anti-IL-13 control conditions with the media control indicates that mean FLG and LOR gene expression levels were recovered towards the level observed within the media control, as all fold change in gene expression relative to the media control were no longer statistically significant. The data thus suggests that expression levels have been restored to a large degree. In contrast, neither anti-IL-18 control nor anti-RSV control restored FLG or LOR gene expression.

[0399] Example 6: IL-18 inhibition

[0400] Example 6a: Neutralisation ofhuman IL-18 by TPP-16674

[0401] The IFNy MSD assay was used to test the ability of TPP-16674 to neutralise IL- 18 induced IFNy signalling in the KG-1 cell line. KG-1 cells were stimulated with 10 ng / mL human TNFa in assay media (IMDM (Gibco 21980-032) + 10% FBS (Gibco 10100-147) and incubated overnight at 37°C, 5% CO2. Post incubation, 3.5 pM -13332 pM TPP-16674 (or control molecules anti-IL-18 control, anti-IL-18 control 2, and anti-RSV control) were pre-incubated with 332 pM human IL-18 in a 1: 1 ratio for 30 minutes at room temperature. Following pre-incubation, 100 pl of antibodyantigen complex was added per well to a F-bottom 96 well plate (Coming 3596). Additionally, 70541FF either 100 pl media alone or 100 pl media containing 166 pM human IL- 18 was added to control wells as a negative and positive controls, respectively. To the preincubated mAbs or control wells, 100 pl of KG-1 cells (IxlO6cells / ml) were added and mixed using an orbital rocker for 30 seconds The cells were returned to the incubator overnight at 37°C, 5% CO2. Final assay concentrations were 0.87 pM - 3333 pM HET-mAb / control mAbs, 83 pM human IL-18 and a KG-1 cell density of 0.5x106cells / ml. After incubation, assay plates were centrifuged to pellet the cells before the detection of the IFNy signal from 25 pl of cell supernatant using a standard MSD V-PLEX human IFN-y detection kit (K151QOD-4; Meso Scale Discovery).

[0402] TPP-16674 was found to neutralise human IL-18 with a mean IC50 of 52.99 pM (Table 22). The anti-IL-18 control was observed to be 2.15-fold more potent, with a mean IC50 of 24.59 pM. The anti-IL-18 control 2 had a similar potency to TPP-16674. The negative control (anti-RSV control) was inactive in this assay.

[0403] Table 22 Human IL-18 neutralisation by TPP-16674, parental and control antibodies (N=12)

[0404] Example 6b: Neutralisation of cynomolgus IL-18 by TPP-16674

[0405] An identical protocol to Example 6a was followed for the cynomolgus KG-1 assay, with the exception of replacing the human IL- 18 cytokine with the same concentration of cynomolgus IL- 18.

[0406] TPP-16674 was found to neutralise cynomolgus IL-18 with a mean IC50 of 48.98 pM (Table 23). The anti-IL-18 control was observed to be 2.51-fold more potent, with a mean IC50 of 19.50 pM. anti-IL18 control 2 control had a similar potency to TPP-16674. The negative control (anti-RSV) was inactive in this assay. 70541FF

[0407] Table 23 Cynomolgus IL-18 neutralisation by TPP-16674, parental and control antibodies (N=12)

[0408] Example 7: The dual inhibitory effect of TPP-16674 (cdL-13xIL-18 Het-mAb) on cytokine secretion from CD4+ T cell stimulated with IL-18 and IL-13

[0409] CD4+ T cells were isolated from whole blood derived from healthy human volunteer donors collected by venepuncture into 1% sodium heparin (Wockhardt). Blood was diluted 1: 1 (v:v) in Phosphate buffer saline (PBS) and cell fractions were separated by density gradient centrifugation using Ficoll-Paque plus (Cytiva). The enriched cell fractions were pooled in a 50ml Falcon tube, centrifuged, and the cell pellets washed with PBS and resuspended in EasySep buffer (Stemcell Technologies) to gain a final concentration of 5xl07cells / ml. Centrifugation at the speed of 395x g for 5 minutes were applied between procedures unless stated. All cell counts were performed using the Nucleocounter (Chemonetec). CD4+ T cells were isolated from the PBMCs using the human CD4+ T cell enrichment kit (Stemcell Technologies) according to the manufacturer’s instruction. The enriched CD4+ T cells were centrifuged for 5 minutes at 395x g then resuspended to a final concentration of IxlO6cells / ml in RPMI 1640 (Gibco) cell media containing 10% foetal bovine serum (FBS; Gibco), 1% L-Glutamine (Gibco), 1% Penicillin-Streptomycin (Gibco), and 570 pM human IL-7 (Miltenyi Biotech).

[0410] TPP-16674 (aIL-13xIL-18 Het-mAb), anti-IL-13 control, anti-IL-18 control, and anti-RSV control were titrated as a twelve-point 3 -fold titration with a range of 30 nM to 0. 169 pM in the cell media containing 570 pM of IL-7, 220 pM of IL-12, 167 pM of IL-18, and 244 pM of IL- 13. The recombinant IL- 12 was supplemented in the cell media to promote the synergistic impact of IL- 18 to enhance cytokine secretion from CD4+ T cells. anti-IL-13 control and anti-IL-18 control were added at half of the top concentration of 30 nM (= 15 nM) and combined prior to the titration to mimic TPP-16674. The co-dosed mimic group was then titrated as a twelve-point 3 -fold titration in an identical range as conducted with the other antibodies. The titration range was revised after screening the first two donors, and all antibodies including the mimic- were titrated with the range 70541FF of starting concentration of 10 nM to 0.056 pM and evaluated in an additional nine donors. All antibodies and cytokine concentrations are described as the final concentrations.

[0411] The antibodies and cytokines were incubated for 30 minutes at room temperature before adding to the CD4+ T cells. Cells in the cell media containing IL-7, IL-12, IL-18, and IL-13 without any antibodies were treated as a maximum response, and cells in the cell media without containing cytokines and antibodies (except IL-7) were treated as a minimum response. The prepared antibodies and cytokine cocktails were added into the wells containing CD4+ T cells at IxlO5cells / well in the plates. The plates were incubated for 3 days at 37°C in 5% CO2. After 3 days, the plates were centrifuged for 5 minutes at 395x g, then the supernatants were consolidated and transferred into a new 96 well plate and stored at -80°C until it required.

[0412] U-plex biomarker (hu) assay kit (MSD) and human IFNy assay kit (MSD) were used to quantify the cytokine and chemokine secreted from CD4+ T cells according to the manufacturer’s instruction. Supernatants were centrifuged briefly for 5 minutes at 395x g prior to use. All supernatants were diluted 1 : 1 (v:v) in diluent 43 provided in the U-plex biomarker assay kit to determine multiple cytokine and chemokine. The supernatants were also diluted 1: 10 (v:v) in diluent 100 provided in the IFNy assay kit. Supernatant dilution and transferring the diluted supernatant into the 96-well Sector® plate were automated by using the Velocity 11 Bravo liquid handler (Agilent). Electrochemiluminescence signals generated in the supernatants were detected by using the SECTOR® Imager 600 (MSD).

[0413] Data is shown in Figures 4 and 5. Anti-IL-13 control inhibited the secretion of CCL17 (TARC) and CCL22 (MDC), whereas anti-IL-18 control inhibited the secretion of IFNy, GM-CSF, and IL-22 from CD4+ T cells stimulated with IL- 18 and IL-13. TPP- 16674 (IL-13xIL-18 Het-mAb) inhibited the secretion of IFNy, GM-CSF, IL-22, CCL17, and CCL22, which demonstrated a dual inhibition of the effect observed from the presence of anti-IL-13 control and anti-IL-18 control. Slight reductions in potencies of TPP- 16674 versus the individual anti-IL18 and anti-IL13 controls were observed due to TPP 16674 being monovalent for IL- 18 and IL-13. The individual anti-IL-18 and anti-IL-13 control antibodies are bivalent, with the potential to bind higher amounts of their respective target.

[0414] The isotype control of TPP-16674 (i.e. aRSVxRSV Het-mAb) did not impact on any cytokine secretions from CD4+ T cells stimulated with IL- 18 and IL- 13 which supports the observation that changes in cytokine secretion in this experiment were not associated with the Fc portion of TPP- 16674 (data not shown). 70541FF

[0415] Example 8: Binding epitope of TPP-16674 to IL-13

[0416] The interactions of the IL- 13 arm of the IL-13xIL-18 bispecific antibody TPP-16674 was studied by hydrogen-deuterium exchange mass spectrometry (HDX-MS). Either 20 pmol IL- 13 (apo state) or 10 pmol IL 13 preincubated with molar equivalent of IL 18 and TPP-16674 (ternary complex state) was labelled by a 12-fold dilution in 50 mM MOPS, 150 mM NaCl D2O buffer, pD7.2 at 20°C for periods of 15, 120, 900 and 7200 s. Samples were quenched by an equivalent volume of a 6 M Urea + 1 M TCEP, pH 2.8 solution for 4 minutes at 0.5°C. The quenched sample was then loaded on to an online nepenthesin-2 digestion column followed by 4 min trapping to a Cl 8 column, followed by a 15 min reverse phase gradient at 0.5°C. Samples were then analysed online using a Waters Cyclic IMS mass spectrometer in HDMS acquisition mode and sensitivity mode. 4- 5 replicates were performed per time point in both apo IL- 13 and ternary complex states. Peptide identification was performed in a similar manner in HDMSEacquisition mode, with a mass loading of 40 pmol IL13 using Waters PLGS 3.0.2 software. All data including pairwise Welch’s t-tests were processed in HDExaminer 3.3.0.

[0417] The final sequence coverage of IL- 13 following data processing and curation was 100 % (47 peptides), with an average peptide length of 10.7 and average redundancy of 4.4 (Fig. 6).

[0418] A hybrid significance test was performed to determine whether the patterns of protection from hydrogen-deuterium exchange (HDX) of the IL13-TPP-16674-IL18 complexes were statistically different from apo IL13 (Hageman and Weis, 2019), at a chosen confidence level of p = 0.01, and visualised as a Volcano Plot (Fig. 7). The protection effects at the peptide level were further resolved by comparison of the differential uptake of overlapping peptides. Protection from hydrogen exchange was observed between residues G35 to V51, C78 to L81 and L134 to N146 (Fig. 8). These HDX protection patterns are located in aA-, aB- and aD-helices of IL-13, and overlap with the IL13:IL13Ra interface plotted onto a crystal structure of the IL13-IL4R-IL13Ral ternary complex (Fig. 9). All numbering is provided in accordance with the Uniprot hIL-13 sequence (#P35225) 70541FF

[0419] SEQUENCE LISTING 70541FF 70541FF 70541FF 70541FF

Claims

1. 70541FFCLAIMSWe claim:

1. An IL-13 binding protein comprising the following 6 CDRs: a) CDRH1 of SEQ ID NO:3; CDRH2 of SEQ ID NO: 4 and CDRH3 of SEQ ID NO: 5; and CDRL1 of SEQ ID NO: 8; CDRL2 of SEQ ID NO: 9; and CDRL3 of SEQ ID NO: 10; b) CDRH1 of SEQ ID NO: 13; CDRH2 of SEQ ID NO: 14 and CDRH3 of SEQ ID NO: 15; and CDRL1 of SEQ ID NO: 18; CDRL2 of SEQ ID NO: 19; and CDRL3 of SEQ ID NO: 20; or c) CDRH1 of SEQ ID NO: 23; CDRH2 of SEQ ID NO: 24 and CDRH3 of SEQ ID NO: 25; and CDRL1 of SEQ ID NO: 28; CDRL2 of SEQ ID NO: 29; and CDRL3 of SEQ ID NO: 30.

2. The IL-13 binding protein according to claim 1 wherein said IL-13 binding protein comprises a) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 2 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 7; b) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 12 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 17; or c) a VH region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 22 and / or a VL region that is at least 90%, 92%, 94%, 96%, 98% or 100% identical to SEQ ID NO: 27.

3. The IL- 13 binding protein according to claim 1 or claim 2 wherein said IL- 13 binding protein comprises a) a VH region that is 100% identical to SEQ ID NO: 2 and / or a VL region that is 100% identical to SEQ ID NO: 7; b) a VH region that is 100% identical to SEQ ID NO: 12 and / or a VL region that is 100% identical to SEQ ID NO: 17; or c) a VH region that is 100% identical to SEQ ID NO: 22 and / or a VL region that is 100% identical to SEQ ID NO: 27.

4. The IL-13 binding protein of claims 1-3 wherein said IL-13 binding protein binds to human IL- 13 with an affinity (KD) of less than 250pM, optionally of less than 150pM, less than lOOpM or less than 75pM.

5. The IL- 13 binding protein according to any preceding claim wherein said IL- 13 binding protein blocks IL-13 from binding to IL-13Ral and IL-13Ra2.

6. The IL-13 binding protein of any preceding claim wherein said IL-13 binding protein is an antibody or an antigen binding fragment thereof, optionally wherein said antibody or antigen binding fragment thereof comprises an Fc region, said Fc region being a modified Fc region, optionally wherein said modified Fc region comprises the amino acid substitutions L235A and G237A (EU index numbering).

7. A multispecific antigen binding protein comprising the IL- 13 binding protein of claims 1-6, optionally wherein said multispecific antigen binding protein is a bispecific antibody.

8. A multispecific antigen binding protein comprising an interleukin 18 (IL- 18) binding domain and an interleukin 13 (IL-13) binding domain.

9. The multispecific antigen binding protein of claim 8 wherein said IL-13 binding domain blocks IL-13 from binding to IL-13Ral and IL-13Ra2.70541FF10. The multispecific antigen binding protein of claim 8 or claim 9 wherein said IL- 18 binding domain comprises the following CDRs: a) CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36; b) CDRH1 of SEQ ID NO: 39, CDRH2 of SEQ ID NO: 40, CDRH3 of SEQ ID NO: 41, CDRL1 of SEQ ID NO: 42, CDRL2 of SEQ ID NO: 43 and CDRL3 of SEQ ID NO: 44; or c) CDRH1 of SEQ ID NO: 103, CDRH2 of SEQ ID NO: 104, CDRH3 of SEQ ID NO: 105, CDRL1 of SEQ ID NO: 106, CDRL2 of SEQ ID NO: 107 and CDRL3 of SEQ ID NO: 108.

11. The multispecific antigen binding protein of claims 8-10 wherein said IL- 13 binding domain comprises the following CDRs: a. CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10; b. CDRH1 of SEQ ID NO: 13, CDRH2 of SEQ ID NO: 14, CDRH3 of SEQ ID NO: 15, CDRL 1 of SEQ ID NO : 18, CDRL2 of SEQ ID NO : 19 and CDRL3 of SEQ ID NO : 20; c. CDRH1 of SEQ ID NO: 23, CDRH2 of SEQ ID NO: 24, CDRH3 of SEQ ID NO: 25, CDRL1 of SEQ ID NO: 28, CDRL2 of SEQ ID NO: 29 and CDRL3 of SEQ ID NO: 30; d. CDRH1 of SEQ ID NO: 47, CDRH2 of SEQ ID NO: 48, CDRH3 of SEQ ID NO: 49, CDRL1 of SEQ ID NO: 50, CDRL2 of SEQ ID NO: 51 and CDRL3 of SEQ ID NO: 52; e. CDRH1 of SEQ ID NO: 55, CDRH2 of SEQ ID NO: 56, CDRH3 of SEQ ID NO: 57, CDRL1 of SEQ ID NO: 58, CDRL2 of SEQ ID NO: 59 and CDRL3 of SEQ ID NO: 60; f. CDRH1 of SEQ ID NO: 63, CDRH2 of SEQ ID NO: 64, CDRH3 of SEQ ID NO: 65, CDRL1 of SEQ ID NO: 66, CDRL2 of SEQ ID NO: 67 and CDRL3 of SEQ ID NO: 68; g. CDRH1 of SEQ ID NO: 71, CDRH2 of SEQ ID NO: 72, CDRH3 of SEQ ID NO: 73, CDRL1 of SEQ ID NO: 74, CDRL2 of SEQ ID NO: 75 and CDRL3 of SEQ ID NO: 76; h. CDRH1 of SEQ ID NO: 79, CDRH2 of SEQ ID NO: 80, CDRH3 of SEQ ID NO: 81, CDRL1 of SEQ ID NO: 82, CDRL2 of SEQ ID NO: 83 and CDRL3 of SEQ ID NO: 84; or i. CDRH1 of SEQ ID NO: 87, CDRH2 of SEQ ID NO: 88, CDRH3 of SEQ ID NO: 89, CDRL1 of SEQ ID NO: 90, CDRL2 of SEQ ID NO: 91 and CDRL3 of SEQ ID NO: 92.

12. The multispecific antigen binding protein of claims 8-11 wherein said multispecific antigen binding protein comprises an IL-18 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 31, CDRH2 of SEQ ID NO: 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ70541FFID NO: 34 , CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36 and an IL- 13 binding domain comprising the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10.

13. The multispecific antigen binding protein of any of claims 8-12 wherein said IL-18 binding domain comprises a) a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38, b) a VH domain of SEQ ID NO: 45 and a VL domain of SEQ ID NO: 46; or c) a VH domain of SEQ ID NO: 109 and a VL domain of SEQ ID NO: 110.

14. The multispecific antigen binding protein of any of claims 8-13 wherein said IL- 13 binding domain comprises: a. a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7; b. a VH domain of SEQ ID NO: 12 and a VL domain of SEQ ID NO: 17; c. a VH domain of SEQ ID NO: 22 and a VL domain of SEQ ID NO: 27; d. a VH domain of SEQ ID NO: 53 and a VL domain of SEQ ID NO: 54; e. a VH domain of SEQ ID NO: 61 and a VL domain of SEQ ID NO: 62; f. a VH domain of SEQ ID NO: 69 and a VL domain of SEQ ID NO: 70; g. a VH domain of SEQ ID NO: 77 and a VL domain of SEQ ID NO: 78; h. a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86; or i. a VH domain of SEQ ID NO: 93 and a VL domain of SEQ ID NO: 94.

15. The multispecific antigen binding protein of claims 8-14 wherein said multispecific antigen binding protein comprises: i. an IL-18 binding domain comprising a VH domain of SEQ ID NO: 37 and a VL domain of SEQ ID NO: 38; and ii. an IL- 13 binding domain comprising a VH domain of SEQ ID NO: 2 and a VL domain of SEQ ID NO: 7.

16. The multispecific antigen binding protein of claims 8-15 comprising an Fc domain, optionally wherein the Fc domain comprises a half-life extending mutation of set of mutations, optionally M252Y, S254T and T256E (EU index numbering).

17. The multispecific antigen binding protein of claim 16 wherein said Fc domain further comprises the amino acid substitutions L235A and G237A (EU index numbering).

18. The multispecific antigen binding protein according to claim 8-17 wherein said multispecific antigen binding protein comprises an IL- 18 binding domain having a heavy chain of SEQ ID NO: 95 and a light chain of SEQ ID NO: 97 and an IL-13 binding domain having a heavy chain of SEQ ID NO: 96 and a light chain of SEQ ID NO: 98.

19. The multispecific antigen binding protein claims 8-18 wherein said multispecific antigen binding protein is a bispecific antigen binding protein, optionally wherein said bispecific antigen binding protein is a bispecific antibody.

20. An anti-IL-18 and anti-IL-13 bispecific antibody, comprising:70541FF anti-IL- 18 having the following CDRs : CDRH 1 of SEQ ID NO : 31 , CDRH2 of SEQ ID NO : 32, CDRH3 of SEQ ID NO: 33, CDRL1 of SEQ ID NO: 34, CDRL2 of SEQ ID NO: 35 and CDRL3 of SEQ ID NO: 36; anti-IL-13 having the following CDRs: CDRH1 of SEQ ID NO: 3, CDRH2 of SEQ ID NO: 4, CDRH3 of SEQ ID NO: 5, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9 and CDRL3 of SEQ ID NO: 10, wherein anti-IL- 18 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 95 and a light chain having a sequence at least 95% identical to SEQ ID NO: 97 and anti-IL-13 comprises a heavy chain having a sequence at least 95% identical to SEQ ID NO: 96, and a light chain having a sequence at least 95% identical to SEQ ID NO: 98.

21. A nucleic acid sequence encoding the IL-13 binding protein of claims 1-6, the multispecific antigen binding protein of claims 7-19 or the bispecific antibody of claims 20.

22. A nucleic acid sequence encoding any one, two, three or all four of the following amino acid sequences: a heavy chain of SEQ ID NO: 95, a light chain of SEQ ID NO: 97, a heavy chain of SEQ ID NO: 96, and a light chain of SEQ ID NO: 98.

23. An expression vector comprising the nucleic acid sequence(s) of claim 21 or claim 22.

24. A recombinant host cell comprising the nucleic acid sequence(s) according to claim 21 or claim 22 or the expression vector(s) according to claim 23.

25. A method for the production of an IL- 13 binding protein, a multispecific antigen binding protein or a bispecific antibody said method comprising culturing the recombinant host cell according to claim 24 under conditions suitable for expression of said nucleic acid sequence(s) or vector(s), whereby said IL- 13 binding protein, multispecific antigen binding protein or bispecific antibody is produced.

26. An IL-13 binding protein, multispecific antigen binding protein or bispecific antibody produced by the method of claim 25.

27. A cell line engineered to express the IL- 13 binding protein according to any of claims 1-6, the multispecific antigen binding protein according to any one of claims 7-19 or the bispecific antibody according to claim 20.

28. A pharmaceutical composition comprising the IL-13 binding protein of claims 1-6, the multispecific antigen binding protein according to any one of claims 7-19 or the bispecific antibody according to claim 20 in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

29. A method for the prevention or treatment of a disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the IL-13 binding protein of claims 1-6, the multispecific antigen binding protein according to any one of claims 7-19, the bispecific antibody according to claim 20, or the pharmaceutical composition according to claim 28.

30. A method for the prevention or treatment of an immunoinflammatory disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the70541FFIL- 13 binding protein of claims 1-6, the multispecific antigen binding protein according to any one of claims 7-19, the bispecific antibody according to claim 20, or the pharmaceutical composition according to claim 28.

31. The method of claim 30 wherein the immunoinflammatory disease is an immunoinflammatory skin condition, optionally wherein the immunoinflammatory skin condition is atopic dermatitis.

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