Antigen binding proteins

Abstract

The present disclosure relates to novel combinations of antigen binding proteins. In particular, the present disclosure relates to combinations of antigen binding proteins targeting interleukin 33 (IL-33) and antigen binding proteins targeting thymic stromal lymphopoietin (TSLP) as well as the use of said combinations in medicine.

Description

[0001] [70558W001]

[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 " Sequence Listing 70558W001.xml". The XML file has a size of about 101,592 bytes and was created on or about December 11, 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 antigen binding proteins targeting interleukin 33 (IL-33) and antigen binding proteins targeting thymic stromal lymphopoietin (TSLP) as well as the use of said antigen binding proteins in medicine.

[0007] BACKGROUND TO THE INVENTION

[0008] Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Symptoms include cough, difficulty breathing, wheezing and tiredness.

[0009] COPD is the fourth leading cause of death worldwide, causing 3.5 million deaths in 2021, approximately 5% of all global deaths. Tobacco smoking accounts for over 70% of COPD cases in high-income countries. In low- and middle-income countries tobacco smoking accounts for 30-40% of COPD cases, with household air pollution also a major risk factor (WHO, Fact Sheet on COPD, dated 6 November 2024).

[0010] Lung inflammation in COPD is characterized by influx of innate inflammatory cells including macrophages, neutrophile granulocytes and adaptive inflammatory cells, including T-lymphocytes, especially CD8+ T- lymphocytes and CD20+ B-cells. The immune cells mediate the release of several pro-inflammatory and inflammatory mediators, including IL-8, TNF- alpha (TNF-[alpha]), IL-6, LTB4, TGF-beta (TGF-[beta]), MCP-I and proteases. The inflammation results in chronic obstructive bronchitis, increased mucus production, plugging and destruction of alveoli resulting in emphysema. Fibrosis is also a prominent feature and may be one of the most important factors causing the increased airway resistance.

[0011] Acute exacerbations of the disease are common and result in further decline of the lung function. The exacerbations seem to be due to an enhanced inflammatory response and may be [70558W001]

[0012] initiated by bacterial and viral infections. COPD patients progress through several stages characterized by increasing symptoms and decreased lung function.

[0013] Traditionally, the main therapies of COPD included two classes of drugs: bronchodilators and anti-inflammatory agents. The main categories of bronchodilators included beta2-agonists, methylxanthines and anticholinergics. The anti-inflammatory agents included inhaled corticosteroids and leukotriene antagonists. Often bronchodilators and anti-inflammatory agents have been used simultaneously. During acute exacerbation antibiotics are added if a bacterial infection is suspected.

[0014] However, owing to the inflammatory nature of COPD there is extensive work ongoing investigating the utility of biologies in the treatment of COPD. Indeed, in 2024, dupilumab became the first biologic to get FDA approval for the treatment of COPD having shown a 34% reduction in exacerbations in patients diagnosed with COPD with a peripheral blood eosinophil count of at least 300 cells / pL and suffering frequent exacerbations (Kersul AL, Cosio BG. Biologies in COPD. Open Respir Arch. 2024 Feb 15;6(2)).

[0015] However, there remains a large unmet medical need for more efficacious therapies with favorable side effect profiles, especially since a large patient population exists who suffer frequent exacerbations (Vogelmeier, C. F., Kostikas, K., Fang, J. et al. Respir Res 20, 178 (2019)).

[0016] SUMMARY OF THE INVENTION

[0017] The inventors of the present application identified that COPD patients with elevated levels of IL-33 and TSLP in sputum experienced more frequent exacerbation events and reduced FEV1 (%). They further discovered that COPD risk may be reduced in people with genetically lower IL-33 and TSLP expression. Together, this data supports the use of both an IL-33 binding protein and a TSLP binding protein, in combination, as a therapeutic strategy in COPD.

[0018] The inventors of the present application further identified that the combination of an IL-33 binding protein and a TSLP binding protein could inhibit type 2 cytokine release (e.g., IL-5 and IL-13) to a significantly greater extent than either binding protein as monotherapies. This data suggests that the combination of antigen binding proteins of the present disclosure can generate a broader anti-inflammatory effect, and thus improved efficacy in the treatment of COPD, than either binding protein when administered as a monotherapy.

[0019] Thus, in one aspect, there is provided a combination of antigen binding proteins comprising an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein.

[0020] In another aspect, there is provided a method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in [70558W001]

[0021] need thereof comprising administering to said subject a therapeutically effective amount of the combination provided herein.

[0022] In a further aspect, there is provided a method of decreasing hospital admissions in a subject with COPD comprising administering to said subject a therapeutically effective amount of the combination provided herein, optionally wherein said hospital admissions are as a result of the subject experiencing acute exacerbation episodes.

[0023] In a further aspect, there is provided a method of decreasing the annualized rate of moderate-to-severe AECOPD events in a subject said method comprising administering to said subject a therapeutically effective amount of the combination provided herein.

[0024] In a further aspect, there is provided a method of improving pre- and / or post-bronchodilator FEV1 in a subject with COPD said method comprising administering to said subject a therapeutically effective amount the combination provided herein.

[0025] In a further aspect, there is provided the combinations disclosed herein for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD). In yet another aspect, there is provided the use of the combinations disclosed herein in the manufacture of a medicament for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) in a subject.

[0026] DESCRIPTION OF DRAWINGS / FIGURES

[0027] FIG. 1: Venn diagram showing that in a data agnostic setting (Panel A), IL-5, TSLP and IL-33 show large numbers of overlapping pathways and nodes towards differentially expressed genes (DEGs). However, following addition of omics readout data to the causal network during mechanistic inference from multi-omics data (MIMO) analysis (Panel B), IL-5 and TSLP were identified as having more extensive overlap in paths and nodes towards DEGs.

[0028] FIG. 2: Comparison of TSLP / IL-5 (Panel A) and IL-33 / IL5 (Panel B) node enrichments demonstrating that IL-5 / TSLP share a common downstream signaling pathway via JAK-STAT3 / 5-MAPK / RELA / NFkB.

[0029] FIG. 3: COPD risk is reduced in people with genetically lower IL-33 and TSLP expression (OR, odds ratio, with 95% CI).

[0030] FIG.4: Inhibition of IL-5 and IL-13 release by HU179-33 and 22A06-458 combination treatment and individual treatments, at the three antibody concentrations tested, following 48 hour stimulation of human PBMCs with rhIL-33 and rhTSLP. Box-plots were generated based on the deviation of the percentage of IL-5 (A, C and E) or IL-13 (B, D and F) response at the three concentrations of antibody tested (50nM, 16.67nM and 5.56nM, respectively). The data were [70558W001]

[0031] collected from 4 independent experiments in total with 3-4 donors in each experiment (n=15). Each dot represents one individual donor. Each symbol represents independent experiment, denoted by ELN number.

[0032] FIG. 5: Inhibition of TARC release by HU179-33 and 22A06-458 combination treatment and individual treatments, at the three antibody concentrations tested, following 48 hour stimulation of human PBMCs with rhIL-33 and rhTSLP. Box-plots were generated based on the deviation of percentage of TARC response at the three concentrations of antibody tested, 50nM (A), 16.67nM (B) and 5.56nM (C). The data were collected from 4 independent experiments in total with 3-4 donors in each experiment (n=15). Each dot represents one individual donor. Each symbol represents independent experiment, denoted by ELN number.

[0033] FIG. 6: Inhibition of IL-5 and IL-13 release by control anti-IL-33 mAb and Tezepelumab combination treatment and individual treatments, at the three antibody concentrations tested, following 48 hour stimulation of human PBMCs with rhIL-33 and rhTSLP. Box-plots were generated based on the deviation of the percentage of IL-5 (A, C and E) or IL-13 (B, D and F) response at the three concentrations of antibody tested (50nM, 16.67nM and 5.56nM, respectively). The data were collected from 3 independent experiments in total with 2-3 donors in each experiment (n=7). Each dot represents one individual donor. Each symbol represents independent experiment, denoted by ELN number.

[0034] FIG. 7: Inhibition of TARC release by control anti-IL-33 mAb and Tezepelumab combination treatment and individual treatments, at the three antibody concentrations tested, following 48 hour stimulation of human PBMCs with rhIL-33 and rhTSLP. Box-plots were generated based on the deviation of percentage of TARC response at the three concentrations of antibody tested, 50nM (A), 16.67nM (B) and 5.56nM (C). The data were collected from 3 independent experiments in total with 2-3 donors in each experiment (n=7). Each dot represents one individual donor. Each symbol represents independent experiment, denoted by ELN number.

[0035] FIG. 8: Scatter plot showing correlation between Log2 normalised sputum TSLP and Log2 normalised sputum IL-33 protein expression in samples obtained from the ECLIPSE study.

[0036] FIG. 9: Box and Whisker plots demonstrating the relationship between patients having either high IL-33 / TSLP co-expression or low IL-33 / TSLP co-expression and FEV1 (%). In Gold II subjects, the high co-expression group associated with significantly (p<0.01) lower FEV1.

[0037] FIG. 10: Graph showing prospective 1 year moderate to severe exacerbation rates in patients with either high co-expression of IL-33 and TSLP or low co-expression of IL-33 and TSLP. The analysis demonstrates that the high co-expression sub-group was linked with more frequent future exacerbations, most notably in severe COPD (GOLD III / IV) patients. [70558W001]

[0038] DETAILED DESCRIPTION

[0039] 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.

[0040] " Affinity", also referred to as "binding affinity", is the strength of binding at a single interaction site, i.e., of one molecule, e.g., an antigen binding protein, to another molecule, e.g., its target antigen, at a single binding site. The binding affinity of an antigen binding protein to its target may be determined by equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g., BIACORE analysis).

[0041] " Alternative antibody formats" include alternative scaffolds in which one or more CDRs of the antigen binding protein can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U. S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301) or an EGF domain.

[0042] " 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, and humanised antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(abQ2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, 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 terms full, whole or intact antibody, used interchangeably herein, refer 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 a 'Y' shape with three functional domains comprising two antigen-binding fragments, known as 'Fab' fragments (the 'top' of the 'Y7), and an 'Fc' crystallizable fragment (the 'bottom' of the V). 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, £ and 5, respectively; each heavy chain can pair with either a K or A light chain. The majority of antibodies in the serum [70558W001]

[0043] 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.

[0044] Fully human antibodies can be obtained using a variety of methods, for example, using yeast-based libraries or transgenic animals (e.g., mice) that are capable of producing repertoires of human antibodies. Yeast presenting human antibodies on their surface that bind to an antigen of interest can be selected using FACS (Fluorescence-Activated Cell Sorting) based methods or by capture on beads using labelled antigens. Transgenic animals that have been modified to express human immunoglobulin genes can be immunised with an antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. Human antibodies produced using these techniques can then be characterised for desired properties such as affinity, developability and selectivity.

[0045] " Antigen binding protein" as used herein refers to isolated proteins, antibodies, antigen binding fragments thereof (e.g., Fabs), and other protein constructs, such as domains, that are capable of binding to an antigen. Also included are alternative scaffolds in which the one or more CDRs of any molecules in accordance with the disclosure can be arranged onto a suitable nonimmunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U. S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301) or an EGF domain. An antigen binding protein also includes antigen binding fragments of such antibodies or other molecules. The antigen binding protein may comprise an antibody that is an IgGl, lgG2, lgG3, or lgG4; or IgM; IgA, IgE or IgD or a modified variant thereof. The constant domain of the antibody heavy chain may be selected accordingly. The light chain constant domain may be a kappa or lambda constant domain. The antigen binding protein may also be a chimeric antibody of the type described in WO86 / 01533, which comprises an antigen binding region and a non-immunoglobulin region.

[0046] " Antigen binding site" and "paratope" are used interchangeably herein and refer to a particular site on an antigen binding protein that makes contact with and is capable of specifically binding to a site (i.e., epitope) on an antigen. The antigen binding site may be formed by a single variable domain, or paired VH / VL domains as can be found on a standard antibody. Single-chain Fv (ScFv) domains can also provide antigen binding sites.

[0047] " Avidity" also referred to as functional affinity, is the cumulative strength of binding at multiple interaction sites, e.g., the sum total of the strength of binding of two molecules (or more) to one another at multiple sites, e.g., taking into account the valency of the interaction.

[0048] " CDRs" are defined as the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light [70558W001]

[0049] chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. In one embodiment, the CDRs are defined based on the Kabat definition. In another embodiment, the CDRs are defined based on the Chothia definition. In a further embodiment, the Chothia definition is from Discovery Studio which uses the definitions from Chothia and Lesk, Jmol Biol. 196(4):901-17 (1987) and Morea et al, Methods, 20:267-279 (2000). In another embodiment, the Chothia definition is based on the Chothia from Abysis definition. In a further embodiment, the CDRs are defined based on the IMGT definition. In another embodiment, the CDRs are defined based on the Honegger definition. In another embodiment, the CDRs are defined based on the contact definition. Thus, " CDRs" as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

[0050] It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. 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 antigen 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.

[0051] Other numbering conventions for CDR sequences available to a skilled person include " AbM" (University of Bath) and "contact" (University College London) methods.

[0052] Table 1 below represents one definition using each numbering convention for each CDR or binding unit. The Kabat numbering scheme is used in Table 1 to number the variable domain amino acid sequence. It should be noted that some of the CDR definitions may vary depending on the individual publication used.

[0053] Table 1: CDR definition using each numbering convention for each CDR or binding unit

[0054] Kabat CDR Chothia CDR AbM CDR Contact CDR

[0055] Hl 31-35 / 35A / 35B 26-32 / 33 / 34 26-35 / 35A / 35B 30-35 / 35A / 35B

[0056] H2 50-65 52-56 50-58 47-58

[0057] H3 95-102 95-102 95-102 93-101

[0058] LI 24-34 24-34 24-34 30-36

[0059] L2 50-56 50-56 50-56 46-55

[0060]

[0061] [70558W001]

[0062] L3 89-97 89-97 89-97 89-96

[0063]

[0064] CDRs may be modified by at least one amino acid substitution, deletion or addition, wherein the variant antigen binding protein substantially retains the biological characteristics of the unmodified protein.

[0065] It will be appreciated that each of CDR Hl, H2, H3, LI, L2, L3 may be modified alone or in combination with any other CDR, in any permutation or combination. In one embodiment, a CDR is modified by the substitution, deletion or addition of up to 3 amino acids, for example, 1 or 2 amino acids, for example, 1 amino acid. Typically, the modification is a substitution, particularly a conservative substitution, for example, as shown in Table 2 below.

[0066] Table 2: summary of amino acid types allowing for conservative substitution

[0067] Side chain Members

[0068] Hydrophobic Met, Ala, Vai, Leu, He

[0069] Neutral hydrophilic Cys, Ser, Thr

[0070] Acidic Asp, Glu

[0071] Basic Asn, Gin, His, Lys, Arg

[0072] Residues that influence chain orientation Gly, Pro

[0073] Aromatic Trp, Tyr, Phe

[0074]

[0075] For example, in a variant CDR, the flanking residues that comprise the CDR as part of alternative definition(s), e.g., Kabat or Chothia, may be substituted with a conservative amino acid residue.

[0076] Such antigen binding proteins comprising variant CDRs as described above may be referred to herein as "functional CDR variants".

[0077] " Domain" refers to a folded polypeptide structure that 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.

[0078] " Effector Function" as used herein refers to one or more of antibody-mediated effects including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated complement activation including complement-dependent cytotoxicity (CDC), complement-dependent cell- [70558W001]

[0079] mediated phagocytosis (CDCP), antibody dependent complement-mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP).

[0080] The interaction between the Fc region of an antigen binding protein or antibody and various Fc receptors (FcR), including FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), FcRn, Clq, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.

[0081] 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.

[0082] Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38.

[0083] 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.

[0084] Throughout this specification, amino acid residues in Fc regions, in antibody sequences or full-length antigen binding protein sequences, are numbered according to the EU index numbering convention.

[0085] " Epitope" as used herein refers to the portion of an antigen (e.g., gpl20) that makes contact with and is capable of specifically binding to a particular site (paratope) on an antigen binding protein. An epitope may be linear or conformational / discontinuous. A conformational / discontinuous epitope comprises amino acid residues that are separated by other sequences, i.e., it does not comprise a continuous sequence in the antigen's primary amino acid sequence, but instead relies on the tertiary folding of the polypeptide. Although the residues within a confirmational / discontinuous epitope may be from different regions of the polypeptide chain, they are in close proximity in the three-dimensional structure of the antigen. [70558W001]

[0086] In the case of multimeric antigens, a conformational or discontinuous epitope may include residues from different polypeptide chains. Particular residues comprised within an epitope can be determined through computer modelling programs or via three-dimensional structures obtained through methods known in the art, such as X-ray crystallography.

[0087] Epitope mapping can be carried out using various techniques known to persons skilled in the art as described in publications such as Methods in Molecular Biology 'Epitope Mapping Protocols', by Mike Schutkowski and Ulrich Reineke (volume 524, 2009) and Johan Rockberg and Johan Nilvebrant (volume 1785, 2018). Exemplary methods include peptide-based approaches, such as pepscan, whereby a series of overlapping peptides are screened for binding using 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 including X-ray crystallography, solution nuclear magnetic resonance (NMR) spectroscopy and cryogenic-electron microscopy (cryo-EM). Mutagenesis, such as alanine scanning, is an effective approach whereby loss of binding analysis is used for epitope mapping. Another method is hydrogen / deuterium exchange (HDX) combined with proteolysis and liquid-chromatography mass spectrometry (LC-MS) analysis to characterize discontinuous or conformational epitopes.

[0088] Further, antigen binding proteins of the invention that bind to the conformational epitope described herein may be screened by competition studies, such as SPR or ELISA. Typically, these experiments are performed by pre-forming antigen complexes with the novel antibody, followed by testing the ability of these complexes to bind to a mAb with known epitope, e.g., by SPR. In case of overlapping epitopes, no binding of the complex to the mAb will be observed, while in case of distal epitopes the complex will bind, thus allowing for approximate mapping of the novel antibody's binding site.

[0089] " Exacerbation of COPD" or " Acute Exacerbation of COPD (AECOPD)" as used herein refers to a period of acute worsening of one or more respiratory symptoms, which may be further characterized by exacerbation rate, time to first exacerbation or having one or more exacerbations. Exacerbations of COPD can include, but are not limited to, increase in dyspnea, increase in wheezing, increase in cough, increase in sputum volume and / or increase in sputum purulence. AECOPD may require treatment with systemic corticosteroids (oral, intravenous, or intramuscular), treatment with antibiotics, and / or hospitalization.

[0090] " Half-life" or "tl / 2" 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.

[0091] 24: 542-548. According to this method, radio-labelled protein is injected intravenously into mice and [70558W001]

[0092] 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.

[0093] " Percent identity" or"% identity" between a query amino acid sequence and a subject amino acid sequence is the " Identities" value, expressed as a percentage, that is calculated using a suitable algorithm (e.g., BLASTP, FASTA, Needleman-Wunsch, Smith-Waterman, LALIGN, or GenePAST / KERR) or software (e.g., DNASTAR Lasergene, GenomeQuest, 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 (e.g., Needleman-Wunsch or GenePAST / KERR) or software (e.g., DNASTAR Lasergene or GenePAST / KERR). Importantly, a query amino acid sequence may be described by an amino acid sequence disclosed herein, in particular, in one or more of the claims.

[0094] The query sequence may be 100% identical to the subject sequence, or it may include up to a certain integer number of amino acid alterations as compared to the subject sequence such that the % identity is less than 100%. For example, the query sequence is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the subject sequence. In the case of amino acid sequences, such alterations include at least one amino acid residue deletion, substitution (including conservative and non-conservative substitutions), or insertion, 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 acid residues in the query sequence or in one or more contiguous groups within the query sequence.

[0095] For antibody sequences, 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.

[0096] " 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 origin.

[0097] 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 [70558W001]

[0098] 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.

[0099] The protein scaffold may be a non-Ig scaffold. The protein scaffold may be a derivative of a scaffold selected from one or more 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; Ctype 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 gpl20 or gp41.

[0100] " Single variable domain" refers to a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains such as VH, VHH and VL and modified antibody variable domains, for example, in which one or more loops have been replaced by sequences that are not characteristic of antibody variable domains, or antibody variable domains that have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of variable domains that retain at least the binding activity and specificity of the full-length domain. A single variable domain as defined herein is capable of binding an antigen or epitope independently of a different variable region or domain. A "domain antibody" or " DAB" may be considered the same as a human "single variable domain". A single variable domain may be a human single variable domain, but also includes single variable domains from other species such as rodent (for example, as disclosed in WO 00 / 29004), nurse shark and Camelid VHHs Camelid VHHs are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain only antibodies naturally devoid of light chains. Such VHH domains may be humanised according to standard techniques available in the art, and such domains are considered to be "single variable domains".

[0101] A "variant sequence" substantially retains the biological characteristics of the unmodified protein. In the case of an antibody sequence disclosed herein, the VH or VL (or HC or LC) sequence may be a variant sequence with up to 10 amino acid substitutions, additions or deletions. For example, the variant sequence may have up to 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitution(s), addition(s) or deletion(s). The sequence variation 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. [70558W001]

[0102] Combination of IL-33 and TSLP binding proteins

[0103] In one aspect of the invention, there is provided a combination of antigen binding proteins, comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein. Thus, the combination may comprise at least one IL-33 binding protein and at least one TSLP binding protein.

[0104] In another aspect of the invention, there is provided a kit-of-parts comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein. Thus, the kit-of-parts may comprise at least one IL-33 binding protein and at least one TSLP binding protein.

[0105] In another aspect of the invention, there is provided a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein for simultaneous, separate, or sequential use in prevention or therapy. Thus, the product may comprise at least one IL-33 binding protein and at least one TSLP binding protein.

[0106] Certain embodiments of these combinations, kits-of-parts and products are described in more detail below.

[0107] IL-33 binding proteins of the combination

[0108] Interleukin 33 (IL-33 or IL33) is an alarmin and a pleotropic cytokine that is released by epithelium, endothelium, and other cell types following damage or infection (Cayrol and Girard, Cytokine, 2022, 156, 155891). IL-33 promotes inflammation through binding to its receptor (transmembrane ST2) which is present on multiple cells including endothelial cells, type 2 innate lymphoid cells (ILC2s), mast cells, myeloid cells, natural killer (NK) cells, T-cells, NK T-cells, and basophils (Calderon et al., Eur Respir Rev, 2023 32(167), 220144, Erratum in: Eur Respir Rev, 2023, 32(168)). IL-33 promotes the production of cytokines associated with Type 1 (e.g., interferon gamma, IL-6, IL-8) and Type 2 (e.g., IL-4, IL-5, IL-13) immune responses resulting in further immune cell recruitment to sites of inflammation (Afferni et al., Front Immunol., 2018, 13, 9, 2601; Calderon et al., Eur Respir Rev., 2023, 32(167), 220144, Erratum in: Eur Respir Rev., 2023, 32(168); Yagami et al., J Immunol., 2010, 185(10), 5743-50). IL-33 has also been implicated as a mediator of eosinophil accumulation, maturation, and release from bone marrow by its effects on ILC2s (Johansson et al., Immunology, 2018, 153(2), 268-278; Johnston et al., J Immunol., 2016, 197(9), 3445-3453; Wu YH, et al., Allergy, 2020, 75(4), 818-830).

[0109] In humans, the IL-33 gene is located on chromosome 9p24.1, encoding a full-length protein of 270 amino acids (SEQ ID NO: 81) with a calculated molecular weight of 30.759 kDa. Under resting conditions, the full-length protein resides in the nucleus where it associates with histone [70558W001]

[0110] complexes. IL-33 does not possess a signal peptide; therefore, release of IL-33 is thought to require a cell damage event, where the initial release of full-length IL-33-histone complexes occurs. This complex is rapidly cleaved by proteases such as calpain, neutrophil elastase, chymase, and cathepsin-G producing shorter isoforms of IL-33 which are more biologically active than the full-length version of the protein. IL-33 is released from the airway epithelium by all the key environmental stressors thought to have an impact on lung sensitivity in asthmatics, for example, respiratory (particularly viral) infections, allergens, and various pollutants, including smoke and other inhaled particulates.

[0111] The term " IL-33 binding protein" or "anti-IL-33 binding protein" (or merely anti-IL-33) are used interchangeably herein and refer to antibodies and fragments thereof, alternative antibody formats, and other protein constructs, such as domains, that are capable of binding to human interleukin 33 (also referred to as IL-33 or IL33), or in other words are capable of binding to IL-33 or otherwise blocking IL-33 binding. The amino acid sequence of an exemplary human IL-33 is provided in SEQ ID NO: 81.

[0112] It is also contemplated within the scope of the invention that the IL-33 binding protein could in fact be a ST2 binding protein. ST2 is a binding receptor for IL-33. Thus, there is further provided combinations of antigen binding proteins, comprising at least an ST2 binding protein and a TSLP binding protein (e.g., at least one ST2 binding protein and at least one TSLP binding protein). There is also provided combinations of antigen binding proteins, comprising at least an ST2 binding protein and a TSLP receptor (TSLPR) binding protein (e.g., at least one ST2 binding protein and at least one TSLPR binding protein).

[0113] In some embodiments, the IL-33 binding protein of the combination comprises (a) (i) any one or a combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 7, 17, 27 or 37 and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 8, 18, 28 or 38; or (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% identical to the sequence of SEQ ID NO: 7, 17, 27 or 37; and / or a VL region comprising a sequence at least 80% identical to the sequence of SEQ ID NO: 8, 18, 28 or 38.

[0114] Alternatively, the sequence identity may be at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. The sequence identity may be 100%. For example, and without limitation, the IL-33 binding protein may contain one to six CDRs selected from CDRH1, CDRH2, and / or CDRH3 from SEQ ID NOs: 7, 17, 27 or 37 and / or CDRL1, CDRL2, and / or CDRL3 from SEQ ID NOs: 8, 18, 28 or 38. As described herein, CDRs may be defined within a VH or VL region by a number of different numbering conventions. However, the CDRs referred to herein are all defined according to the Kabat numbering convention. [70558W001]

[0115] In an embodiment, the CDR of (a) (i) is: a CDRH1 selected from SEQ ID NOs: 1, 11, 21 or 31; a CDRH2 selected from SEQ ID NOs: 2, 12, 22 or 32; and / or a CDRH3 selected from SEQ ID NOs: 3, 13, 23 or 33; a CDRL1 selected from SEQ ID NOs: 4, 14, 24 or 34; a CDRL2 selected from SEQ ID NOs: 5, 15, 25 or 35; and / or CDRL3 selected from SEQ ID NOs: 6, 16, 26 or 36. In an embodiment, said IL-33 binding protein comprises: a CDRH1 that is 100% identical to SEQ ID NOs: 1, 11, 21 or 31; a CDRH2 that is 100% identical to SEQ ID NOs: 2, 12, 22 or 32; and / or a CDRH3 that is 100% identical to SEQ ID NOs: 3, 13, 23 or 33; a CDRL1 that is 100% identical to SEQ ID NOs: 4, 14, 24 or 34; a CDRL2 that is 100% identical to SEQ ID NOs: 5, 15, 25 or 35; and / or a CDRL3 that is 100% identical to SEQ ID NOs: 6, 16, 26 or 36. In an embodiment, all six CDRs are present in the IL-33 binding protein. In an embodiment, said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7, 17, 27 or 37 and / or a VL region that is 100% identical to SEQ ID NO: 8, 18, 28 or 38.

[0116] In an embodiment, the IL-33 binding protein of the combination comprises the following 6 CDRs:

[0117] a) CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6;

[0118] b) CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16;

[0119] c) CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26; or

[0120] d) CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36.

[0121] However, in a most particular embodiment, the IL-33 binding protein of the combination comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5 and CDRL3 of SEQ ID NO: 6.

[0122] In an embodiment, said IL-33 binding protein of the combination comprises:

[0123] a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 8;

[0124] b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 17 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 18; [70558W001]

[0125] c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 27 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 28; or

[0126] d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 37 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 38.

[0127] However, in a most particular embodiment, the IL-33 binding protein of the combination comprises a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and a VL region that is at least 90%, at least 92%, at least 94%, 96%, at least 98% or 100% identical to SEQ ID NO: 8.

[0128] In an embodiment, said IL-33 binding protein of the combination comprises:

[0129] a) a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8;

[0130] b) a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18;

[0131] c) a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28; or

[0132] d) a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38.

[0133] However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8.

[0134] In an embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein:

[0135] a) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 9 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 10;

[0136] b) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 19 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 20; [70558W001]

[0137] c) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 29 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 30; or

[0138] d) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 39 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 40.

[0139] In an embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein:

[0140] a) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and the amino acid sequence of the light chain is shown in SEQ ID NO: 10;

[0141] b) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 19 and the amino acid sequence of the light chain is shown in SEQ ID NO: 20;

[0142] c) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 29 and the amino acid sequence of the light chain is shown in SEQ ID NO: 30; or

[0143] d) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 39 and the amino acid sequence of the light chain is shown in SEQ ID NO: 40.

[0144] However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and the amino acid sequence of the light chain is shown in SEQ ID NO: 10.

[0145] In some embodiments, the IL-33 binding protein of the combination binds to an epitope comprising one or more amino acids within the region consisting of Y164-L182 and V219-C227 of SEQ ID NO: 81. In an embodiment, said epitope is flanked by epitope regions comprising one or more amino acids within the region consisting of S117-Y122, V252-L258 and / or L267-E269 of SEQ ID NO: 81. In this respect, the IL-33 binding protein binds to a conformational epitope, wherein a conformational epitope refers to an epitope that is not a linear epitope and is instead discontinuous in protein sequence, yet the residues come together within close proximity to form an antigenic surface on the target protein's three-dimensional structure. It will be acknowledged by the person [70558W001]

[0146] skilled in the art that said epitope may also be found at their equivalent position in other IL-33 amino acid sequences known to the skilled person, for example, from other non-human species.

[0147] In some embodiments, the IL-33 binding protein of the combination is an IgG antibody. In some embodiments, the IL-33 binding protein of the combination is an IgGl antibody. In some embodiments, the IL-33 binding protein of the combination is an isolated or purified monoclonal antibody. In some embodiments, the IL-33 binding protein of the combination is an isolated or purified human IgGl antibody, optionally an IgGlK antibody.

[0148] Functional activity

[0149] In some embodiments, the equilibrium dissociation constant (KD) of the IL-33 binding protein (of the combination) binding to IL-33 is 100 nM or less, 10 nM or less, 2 nM or less, or 1 nM or less. Alternatively, the KD may be between 1 pM and 500 pM or between 500 pM and 1 nM. In one embodiment, the KD is less than or equal to 500 pM, less than or equal to 400 pM, less than or equal to 300 pM, less than or equal to 200 pM, less than or equal to 100 pM, less than or equal to 75 pM, less than or equal to 50 pM, less than or equal to 40 pM, less than or equal to 30 pM, less than or equal to 25 pM, less than or equal to 20 pM, less than or equal to 10 pM, or less than or equal to 5 pM. In an embodiment, the KD is between 1 pM and 10 pM (e.g., between 1.8 pM and 6 pM). In another embodiment, the KD is between 0.01 pM and 100 pM (e.g., between 0.1 pM and 45 pM).

[0150] In an embodiment, the affinity of the IL-33 binding protein of the combination for human IL-33 is less than or equal to 5 pM (e.g., 3.3 pM) at 25°C. In an embodiment, the affinity of the IL-33 binding protein of the combination for human IL-33 is less than or equal to 15 pM (e.g., 13.5pM) at 37°C. In an embodiment, the affinity of the IL-33 binding protein of the combination for cynomolgus IL-33 at 25°C is less than or equal to 30 pM (e.g., 27.5 pM). In an embodiment, the affinity of the IL-33 binding protein of the combination for cynomolgus IL-33 at 25°C is less than or equal to 60 pM at 37°C (e.g., 56.5 pM). In an embodiment, affinity (KD) is measured using surface plasmon resonance (SPR).

[0151] For antigen binding proteins herein, a smaller KD numerical value corresponds with stronger binding to an antigen (e.g., IL-33 or TSLP). The reciprocal of KD (i.e., 1 / KD) is the equilibrium association constant (KA) having units M-1. For antigen binding proteins herein, a larger KA numerical value corresponds with stronger binding to an antigen (e.g., IL-33 or TSLP). [70558W001]

[0152] In an embodiment, the IL-33 binding protein of the combination does not bind to human IL-1α and / or human IL-1β. In an embodiment, the IL-33 binding protein of the combination does not bind to human IL-1α and human IL-1β.

[0153] In an embodiment, the IL-33 binding protein of the combination does not bind to human oxidized IL-33 and / or cynomolgus oxidized IL-33. In an embodiment, the IL-33 binding protein of the combination does not bind to human oxidized IL-33 and cynomolgus oxidized IL-33.

[0154] In an embodiment, the IL-33 binding proteins of the combination show cross-reactivity between human IL-33 and IL-33 from another species, such as cynomolgus IL-33 or rhesus IL-33. An IL-33 binding protein of the combination may specifically bind human IL-33 and cynomolgus IL-33. Such cross-reactivity can be exploited during preclinical research, e.g., in one or more non-human primate systems such as rhesus monkey or cynomolgus monkey. Such preclinical research can be performed before the antigen binding protein or combination is tested in humans. Such cross-reactivity can be exploited to make one or more side-by-side comparisons of using an antigen binding protein herein. In one embodiment, cross reactivity between other species used in disease models such as dog or mouse is also envisaged. Optionally, the binding affinity of the antigen binding protein for cynomolgus IL-33 and the binding affinity for human IL-33 differ by no more than a factor of 2, 5, 10, 50, or 100. In an embodiment, the binding affinity of the antigen binding protein for cynomolgus IL-33 and the binding affinity for human IL-33 differ by no more than a factor of 10.

[0155] An IL-33 binding protein of the combination can be neutralizing. The reduction or inhibition in biological activity may be partial or total. A neutralizing antigen binding protein may neutralize the activity of IL-33 by at least 20%, at least 30%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% relative to IL-33 activity in the absence of the antigen binding protein. Neutralization may be determined or measured using one or more assays known to the skilled person or as described herein.

[0156] In one embodiment, an IL-33 binding protein of the combination inhibits IL-33 induced superoxide generation from isolated eosinophils. In one embodiment, the IL-33 binding protein of the combination inhibits IL-33 induced superoxide generation from isolated eosinophils with an IC₅₀ of less than or equal to 100 pM, less than or equal to 75 pM, less than or equal to 50 pM, less than or equal to 40 pM, less than or equal to 30 pM, less than or equal to 25 pM, or less than or equal to 20 pM (e.g., 19.65 pM).

[0157] In one embodiment, an IL-33 binding protein of the combination inhibits IL-33 induced IFN-y secretion from CD4+ T cells. In one embodiment, the IL-33 binding protein of the combination [70558W001]

[0158] inhibits IL-33 induced IFN-y secretion from CD4+ T cells with an IC₅₀ of less than or equal to 1000 pM, less than or equal to 900 pM, less than or equal to 800 pM, or less than or equal to 700 pM (e.g., 675.14).

[0159] In one embodiment, an IL-33 binding protein of the combination inhibits IL-33 induced IL-8 and / or IL-6 secretion from human umbilical vein endothelial cells (HUVECs). In one embodiment, an IL-33 binding protein of the combination inhibits IL-33 induced IL-8 secretion from human umbilical vein endothelial cells (HUVECs). In one embodiment, the IL-33 binding protein of the combination inhibits IL-33 induced IL-8 secretion from HUVECs with an IC₅₀ of less than or equal to 500 pM (e.g., less than or equal to 400 pM). In one embodiment, the IL-33 binding protein of the combination inhibits IL-33 induced IL-6 secretion from HUVECs with an IC₅₀ of less than or equal to 300 pM (e.g., less than or equal to 225 pM).

[0160] In one embodiment, an IL-33 binding protein of the combination inhibits IL-33 induced β-hexosaminidase release from basophils. In one embodiment, the IL-33 binding protein of the combination inhibits IL-33 induced β-hexosaminidase release from basophils with an ICso of less than or equal to 10 nM (e.g., less than or equal to 3 nM).

[0161] In one embodiment, the affinity of IL-33 for the ST2 receptor is not affected when IL-33 is complexed with an IL-33 binding protein of the combination.

[0162] In one embodiment, an IL-33 binding protein of the combination pre-complexed with IL-33 demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood. In one embodiment, the IL-33 binding protein of the combination pre-complexed with IL-33 demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood with an IC50 value of less than or equal to 4 nM (e.g., 3.90 nM) for IL-33 concentrations of lOOng / mL. In one embodiment, the IL-33 binding protein of the combination pre-complexed with IL-33 demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood with an IC50 value of less than or equal to 3.50 (e.g., 3.25 nM) for IL-33 concentrations of 30ng / mL. In one embodiment, the IL-33 binding protein of the combination precomplexed with IL-33 demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood with an IC50 value of less than or equal to 2.5 nM (e.g., 1.95 nM) for IL-33 concentrations of lOng / mL.

[0163] In one embodiment, an IL-33 binding protein of the combination that is not pre-complexed with IL-33 also demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood. In one embodiment, the IL-33 binding protein of the combination that is not precomplexed with IL-33 demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood with an IC50 value of less than or equal to 2 nM (e.g., 1.57 nM) for IL- [70558W001]

[0164] 33 concentrations of 30ng / mL. In one embodiment, the IL-33 binding protein of the combination that is not pre-complexed with IL-33 demonstrates concentration dependent inhibition of IL-33 / IL-12 stimulated IFN-y release in whole blood with an IC50 value of less than or equal to 1 nM (e.g., 0.37 nM) for IL-33 concentrations of lOng / mL.

[0165] In one embodiment, an IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-6, TNF-o, IL-13, and / or IL-18. In one embodiment, an IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-6, TNF-o, IL-13, and IL-18. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-6 with an IC50 value of less than or equal to 50 pM (e.g., 31.21 pM) at an IL-33 concentration of Ing / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-6 with an IC50 value of less than or equal to 600 pM (e.g., 566 pM) at an IL-33 concentration of lOng / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated TNF-o with an IC50 value of less than or equal to 50 pM (e.g., 37.35 pM) at an IL-33 concentration of Ing / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated TNF-o with an IC50 value of less than or equal to 600 pM (e.g., 581 pM) at an IL-33 concentration of lOng / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-13 with an IC50 value of less than or equal to 50 pM (e.g., 28.01 pM) at an IL-33 concentration of Ing / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-13 with an IC50 value of less than or equal to 600 pM (e.g., 567 pM) at an IL-33 concentration of lOng / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-18 with an IC50 value of less than or equal to 100 pM (e.g., 61.26 pM) at an IL-33 concentration of Ing / mL. In one embodiment, the IL-33 binding protein of the combination can completely block production of human IL-33 stimulated IL-18 with an IC50 value of less than or equal to 700 pM (e.g., 631 pM) at an IL-33 concentration of lOng / mL.

[0166] Additional details regarding the examples above can be found in U. S. Application No.

[0167] 63 / 602,704, filed November J, 2023, and PCT / IB2024 / 061799, filed November 25, 2024, each of which is incorporated herein by reference in its entirety. PCT / IB2024 / 061799 published as WO2025114862.

[0168] Fc modifications [70558W001]

[0169] In some embodiments, the IL-33 binding protein of the combination comprises at least one Fc modification.

[0170] Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antigen binding protein, in particular, 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.

[0171] The interaction between the Fc region of an antigen binding protein or antibody and various Fc receptors (FcR), including FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), FcRn, Clq, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.

[0172] 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 eta / ., 2001, The Journal of Biological Chemistry, Vol. 276, p. 6591-6604; Chappel etal., 1993, The Journal of Biological Chemistry, Vol 268, p. 25124-25131; Lazar etaL, 2006, PNAS, 103; 4005-4010.

[0173] Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38.

[0174] 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 etaL, Antibodies 2017, 6(3); Monnet et al., 2014 mAbs, 6:2, 422-436.

[0175] Throughout this specification, amino acid residues in Fc regions, in antibody sequences or full-length antigen binding protein sequences, are numbered according to the EU index numbering convention.

[0176] 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 etaL, Nature Biotech. 15: 637-640, 1997; Hinton etaL, JBC 279: 6213- [70558W001]

[0177] 6216, 2004; Dall'Acqua eta / ., 10 J Immunol 117: 1129-1138, 2006). The in-vivo half-life of antigen binding proteins of the present invention may be altered by modification of a heavy chain constant domain or an FcRn binding domain therein.

[0178] In adult mammals, FcRn 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 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.

[0179] 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 ai. (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 antigen binding proteins of the invention.

[0180] Antigen binding proteins of the present invention 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 antigen binding protein of the invention comprises all or a portion (an FcRn binding portion) of an IgG constant domain having one or more of the following amino acid modifications.

[0181] 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 ai. 2018).

[0182] 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).

[0183] 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 (WQ00 / 09560, US4703039).

[0184] In some embodiments, the IL-33 binding protein of the combination comprises a Fc region, the Fc region comprising at least one modification. In some embodiments, the Fc region is an IgGl. [70558W001]

[0185] Accordingly, in some embodiments, the IL-33 binding protein comprises at least one modification which extends the half-life of the binding protein compared to an unmodified binding protein. In a most particular embodiment, the IL-33 binding protein of the combination comprises an M252Y substitution, an S254T substitution, and a T256E substitution according to EU numbering. In some embodiments, the IL-33 binding protein having the substitutions is an IgGl.

[0186] Nucleic acids

[0187] In some aspects of the invention, the combination, the kit-of-parts, or the product described herein may comprise IL-33 antigen binding proteins encoded by nucleic acid sequences. Accordingly, in one embodiment, there is provided a nucleic acid sequence which encodes any of the IL-33 binding proteins described herein. In some embodiments, the nucleic acid sequence encodes for a sequence with at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with the heavy chain of SEQ ID NO: 9 and / or a sequence with at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with the light chain of SEQ ID NO: 10. In some embodiments, the nucleic acid sequence encodes for the heavy chain of SEQ ID NO: 9 and / or the light chain of SEQ ID NO: 10. The nucleic acid coding for the IL-33 binding proteins may be modified or unmodified. The nucleic acids coding for the IL-33 binding proteins 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. Also provided herein is a method of producing an IL-33 binding protein in a cell, tissue, or organism comprising contacting said cell, tissue, or organism with a composition comprising an isolated nucleic acid comprising at least one chemical modification and which encodes the IL-33 binding protein. Also provided herein is a method of producing an IL-33 binding protein in a cell, tissue or organism comprising contacting said cell, tissue or organism with a composition comprising a polynucleotide comprising at least one chemical modification and which encodes an IL-33 binding protein. Also provided herein is a method of producing an IL-33 binding protein in a cell, in vitro or in vivo, comprising contacting said cell with a composition comprising a nucleic acid comprising at least one chemical modification and which encodes an IL-33 binding protein.

[0188] A subject in need may be delivered one or more nucleic acids encoding an IL-33 binding protein provided herein, such as a heavy chain and a light chain of an anti-IL-33 antibody. The heavy chain and the light chain of the antibody may be delivered by the same or separate nucleic acids. The nucleic acids may be DNA or RNA. The nucleic acids encoding the IL-33 binding protein [70558W001]

[0189] 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 acids encoding the IL-33 binding protein may be delivered without a delivery vehicle (i.e., "naked") or delivered with a viral or non-viral delivery vehicle (i.e., as a viral vector, adsorbed to or encapsulated in liposomes or polymer-based vehicles, and the like). The nucleic acid may include elements such as a poly-A tail, and a 5' and / or 3' untranslated region (UTR). The nucleic acids may be mRNA. The mRNA may include a cap structure. The mRNA may be self-amplifying RNA.

[0190] In some aspects of the invention, there is provided an expression vector comprising the nucleic acids described herein. Accordingly, in some embodiments, the expression vector may contain nucleic acid sequence(s) that encode for the heavy chain of SEQ ID NO: 9 and / or the light chain of SEQ ID NO: 10. In some aspects of the invention, there is provided an expression vector comprising the nucleic acid sequence as defined herein. Said expression vector can be an isolated nucleic acid which can be used to introduce nucleic acid sequences of interest into a cell, such as a eukaryotic cell or prokaryotic cell, or a cell free expression system where the nucleic acid sequence of interest is expressed as a peptide chain such as a protein. The nucleic acid sequences described herein may encode any of the IL-33 binding proteins of the combination that are provided herein or a fragment thereof. Such expression vectors may be, for example, cosmids, plasmids, viral sequences, transposons, and linear nucleic acids comprising a nucleic acid of interest. Once the expression vector is introduced into a cell or cell free expression system (e.g., reticulocyte lysate) the protein encoded by the nucleic acid of interest is produced by the transcription / translation machinery.

[0191] Expression vectors within the scope of the disclosure may provide necessary elements for eukaryotic or prokaryotic expression and include viral promoter driven vectors, such as CMV promoter driven vectors, e.g., pcDNA3.1, pCEP4, and their derivatives, Baculovirus expression vectors, Drosophila expression vectors, and expression vectors that are driven by mammalian gene promoters such as human Ig gene promoters. Other examples include prokaryotic expression vectors, such as T7 promoter driven vectors, e.g., pET41, lactose promoter driven vectors, and arabinose gene promoter driven vectors. Those of ordinary skill in the art will recognise many other suitable expression vectors and expression systems.

[0192] TSLP binding proteins of the combination

[0193] Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine produced in response to pro-inflammatory stimuli. TSLP has been discovered to promote allergic inflammatory responses primarily through its activity on dendritic and mast cells (Soumelis et al., Nat Immun 3(7): 673-680 (2002), Allakhverdi et al., J. Exp. Med. 204(2):253-258 (2007). [70558W001]

[0194] The term " TSLP binding protein" or "anti-TSLP binding protein" (or merely anti-TSLP) are used interchangeably herein and refer to antibodies and fragments thereof, alternative antibody formats, and other protein constructs, such as domains, that are capable of binding to thymic stromal lymphopoietin (also referred to as TSLP), or in other words are capable of binding to TSLP. The amino acid sequence of an exemplary human TSLP is provided in SEQ ID NO: 82.

[0195] It is also contemplated within the scope of the invention that the TSLP binding protein could in fact be a TSLP receptor (TSLPR) binding protein. Thus, there is further provided combinations of antigen binding proteins, comprising at least an IL-33 binding protein and a TSLPR binding protein (e.g., at least one IL-33 binding protein and at least one TSLPR binding protein). There is also provided combinations of antigen binding proteins, comprising at least an ST2 binding protein and a TSLPR binding protein (e.g., at least one ST2 binding protein and at least one TSLPR binding protein).

[0196] In some embodiments, the TSLP binding protein of the combination comprises (a) (i) any one or a combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 47, 57, 67 or 77 and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 48, 58, 68 or 78; or (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% identical to the sequence of SEQ ID NO: 47, 57, 67 or 77; and / or a VL region comprising a sequence at least 80% identical to the sequence of SEQ ID NO: 48, 58, 68 or 78. Alternatively, the sequence identity may be at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. The sequence identity may be 100%. For example, and without limitation, the TSLP binding protein may contain one to six CDRs selected from CDRH1, CDRH2, and / or CDRH3 from SEQ ID NOs: 47, 57, 67 or 77 and / or CDRL1, CDRL2, and / or CDRL3 from SEQ ID NOs: 48, 58, 68 or 78. As described herein, CDRs may be defined within a VH or VL region by a number of different numbering conventions. However, the CDRs referred to herein are all defined according to the Kabat numbering convention.

[0197] In an embodiment, the CDR of (a) (i) is: a CDRH1 selected from SEQ ID NOs: 41, 51, 61 or 71; a CDRH2 selected from SEQ ID NOs: 42, 52, 62 or 72; and / or a CDRH3 selected from SEQ ID NOs: 43, 53, 63 or 73; a CDRL1 selected from SEQ ID NOs: 44, 54, 64 or 74; a CDRL2 selected from SEQ ID NOs: 45, 55, 65 or 75; and / or CDRL3 selected from SEQ ID NOs: 46, 56, 66 or 76. In an embodiment, said TSLP binding protein of the combination comprises: a CDRH1 that is 100% identical to SEQ ID NOs: 41, 51, 61 or 71; a CDRH2 that is 100% identical to SEQ ID NOs: 42, 52, 62 or 72; and / or a CDRH3 that is 100% identical to SEQ ID NOs: 43, 53, 63 or 73; a CDRL1 that is 100% identical to SEQ ID NOs: 44, 54, 64 or 74; a CDRL2 that is 100% identical to SEQ ID NOs: 45, 55, 65 or 75; and / or a CDRL3 that is 100% identical to SEQ ID NOs: 46, 56, 66 or 76. In an [70558W001]

[0198] embodiment, all six CDRs are present in the TSLP binding protein. In an embodiment, said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47, 57, 67 or 77 and / or a VL region that is 100% identical to SEQ ID NO: 48, 58, 68 or 78.

[0199] In an embodiment, the TSLP binding protein of the combination comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46;

[0200] b) CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56;

[0201] c) CDRH1 of SEQ ID NO: 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66; or

[0202] d) CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

[0203] However, in a most particular embodiment, the TSLP binding protein of the combination comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0204] In an embodiment, said TSLP binding protein of the combination comprises:

[0205] a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 47 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 48;

[0206] b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 57 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 58;

[0207] c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 67 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 68; or

[0208] d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 77 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 78.

[0209] However, in a most particular embodiment, the TSLP binding protein of the combination comprises a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 47 and a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 48.

[0210] In an embodiment, said TSLP binding protein of the combination comprises: [70558W001]

[0211] a) a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48;

[0212] b) a VH region that is 100% identical to SEQ ID NO: 57 and / or a VL region that is 100% identical to SEQ ID NO: 58;

[0213] c) a VH region that is 100% identical to SEQ ID NO: 67 and / or a VL region that is 100% identical to SEQ ID NO: 68; or

[0214] d) a VH region that is 100% identical to SEQ ID NO: 77 and / or a VL region that is 100% identical to SEQ ID NO: 78.

[0215] However, in a most particular embodiment, said TSLP binding protein of the combination comprises a VH region that is 100% identical to SEQ ID NO: 47 and a VL region that is 100% identical to SEQ ID NO: 48.

[0216] In an embodiment, said TSLP binding protein of the combination comprises a heavy chain and a light chain, wherein:

[0217] a) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 49 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 50;

[0218] b) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 59 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 60;

[0219] c) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 69 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 70; or

[0220] d) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 79 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 80. [70558W001]

[0221] In an embodiment, said TSLP binding protein of the combination comprises a heavy chain and a light chain, wherein:

[0222] a) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 49 and the amino acid sequence of the light chain is shown in SEQ ID NO: 50;

[0223] b) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 59 and the amino acid sequence of the light chain is shown in SEQ ID NO: 60;

[0224] c) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 69 and the amino acid sequence of the light chain is shown in SEQ ID NO: 70; or

[0225] d) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 79 and the amino acid sequence of the light chain is shown in SEQ ID NO: 80.

[0226] However, in a most particular embodiment, said TSLP binding protein of the combination comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 49 and the amino acid sequence of the light chain is shown in SEQ ID NO: 50.

[0227] In some embodiments, the TSLP binding protein of the combination is a humanized IgG antibody. In some embodiments, the TSLP binding protein of the combination is a humanized IgGl antibody. In some embodiments, the TSLP binding protein of the combination is an isolated or purified monoclonal antibody. In some embodiments, the TSLP binding protein of the combination is an isolated or purified humanized IgGl antibody.

[0228] Functional activity

[0229] In some embodiments, the equilibrium dissociation constant (KD) of the TSLP binding protein (of the combination) binding to human TSLP is 100 nM or less, 10 nM or less, 2 nM or less, or 1 nM or less. In a particular embodiment, the KD is InM or less, 500pM or less, 250pM or less, 100pM or less, or 50pM or less. In a particular embodiment, the KD of the TSLP binding protein of the combination is less than lOpM. In an embodiment, the affinity of TSLP binding proteins of the combination for binding to human TSLP is determined by surface plasmon resonance (SPR) at either 25°C or 37°C.

[0230] In an embodiment, the TSLP binding protein of the combination blocks the binding of TSLP to the extracellular domain of recombinantly expressed TSLPR with an IC50 of less than lOnM, optionally less than 5nM, optionally less than InM. An exemplar method used to determine the ability of TSLP binding proteins to block the binding of TSLP to recombinantly expressed TSLPR may be found, for example, in WO2020244544. [70558W001]

[0231] In an embodiment, the TSLP binding protein of the combination is capable of inhibiting proliferation of BaF3-TSLPR / IL7R cells induced by native TSLP. In an embodiment, said TSLP binding protein of the combination is capable of inhibiting proliferation of BaF3-TSLPR / IL7R cells with an IC50 of less than lOnM, optionally less than 5nM. However, in a particular embodiment, said TSLP binding protein of the combination is capable of inhibiting proliferation of BaF3-TSLPR / IL7R cells with an IC50 of less than InM, optionally less than 0.5nM and optionally less than O.lnM. An exemplar method used to determine the ability of TSLP binding proteins to inhibit proliferation of BaF3-TSLPR / IL7R cells may be found, for example, in WO2020244544.

[0232] Fc modifications

[0233] In some embodiments, the TSLP binding protein of the combination comprises at least one Fc modification.

[0234] Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antigen binding protein, in particular, 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.

[0235] The interaction between the Fc region of an antigen binding protein or antibody and various Fc receptors (FcR), including FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), FcRn, Clq, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.

[0236] 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 eta / ., 2001, The Journal of Biological Chemistry, Vol. 276, p. 6591-6604; Chappel etaL, 1993, The Journal of Biological Chemistry, Vol 268, p. 25124-25131; Lazar etaL, 2006, PNAS, 103; 4005-4010.

[0237] Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38. [70558W001]

[0238] 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 eta / ., Antibodies 2017, 6(3); Monnet et al., 2014 mAbs, 6:2, 422-436.

[0239] Throughout this specification, amino acid residues in Fc regions, in antibody sequences or full-length antigen binding protein sequences, are numbered according to the EU index numbering convention.

[0240] 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 etai., Nature Biotech. 15: 637-640, 1997; Hinton etai., JBC 279: 6213-6216, 2004; Dall'Acqua et al., 10 J Immunol 117: 1129-1138, 2006). The in-vivo half-life of antigen binding proteins of the present invention may be altered by modification of a heavy chain constant domain or an FcRn binding domain therein.

[0241] In adult mammals, FcRn, 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 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.

[0242] 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 ai. (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 antigen binding proteins of the invention.

[0243] Antigen binding proteins of the present invention 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 antigen binding protein of the invention comprises all or a portion (an FcRn binding portion) of an IgG constant domain having one or more of the following amino acid modifications.

[0244] 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 [70558W001]

[0245] pH 6.0 (Wang et al. 2018). In an embodiment, the TSLP binding protein of the combination comprises an Fc domain with the YTE mutations.

[0246] 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).

[0247] 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).

[0248] In some embodiments, the TSLP binding protein comprises a Fc region, the Fc region comprising at least one modification. In some embodiments, the Fc region is an IgGl. In some embodiments, the TSLP binding protein of the combination comprises at least one modification which extends the half-life of the binding protein compared to an unmodified binding protein. In a most particular embodiment, the TSLP binding protein of the combination comprises an M252Y substitution, an S254T substitution, and a T256E substitution according to EU numbering.

[0249] Nucleic acids

[0250] In some aspects of the invention, the combination, the kit-of-parts, or the product described herein may comprise TSLP antigen binding proteins encoded by nucleic acid sequences. Accordingly, in one embodiment, there is provided a nucleic acid sequence which encodes any of the TSLP binding proteins of the combination that are described herein. In some embodiments, the nucleic acid sequence encodes for a sequence with at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with the heavy chain of SEQ ID NO: 49 and / or a sequence with at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with the light chain of SEQ ID NO: 50. In some embodiments, the nucleic acid sequence encodes the heavy chain of SEQ ID NO: 49 and / or the light chain of SEQ ID NO: 50. The nucleic acid coding for the TSLP binding protein of the combination may be modified or unmodified. The nucleic acids coding for the TSLP binding protein of the combination 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. Also provided herein is a method of producing a TSLP binding protein of the combination in a cell, tissue, or organism comprising contacting said [70558W001]

[0251] cell, tissue, or organism with a composition comprising an isolated nucleic acid comprising at least one chemical modification and which encodes the TSLP binding protein. Also provided herein is a method of producing a TSLP binding protein of the combination in a cell, tissue or organism comprising contacting said cell, tissue or organism with a composition comprising a polynucleotide comprising at least one chemical modification and which encodes a TSLP binding protein. Also provided herein is a method of producing a TSLP binding protein of the combination in a cell, in vitro or in vivo, comprising contacting said cell with a composition comprising a nucleic acid comprising at least one chemical modification and which encodes a TSLP binding protein.

[0252] A subject in need may be delivered one or more nucleic acids encoding a TSLP binding protein provided herein, such as a heavy chain and a light chain of an anti-TSLP antibody. The heavy chain and the light chain of the antibody may be delivered by the same or separate nucleic acids. The nucleic acids may be DNA or RNA. The nucleic acids encoding the TSLP binding protein 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 acids encoding the TSLP binding protein may be delivered without a delivery vehicle (i.e., "naked") or delivered with a viral or non-viral delivery vehicle (i.e., as a viral vector, adsorbed to or encapsulated in liposomes or polymer-based vehicles, and the like). The nucleic acid may include elements such as a poly-A tail, and a 5' and / or 3' untranslated region (UTR). The nucleic acids may be mRNA. The mRNA may include a cap structure. The mRNA may be self-amplifying RNA.

[0253] In some aspects of the invention, there is provided an expression vector comprising the nucleic acid sequence as defined herein. Accordingly, in some embodiments, the expression vector may contain nucleic acid sequence(s) that encode the heavy chain of SEQ ID NO: 49 and / or the light chain of SEQ ID NO: 50. Said expression vector can be an isolated nucleic acid which can be used to introduce nucleic acid sequences of interest into a cell, such as a eukaryotic cell or prokaryotic cell, or a cell free expression system where the nucleic acid sequence of interest is expressed as a peptide chain such as a protein. The nucleic acid sequences described herein may encode any of the TSLP binding proteins provided herein or a fragment thereof. Such expression vectors may be, for example, cosmids, plasmids, viral sequences, transposons, and linear nucleic acids comprising a nucleic acid of interest. Once the expression vector is introduced into a cell or cell free expression system (e.g., reticulocyte lysate) the protein encoded by the nucleic acid of interest is produced by the transcription / translation machinery. Expression vectors within the scope of the disclosure may provide necessary elements for eukaryotic or prokaryotic expression and include viral promoter driven vectors, such as CMV promoter driven vectors, e.g., pcDNA3.1, pCEP4, and their derivatives, Baculovirus expression vectors, Drosophila expression vectors, and expression vectors that are [70558W001]

[0254] driven by mammalian gene promoters such as human Ig gene promoters. Other examples include prokaryotic expression vectors, such as T7 promoter driven vectors, e.g., pET41, lactose promoter driven vectors, and arabinose gene promoter driven vectors. Those of ordinary skill in the art will recognise many other suitable expression vectors and expression systems.

[0255] As previously described, there is herein provided a combination of antigen binding proteins comprising at least an IL-33 binding protein and a TSLP binding protein, a kit-of-parts comprising an IL-33 binding protein and a TSLP binding protein and a product comprising an IL-33 binding protein and a TSLP binding protein as a combined preparation for simultaneous, separate, or sequential use in prevention or therapy. Thus, each of the combinations, kit-of-parts and products described herein comprise both an IL-33 binding protein and a TSLP binding protein. Said combinations, kit-of-parts or products may comprise any of the IL-33 binding proteins of the combination as described in the section above entitled " IL-33 binding proteins of the combination" in addition to any of the TSLP binding proteins of the combination as described in the section above entitled " TSLP binding proteins of the combination". However, for the avoidance of doubt specific combinations of IL-33 binding protein and TSLP binding protein are provided below as follows (as defined by their six CDR regions):

[0256] i. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0257] ii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56. [70558W001]

[0258] iii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66.

[0259] iv. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

[0260] v. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0261] vi. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56.

[0262] vii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal [70558W001]

[0263] lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66.

[0264] viii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

[0265] ix. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0266] x. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56.

[0267] xi. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID [70558W001]

[0268] NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66.

[0269] xii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

[0270] xiii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0271] xiv. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56.

[0272] xv. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: [70558W001]

[0273] 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66.

[0274] xvi. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

[0275] For the further avoidance of doubt, specific combinations of IL-33 binding protein and TSLP binding protein are provided below as follows (as defined by their VH / VL sequences):

[0276] i. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48.

[0277] ii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 57 and / or a VL region that is 100% identical to SEQ ID NO: 58.

[0278] iii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 67 and / or a VL region that is 100% identical to SEQ ID NO: 68.

[0279] iv. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region [70558W001]

[0280] that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 77 and / or a VL region that is 100% identical to SEQ ID NO: 78.

[0281] v. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48.

[0282] vi. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 57 and / or a VL region that is 100% identical to SEQ ID NO: 58.

[0283] vii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 67 and / or a VL region that is 100% identical to SEQ ID NO: 68.

[0284] viii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 77 and / or a VL region that is 100% identical to SEQ ID NO: 78.

[0285] ix. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48. [70558W001]

[0286] x. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 57 and / or a VL region that is 100% identical to SEQ ID NO: 58.

[0287] xi. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 67 and / or a VL region that is 100% identical to SEQ ID NO: 68.

[0288] xii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 77 and / or a VL region that is 100% identical to SEQ ID NO: 78.

[0289] xiii. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48.

[0290] xiv. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 57 and / or a VL region that is 100% identical to SEQ ID NO: 58.

[0291] xv. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID [70558W001]

[0292] NO: 38 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 67 and / or a VL region that is 100% identical to SEQ ID NO: 68.

[0293] xvi. In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 77 and / or a VL region that is 100% identical to SEQ ID NO: 78.

[0294] In an embodiment, there is provided a combination of antigen binding proteins, a kit-of-parts or a product comprising at least an IL-33 binding protein and a TSLP binding protein; wherein said combination is capable of inhibiting upregulation of IL-5 and IL-13 in PBMCs by at least 5%, at least 10%, at least 15%, at least 20% or at least 25% compared to an IL-33 binding protein alone or a TSLP binding protein alone.

[0295] Combination of IL-33 and IL-5 binding proteins

[0296] Also envisaged within the scope of the present disclosure are combinations of antigen binding proteins, comprising at least an interleukin 33 (IL-33) binding protein and an interleukin 5 (IL-5) binding protein. Thus, a combination may comprise at least one IL-33 binding protein and at least one IL-5 binding protein. The amino acid sequence of an exemplary human IL-33 is provided in SEQ ID NO: 105.

[0297] In another aspect of the invention, there is provided a kit-of-parts comprising an interleukin 33 (IL-33) binding protein and an interleukin 5 (IL-5) binding protein. Thus, the kit-of-parts may comprise at least one IL-33 binding protein and at least one IL-5 binding protein.

[0298] In another aspect of the invention, there is provided a product comprising an interleukin 33 (IL-33) binding protein and an interleukin 5 (IL-5) binding protein for simultaneous, separate, or sequential use in prevention or therapy. Thus, the product may comprise at least one IL-33 binding protein and at least one IL-5 binding protein.

[0299] In an embodiment, the IL-33 binding protein of the combination comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6; b) CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16; c) CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: [70558W001]

[0300] 25; and CDRL3 of SEQ ID NO: 26; or d) CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab. However, in a most particular embodiment, the IL-33 binding protein of the combination comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5 and CDRL3 of SEQ ID NO: 6 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab.

[0301] In an embodiment, said IL-33 binding protein of the combination comprises: a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 8; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 17 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 18; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical identical to SEQ ID NO: 27 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 28; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 37 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 38 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab. However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 8 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab.

[0302] In an embodiment, said IL-33 binding protein of the combination comprises: a) a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8; b) a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18; c) a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28; or d) a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab. However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a VH region that is [70558W001]

[0303] 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab.

[0304] In an embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein:

[0305] a) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 9 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 10;

[0306] b) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 19 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 20;

[0307] c) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 29 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 30; or

[0308] d) the amino acid sequence of the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 39 and / or the amino acid sequence of the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 40,

[0309] and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab.

[0310] In an embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein: a) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and the amino acid sequence of the light chain is shown in SEQ ID NO: 10; b) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 19 and the amino acid sequence of the light chain is shown in SEQ ID NO: 20; c) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 29 and the amino acid sequence of the light chain is shown in SEQ ID NO: 30; or d) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 39 and the amino acid sequence of the light [70558W001]

[0311] chain is shown in SEQ ID NO: 40 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab. However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and the amino acid sequence of the light chain is shown in SEQ ID NO: 10 and wherein the IL-5 binding protein of the combination is depemokimab, mepolizumab, benralizumab or reslizumab.

[0312] In an embodiment, said IL-33 binding protein of the combination comprises: a) a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8; b) a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18; c) a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28; or d) a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38 and wherein the IL-5 binding protein of the combination comprises: a) a VH region that is 100% identical to SEQ ID NO: 89 and / or a VL region that is 100% identical to SEQ ID NO: 90; b) a VH region that is 100% identical to SEQ ID NO: 93 and / or a VL region that is 100% identical to SEQ ID NO: 94; c) a VH region that is 100% identical to SEQ ID NO: 97 and / or a VL region that is 100% identical to SEQ ID NO: 98; or d) a VH region that is 100% identical to SEQ ID NO: 101 and / or a VL region that is 100% identical to SEQ ID NO: 102.

[0313] In an embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein: a) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and the amino acid sequence of the light chain is shown in SEQ ID NO: 10; b) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 19 and the amino acid sequence of the light chain is shown in SEQ ID NO: 20; c) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 29 and the amino acid sequence of the light chain is shown in SEQ ID NO: 30; or d) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 39 and the amino acid sequence of the light chain is shown in SEQ ID NO: 40 and wherein the IL-5 binding protein of the combination comprises a heavy chain and a light chain, wherein: a) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 91 and the amino acid sequence of the light chain is shown in SEQ ID NO: 92; b) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 95 and the amino acid sequence of the light chain is shown in SEQ ID NO: 96; c) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 99 and the amino acid sequence of the light chain is shown in SEQ ID NO: 100; or d) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 103 and the amino acid sequence of the light chain is shown in SEQ ID NO: 104. [70558W001]

[0314] In a particular embodiment, the IL-5 binding protein of the combination (i.e., present in combination with the IL-33 binding protein) is depemokimab, wherein the amino acid sequence of depemokimab is provided herein as SEQ ID NOs: 83-92.

[0315] Thus, in a particular embodiment, the IL-33 binding protein of the combination comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6; b) CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16; c) CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26; or d) CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36 and wherein the IL-5 binding protein of the combination has the following six CDRs: CDRH1 of SEQ ID NO: 83; CDRH2 of SEQ ID NO: 84 and CDRH3 of SEQ ID NO: 85; and CDRL1 of SEQ ID NO: 86; CDRL2 of SEQ ID NO: 87; and CDRL3 of SEQ ID NO: 88. However, in a most particular embodiment, the IL-33 binding protein of the combination comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5 and CDRL3 of SEQ ID NO: 6 and wherein the IL-5 binding protein of the combination has the following six CDRs: CDRH1 of SEQ ID NO: 83; CDRH2 of SEQ ID NO: 84 and CDRH3 of SEQ ID NO: 85; and CDRL1 of SEQ ID NO: 86; CDRL2 of SEQ ID NO: 87; and CDRL3 of SEQ ID NO: 88.

[0316] In an embodiment, said IL-33 binding protein of the combination comprises: a) a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8; b) a VH region that is 100% identical to SEQ ID NO: 17 and / or a VL region that is 100% identical to SEQ ID NO: 18; c) a VH region that is 100% identical to SEQ ID NO: 27 and / or a VL region that is 100% identical to SEQ ID NO: 28; or d) a VH region that is 100% identical to SEQ ID NO: 37 and / or a VL region that is 100% identical to SEQ ID NO: 38 and wherein the IL-5 binding protein of the combination comprises a VH region that is 100% identical to SEQ ID NO: 89 and / or a VL region that is 100% identical to SEQ ID NO: 90. However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and wherein the IL-5 binding protein of the combination comprises a VH region that is 100% identical to SEQ ID NO: 89 and a VL region that is 100% identical to SEQ ID NO: 90.

[0317] In an embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein: a) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and [70558W001]

[0318] the amino acid sequence of the light chain is shown in SEQ ID NO: 10; b) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 19 and the amino acid sequence of the light chain is shown in SEQ ID NO: 20; c) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 29 and the amino acid sequence of the light chain is shown in SEQ ID NO: 30; or d) the amino acid sequence of the heavy chain is shown in SEQ ID NO: 39 and the amino acid sequence of the light chain is shown in SEQ ID NO: 40 and wherein the IL-5 binding protein of the combination comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 91 and the amino acid sequence of the light chain is shown in SEQ ID NO: 92.

[0319] However, in a most particular embodiment, said IL-33 binding protein of the combination comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 9 and the amino acid sequence of the light chain is shown in SEQ ID NO: 10 and wherein the IL-5 binding protein of the combination comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 91 and the amino acid sequence of the light chain is shown in SEQ ID NO: 92.

[0320] Host cell and production methods

[0321] In some aspects of the invention, there is provided a recombinant host cell comprising any of the nucleic acid sequences described above, or the expression vector described above. The term "recombinant host cell" as used herein refers to a cell that comprises a nucleic acid sequence of interest that was isolated prior to its introduction into the cell. For example, the nucleic acid sequence of interest may be in an expression vector. Host cells described herein may be prokaryotic or eukaryotic. Exemplary eukaryotic cells are mammalian cells, such as but not limited to, COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, HepG2, 653, SP2 / 0, NS0, 293, HeLa, myeloma, lymphoma cells, or any derivative thereof. The eukaryotic cell may be HEK293, NS0, SP2 / 0, or CHO cell. E. coli is an exemplary prokaryotic cell. A recombinant host cell according to the disclosure may be generated by transfection, cell fusion, immortalisation, or other procedures well known in the art. A nucleic acid of interest, such as an expression vector, transfected into a cell may be extrachromosomal or stably integrated into the chromosome of the cell.

[0322] In some aspects of the invention, there is provided a method for the production of an IL-33, a TSLP, or an IL-5 binding protein, which method comprises culturing the host cell as described above herein under conditions suitable for expression of said nucleic acid sequence or vector, whereby a polypeptide comprising the IL-33, TSLP, or IL-5 binding protein is produced. The combination, the kit-of-parts, or the product described herein comprise IL-33, TSLP, or IL-5 antigen binding proteins that may be prepared by any of a number of conventional techniques. For example, [70558W001]

[0323] antigen binding proteins may 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.

[0324] A number of different expression systems and purification regimes can be used to generate the antigen binding proteins of the invention. Generally, host cells are transformed with a recombinant expression vector encoding the desired antigen binding protein. 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. A wide range of host cells can be employed, including Prokaryotes (including Gram-negative or Gram-positive bacteria, for example, Escherichia coii, Bacilli sp., Pseudomonas sp., Corynebacterium sp.), Eukaryotes including yeast (for example, Saccharomyces cerevisiae, Pichia pastoris), fungi (for example, Aspergillus sp.), or higher Eukaryotes including insect cells and cell lines of mammalian origin (for example, CHO, NSO, PER. C6, HEK293, HeLa).

[0325] 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. The host cell may be a microorganism cell.

[0326] Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian host cells are known in the art.

[0327] The cells can be cultured under conditions that promote expression of the antigen binding protein using a variety of equipment such as shake flasks, spinner flasks, and bioreactors. The polypeptide(s) is(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 antigen binding protein may be formulated in a pharmaceutically acceptable composition.

[0328] The skilled person will appreciate that upon production of any of 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 antigen binding proteins that have been subjected to, or have undergone, one or more post-translational modifications. Thus an " IL-33 binding protein" or a " TSLP binding protein" of the disclosure includes those that have undergone a post-translational modification such as those described herein. For example, C-terminal lysine clipping is an enzymatic [70558W001]

[0329] 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-33 binding proteins orTSLP binding proteins disclosed herein. Accordingly, any of the combinations, kits of parts or products described herein may comprise IL-33 binding proteins and TSLP binding proteins with all C-terminal lysine residues removed, with no C-terminal lysine residues removed or populations having a mixture of binding proteins with and without the C-terminal lysine residue.

[0330] Pharmaceutical compositions and methods of use

[0331] The combination, the kit-of-parts, or the product described herein may be used in simultaneous administration or any manner of separate and / or sequential administrations of the IL-33 binding protein or pharmaceutical composition thereof and the TSLP binding protein or pharmaceutical composition thereof.

[0332] In one embodiment, wherein the administration is simultaneous, said IL-33 binding protein and said TSLP binding protein may be combined in a single pharmaceutical composition wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In this embodiment, said IL-33 binding protein and said TSLP binding protein are present as a fixed dose combination product for simultaneous (i.e. single) administration. In another embodiment, said pharmaceutical composition may in some instances be prepared by admixing (for example, close to the time of administration to a subject) the IL-33 binding protein or a pharmaceutical composition thereof and the TSLP binding protein or pharmaceutical composition thereof to present a fixed pharmaceutical composition.

[0333] In an embodiment, there is provided a pharmaceutical composition comprising at least an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a particular embodiment, there is provided a pharmaceutical composition comprising at least an IL-33 binding protein comprising the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and a TSLP binding protein comprising the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a further embodiment, there is provided a pharmaceutical composition comprising at least an IL-33 binding protein [70558W001]

[0334] comprising a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and a TSLP binding protein comprising a VH region that is 100% identical to SEQ ID NO: 47 and a VL region that is 100% identical to SEQ ID NO: 48, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0335] In one embodiment, if the administration is not simultaneous, the IL-33 binding protein or pharmaceutical composition thereof and the TSLP binding protein or pharmaceutical composition thereof are presented separately and are administered in a close time proximity to each other (e.g., within 30 minutes of each other, within 1 hour of each other, within 6 hours of each other, within 12 hours of each other or within 24 hours of each other). Thus, the IL-33 binding protein or pharmaceutical composition thereof and the TSLP binding protein or pharmaceutical composition thereof do not need to be administered in the same dosage form. For example, and not limitation, one binding protein or pharmaceutical composition thereof may be administered intravenously, and the other binding protein or pharmaceutical composition thereof may be administered subcutaneously.

[0336] The combination, the kit-of-parts, or the product described herein may be used in simultaneous administration or any manner of separate and / or sequential administrations of the IL-33 binding protein or pharmaceutical composition thereof and the IL-5 binding protein or pharmaceutical composition thereof.

[0337] In one embodiment, wherein the administration is simultaneous, said IL-33 binding protein and said IL-5 binding protein may be combined in a single pharmaceutical composition wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In this embodiment, said IL-33 binding protein and said IL-5 binding protein are present as a fixed dose combination product for simultaneous (i.e., single) administration. In another embodiment, said pharmaceutical composition may in some instances be prepared by admixing (for example, close to the time of administration to a subject) the IL-33 binding protein or a pharmaceutical composition thereof and the IL-5 binding protein or pharmaceutical composition thereof to present a fixed pharmaceutical composition.

[0338] In an embodiment, there is provided a pharmaceutical composition comprising at least an interleukin 33 (IL-33) binding protein and an interleukin 5 (IL-5) binding protein wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a particular embodiment, there is provided a pharmaceutical composition comprising at least an IL-33 binding protein comprising the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and an IL-5 binding protein comprising the following six CDRs: CDRH1 of SEQ ID NO: [70558W001]

[0339] 83; CDRH2 of SEQ ID NO: 84 and CDRH3 of SEQ ID NO: 85; and CDRL1 of SEQ ID NO: 86; CDRL2 of SEQ ID NO: 87; and CDRL3 of SEQ ID NO: 88, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a further embodiment, there is provided a pharmaceutical composition comprising at least an IL-33 binding protein comprising a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and an IL-5 binding protein comprising a VH region that is 100% identical to SEQ ID NO: 89 and a VL region that is 100% identical to SEQ ID NO: 90, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0340] In one embodiment, if the administration is not simultaneous, the IL-33 binding protein or pharmaceutical composition thereof and the IL-5 binding protein or pharmaceutical composition thereof are presented separately and are administered in a close time proximity to each other (e.g., within 30 minutes of each other, within 1 hour of each other, within 6 hours of each other, within 12 hours of each other or within 24 hours of each other ). Thus, the IL-33 binding protein or pharmaceutical composition thereof and the IL-5 binding protein or pharmaceutical composition thereof do not need to be administered in the same dosage form. For example, and not limitation, one binding protein or pharmaceutical composition thereof may be administered intravenously, and the other binding protein or pharmaceutical composition thereof may be administered subcutaneously.

[0341] The combination, the kit-of-parts, or the product described herein may be administered by injection or continuous infusion via a route, that can include for example, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intraocular, intraportal, or another route. The combination, the kit-of-parts, or the product described herein may be suitable for intravenous administration. In one embodiment, the combination, the kit-of-parts, or the product described herein may be suitable for subcutaneous administration. The combination, the kit-of-parts, or the product described herein may be suitable for topical administration (which can include epicutaneous, intranasal or ocular administration, inhalational administrations or enteral administration).

[0342] The combination, the kit-of-parts, or the product described herein may comprise other medicaments and / or with instructions for use. For convenience, the combination, the kit-of-parts, or the product described herein may comprise the reagents in predetermined amounts with instructions for use. The combination, the kit-of-parts, or the product described herein may also include one or more devices, such as a syringe, a needle, a length of tubing or another device, that can be used for administration.

[0343] The terms "individual", "subject" and "patient" are used herein interchangeably. In one embodiment, the subject is a human. [70558W001]

[0344] The term "treatment" (also known as "therapy") refers to ameliorating or stabilizing the specified condition (e.g., COPD), reducing or eliminating the symptoms of the condition, reducing or eliminating exacerbations of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. The term "prevention" refers to avoidance of the stated disease in a subject who is not suffering from the stated disease.

[0345] It will be appreciated by those skilled in the art that references herein to treatment refer to the treatment of established conditions. However, the binding proteins disclosed herein may, depending on the condition, also be useful in the prevention of certain diseases (i.e., as prophylactics).

[0346] In one aspect, there is provided a method of preventing or treating disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of any of the combinations, the kits of parts, or the products described herein to the subject. In some aspects of the invention, there is provided a combination, kit-of-parts, or product described herein for use in preventing or treating disease in a subject. The combinations, the kits of parts, or the products described herein may find therapeutic uses for treating various diseases, but most especially pathological disorders mediated by both IL-33 and TSLP, i.e., diseases or conditions that involve IL-33 and TSLP dysregulation. The combinations, the kits of parts, or the products described herein may also find therapeutic uses for treating various diseases, but most especially pathological disorders mediated by both IL-33 and IL-5, i.e., diseases or conditions that involve IL-33 and IL-5 dysregulation.

[0347] In one aspect, there is provided a method of preventing or treating a disease, for example, a respiratory disease selected from the group consisting of asthma, non-cystic fibrosis bronchiectasis (NCFB), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSwoNP), chronic rhinosinusitis sans nasal polyps (CRSsNP), eosinophilic esophagitis and chronic obstructive pulmonary disease (COPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of any of the combinations, the kits of parts, or the products described herein to the subject. In some aspects of the invention, there is provided a combination, kit-of-parts, or product described herein for use in preventing or treating a disease, for example, a respiratory disease selected from the group consisting of asthma, non-cystic fibrosis bronchiectasis (NCFB), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSwoNP), chronic rhinosinusitis sans nasal polyps (CRSsNP), eosinophilic esophagitis, and chronic obstructive pulmonary disease (COPD). [70558W001]

[0348] In a particular aspect of the disclosure, there is provided a method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of any of the combinations, the kits of parts, or the products described herein to the subject. A "therapeutically effective amount" of the binding proteins described herein is an amount effective to ameliorate or reduce one or more symptoms of, or to prevent or cure, the disease (e.g., COPD).

[0349] In some aspects of the disclosure, there is provided a combination, kit-of-parts, or product described herein for use in prevention or therapy. In some aspects of the invention, there is provided a combination, kit-of-parts, or product described herein for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD). In a particular embodiment, there is provided a combination, kit-of-parts, or product described herein for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) wherein said combination, kit-of-parts or products comprise both an IL-33 binding protein and a TSLP binding protein and wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46. In a particular embodiment, there is provided a combination, kit-of-parts, or product described herein for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) wherein said combination, kit-of-parts or products comprise both an IL-33 binding protein and a TSLP binding protein and wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and a VL region that is 100% identical to SEQ ID NO: 48.

[0350] As described above, the combination, kit-of-parts, or product described herein may comprise an IL-33 binding protein and a TSLP binding protein and may be used in a method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof. In an embodiment, said method comprises administering the TSLP binding protein to the subject in need thereof, wherein the TSLP binding protein comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH region comprises a HCDR1 of SEQ ID NO: 41, a HCDR2 of SEQ ID NO: 42 and a HCDR3 of SEQ ID NO: 43 and wherein the VL region comprises a LCDR1 of SEQ ID NO: 44, a LCDR2 of SEQ [70558W001]

[0351] ID NO: 45 and a LCDR3 of SEQ ID NO: 46. In an embodiment, the TSLP binding protein comprises a VH region comprising the amino acid sequence as shown in SEQ ID NO: 47 and a VL region comprising the amino acid sequence as shown in SEQ ID NO: 48. In an embodiment, the TSLP binding protein comprises a heavy chain comprising the amino acid sequence as shown in SEQ ID NO: 49 and a light chain comprising the amino acid sequence as shown in SEQ ID NO: 50.

[0352] In a particular embodiment, there is provided a combination, kit-of-parts, or product described herein for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) wherein said combination, kit-of-parts or products comprise both an IL-33 binding protein and an IL-5 binding protein and wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said IL-5 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 83; CDRH2 of SEQ ID NO: 84 and CDRH3 of SEQ ID NO: 85; and CDRL1 of SEQ ID NO: 86; CDRL2 of SEQ ID NO: 87; and CDRL3 of SEQ ID NO: 88. In a particular embodiment, there is provided a combination, kit-of-parts, or product described herein for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) wherein said combination, kit-of-parts or products comprise both an IL-33 binding protein and an IL-5 binding protein and wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and wherein said IL-5 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 89 and a VL region that is 100% identical to SEQ ID NO: 90.

[0353] As described above, the combination, kit-of-parts, or product described herein may comprise an IL-33 binding protein and an IL-5 binding protein and may be used in a method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof. In an embodiment said method comprises administering the IL-5 binding protein to the subject in need thereof, wherein the IL-5 binding protein comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH region comprises a HCDR1 of SEQ ID NO: 83, a HCDR2 of SEQ ID NO: 84 and a HCDR3 of SEQ ID NO: 85 and wherein the VL region comprises a LCDR1 of SEQ ID NO: 86, a LCDR2 of SEQ ID NO: 87 and a LCDR3 of SEQ ID NO: 88. In an embodiment, the IL-5 binding protein comprises a VH region comprising the amino acid sequence as shown in SEQ ID NO: 89 and a VL region comprising the amino acid sequence as shown in SEQ ID NO: 90. In an embodiment, the IL-5 binding protein comprises a heavy chain comprising the amino acid sequence as shown in SEQ ID NO: 91 and a light chain comprising the amino acid sequence as shown in SEQ ID NO: 92. [70558W001]

[0354] In some aspects of the invention, there is provided a use of a combination, kit-of-parts, or product described herein in the manufacture of a medicament for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD).

[0355] Thus, it is established that the combination, kit-of-parts, or product described herein are useful in the prevention or treatment of COPD and / or decreasing acute exacerbations of COPD. In an embodiment, said combination, kit-of-parts or product are administered to COPD patients who have already received an initial treatment for their COPD but said initial treatment has not had a sufficient response (for example, the patient is still suffering from frequent COPD exacerbations). In the case of COPD, the initial treatment a patient may have received prior to being administered with the combination, kit-of-parts of product described herein may include a bronchodilator (for example, a short-acting beta₂ agonist or a short-acting muscarinic antagonist), a long-acting beta₂ agonist (LABA), a long-acting muscarinic antagonist (LAMA), an inhaled corticosteroid or an alternative biologic therapy (for example, dupilumab).

[0356] In an embodiment, the combination, kit-of-parts, or product described herein are used in the prevention or treatment of COPD in a subject regardless of the subjects' blood eosinophil count. However, in an embodiment, the combination, kit-of-parts, or product described herein are used in the prevention or treatment of COPD in a subject wherein the subject has a blood eosinophil count of greater than or equal to 150 cells per µL, such as a blood eosinophil count of greater than or equal to 200 cells per µL, greater than or equal to 250 cells per µL or greater than or equal to 300 cells per µL. In an embodiment, the combination, kit-of-parts, or product described herein are used in the prevention or treatment of COPD in a subject wherein the subject has a blood eosinophil count of less than or equal to 300 cells per µL, such as a blood eosinophil count of less than or equal to 250 cells per µL, less than or equal to 200 cells per µL or less than or equal to 150 cells per µL. In an embodiment, the combination, kit-of-parts, or product described herein are used in the prevention or treatment of COPD in a subject, wherein the subject has a blood eosinophil count of between 150 cells per µL and 300 cells per µL. In an embodiment, the combination, kit-of-parts, or product described herein are used in the prevention or treatment of COPD in a subject wherein the subject has a blood eosinophil count of between 10 cells per µL and 1000 cells per µL, such as between 25 cells per µL and 800 cells per µL, between 50 cells per µL and 600 cells per µL.

[0357] In an embodiment, the combination, kit-of-parts, or product described herein are used in the prevention or treatment of COPD in a subject wherein the subject has a blood eosinophil count of between 10 cells per µL and 150 cells per µL. In an embodiment, the subject has a blood eosinophil count of between 150 cells per µL and 300 cells per µL. In an embodiment, the subject has a blood eosinophil count of greater than 300 cells per pL. In an embodiment, the subject has a blood [70558W001]

[0358] eosinophil count of greater than 600 cells per µL. In an embodiment, the subject has a blood eosinophil count of between 300 cells per µL and 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000 or 9000 cells per µL. In an embodiment, the subject has a blood eosinophil count of less than 150 cells per µL. In an embodiment, the subject has a blood eosinophil count of less than 100 cells per µL. In an embodiment, the subject has a blood eosinophil count of between 5 cells per µL and 25, 50, 75, 100, 125, or 150 cells per µL.

[0359] In certain embodiments, the subject has said blood eosinophil counts prior to commencing treatment with the combination, kit-of-parts, or product described herein. In some embodiments, the subjects are stratified into the following groups: a blood eosinophil count of >300 cells / pL (high blood eosinophils); a blood eosinophil count of between 299 and 150 cells / pL (moderate blood eosinophils); a blood eosinophil count of < 150 cells / pL (low blood eosinophils), wherein the combination, kit-of-parts, or products described herein may be administered i) to subjects with low, moderate or high blood eosinophils, ii) to subjects with low blood eosinophils, iii) to subjects with low or moderate blood eosinophils, iv) to subjects with moderate blood eosinophils, v) to subjects with moderate or high blood eosinophils or vi) to subjects with high blood eosinophils.

[0360] In some embodiments, the subject is between the ages of 40 and 85. In some embodiments, the subject is at least 40 years old, e.g., at least 45 years old, at least 50 years old, at least 55 years old, etc. In some embodiments, the subject is at least 65 years old, e.g., at least 70 years old. In some embodiments, the subject is 75 years of age or older. In some embodiments, the subject is younger than 40 years of age.

[0361] In some embodiments, the subject is a current smoker (such as a cigarette smoker). In some embodiments, the subject is a current smoker and has a smoking history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a current smoker who has a smoking history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or longer. In some embodiments, the subject is a former smoker (such as a former cigarette smoker). In some embodiments, the subject is a former smoker who has a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker who has a smoking history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or longer. In some embodiments, the subject is a former smoker who has ceased smoking for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more. In some embodiments, the subject is a former smoker who has ceased smoking for at least 6 months. In some embodiments, the subject is a former smoker that intends to quit permanently.

[0362] In some embodiments, the subject is classified as having "mild" COPD based on the GOLD classification system. In other embodiments, the subject is classified as having "moderate" COPD [70558W001]

[0363] based on the GOLD classification system. In another embodiment, the subject is classified as having "severe" COPD based on the GOLD classification system. In yet another embodiment, the subject is classified as having "very severe" COPD based on the GOLD classification system. In some embodiments, the subject has had greater than or equal to 2 exacerbations in the past 12 months, for example, in the 12 months prior to treatment. In some embodiments, the subject has had greater than or equal to 2 exacerbations in the 12 months prior to treatment and is classified as having "severe" COPD based on the GOLD classification system. A diagnosis of COPD in a subject may be made according to the guidance provided by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document (2024 update). In pulmonary function testing, a post-bronchodilator FEVi / FVC ratio of <0.7 is commonly considered diagnostic for COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) system categorises airflow limitation into stages (see Table 3).

[0364] Table 3. GOLD grades and severity of airflow obstruction in COPD (based on post-bronchodilator FEV₁)

[0365] In patients with FEVi / FVC <0.7:

[0366] GOLD 1 mild FEV₁ >80% predicted

[0367] GOLD 2 moderate 50% < FEVi <80% predicted

[0368] GOLD 3 severe 30% < FEVi <50% predicted

[0369] GOLD 4 very severe FEVi <30% predicted

[0370]

[0371] In some aspects of the invention, there is provided a method of decreasing hospital admissions in a subject with COPD, said method comprising administering to said subject a therapeutically effective amount of a combination, kit-of-parts, or product as defined herein to the subject.

[0372] Decreasing in this context may mean that the number of hospital admissions (for example, caused by a subject having an acute exacerbation episode) in a defined period is less than prior to administration of the binding protein or pharmaceutical composition. Decreasing may also mean that any hospital admissions are shorter than prior to administration of the combination, kit-of-parts, or product. Decreasing may also mean that there are no hospital admissions as a result of the subjects' COPD.

[0373] In some aspects of the invention, there is provided a method of decreasing the annualized rate of moderate-to-severe AECOPD events in a subject said method comprising administering to said subject a therapeutically effective amount of a combination, kit-of-parts, or product as defined herein to the subject. In certain exemplary embodiments, time to first moderate-to- severe AECOPD event is reduced. [70558W001]

[0374] In some aspects of the invention, there is provided a method of improving pre- and / or postbronchodilator FEV₁ in a subject with COPD, said method comprising administering to said subject a therapeutically effective amount of a combination, kit-of-parts, or product as defined herein to the subject.

[0375] Embodiments are further described in the subsequent numbered clauses:

[0376] 1. A combination of antigen binding proteins comprising an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein.

[0377] 2. A kit-of-parts comprising an IL-33 binding protein and a TSLP binding protein.

[0378] 3. A product comprising an IL-33 binding protein and a TSLP binding protein for simultaneous, separate, or sequential use in prevention or therapy.

[0379] 4. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein comprises (a) (i) any one or a combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 7, 17, 27 or 37 and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 8, 18, 28 or 38; or (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% identical to the sequence of SEQ ID NO: 7, 17, 27 or 37; and / or a VL region comprising a sequence at least 80% identical to the sequence of SEQ ID NO: 8, 18, 28 or 38.

[0380] 5. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6; b) CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16; c) CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26; or d) CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36.

[0381] 6. The combination, the kit-of-parts, or the product for use according to clause 5, wherein the IL- 33 binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6.

[0382] 7. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein comprises a) a VH region that is at least 90%, at least 92%, [70558W001]

[0383] at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 8; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 17 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 18; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 27 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 28; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 37 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 38.

[0384] 8. The combination, the kit-of-parts, or the product for use according to clause 7, wherein the IL- 33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8.

[0385] 9. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein comprises a) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 9 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 10; b) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 19 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 20; c) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 29 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 30; or d) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 39 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 40.

[0386] 10. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein comprises a) a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10; b) a heavy chain as shown in SEQ ID NO: 19 and a light chain as shown in SEQ ID NO: 20; c) a heavy chain as shown in SEQ ID NO: 29 and a light chain as shown in SEQ ID NO: 30; or d) a heavy chain as shown in SEQ ID NO: 39 and a light chain as shown in SEQ ID NO: 40.

[0387] 11. The combination, the kit-of-parts, or the product for use according to clause 9 or 10, wherein the IL-33 binding protein comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10. [70558W001]

[0388] 12. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein comprises a modification which extends the half-life of the binding protein compared to the unmodified binding protein.

[0389] 13. The combination, the kit-of-parts, or the product for use according to clause 12, wherein the modification which extends the half-life of the binding protein compared to the unmodified binding protein is an M252Y substitution, an S254T substitution, and a T256E substitution according to EU numbering.

[0390] 14. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the IL-33 binding protein binds to IL-33 with an affinity (KD) of less than 100pM, optionally wherein affinity (KD) is measured using surface plasmon resonance (SPR) at 37°C.

[0391] 15. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein comprises (a) (i) any one or a combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 47, 57, 67 or 77 and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 48, 58, 68 or 78; or (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% identical to the sequence of SEQ ID NO: 47, 57, 67 or 77; and / or a VL region comprising a sequence at least 80% identical to the sequence of SEQ ID NO: 48, 58, 68 or 78.

[0392] 16. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46; b) CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56; c) CDRH1 of SEQ ID NO: 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66; or d) CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

[0393] 17. The combination, the kit-of-parts, or the product for use according to clause 16, wherein the TSLP binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0394] 18. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein comprises a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 47 and / or a VL [70558W001]

[0395] region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 48; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 57 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 58; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 67 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 68; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 77 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 78.

[0396] 19. The combination, the kit-of-parts, or the product for use according to clause 18, wherein the TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and a VL region that is 100% identical to SEQ ID NO: 48.

[0397] 20. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein comprises a) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 49 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 50; b) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 59 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 60; c) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 69 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 70; or d) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 79 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 80.

[0398] 21. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein comprises a) a heavy chain as shown in SEQ ID NO: 49 and a light chain as shown in SEQ ID NO: 50; b) a heavy chain as shown in SEQ ID NO: 59 and a light chain as shown in SEQ ID NO: 60; c) a heavy chain as shown in SEQ ID NO: 69 and a light chain as shown in SEQ ID NO: 70; or d) a heavy chain as shown in SEQ ID NO: 79 and a light chain as shown in SEQ ID NO: 80.

[0399] 22. The combination, the kit-of-parts, or the product for use according to clause 20 or 21, wherein the TSLP binding protein comprises a heavy chain as shown in SEQ ID NO: 49 and a light chain as shown in SEQ ID NO: 50. [70558W001]

[0400] 23. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein comprises a modification which extends the half-life of the binding protein compared to the unmodified binding protein.

[0401] 24. The combination, the kit-of-parts, or the product for use according to clause 23, wherein the modification which extends the half-life of the binding protein compared to the unmodified binding protein is an M252Y substitution, an S254T substitution, and a T256E substitution according to EU numbering.

[0402] 25. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein the TSLP binding protein binds to human TSLP with an affinity (KD) of less than 100pM, optionally wherein affinity (KD) is measured using surface plasmon resonance (SPR) at 37°C.

[0403] 26. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

[0404] 27. The combination, the kit-of-parts, or the product for use according to any preceding clause, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48.

[0405] 28. The combination, the kit-of-parts, or the product for use according to any preceding clause, further comprising a pharmaceutically acceptable excipient.

[0406] 29. A method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an IL-33 binding protein and a therapeutically effective amount of a TSLP binding protein to the subject.

[0407] 30. A method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the combination, the kit- of-parts, or the product according to any one of clauses 1 to 28. [70558W001]

[0408] 31. A method of decreasing hospital admissions in a subject with COPD comprising administering to said subject a therapeutically effective amount of the combination, the kit-of-parts, or the product, according to any one of clauses 1 to 28, optionally wherein said hospital admissions are as a result of the subject experiencing acute exacerbation episodes.

[0409] 32. A method of decreasing the annualized rate of moderate-to-severe AECOPD events in a subject said method comprising administering to said subject a therapeutically effective amount of the combination, the kit-of-parts, or the product, according to any one of clauses 1 to 28.

[0410] 33. A method of improving pre- and / or post-bronchodilator FEV1 in a subject with COPD said method comprising administering to said subject a therapeutically effective amount the combination, the kit-of-parts, or the product, according to any one of clauses 1 to 28.

[0411] 34. The combination, the kit-of-parts, or the product according to according to any one of clauses 1 to 28 for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD).

[0412] 35. Use of the combination, the kit-of-parts, or the product according to any one of clauses 1 to 28, in the manufacture of a medicament for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) in a subject.

[0413] 36. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 35, wherein the subject is eligible for treatment with the combination, the kit-of-parts, or the product regardless of the subjects' blood eosinophil count.

[0414] 37. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 35, wherein the subject has a blood eosinophil count of between 10 cells per µL and 150 cells per µL, between 150 cells per µL and 300 cells per µL or greater than 300 cells per pL.

[0415] 38. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 37, wherein the subject has mild, moderate, severe, or very severe COPD based on the GOLD classification system.

[0416] 39. The method; the combination, kit-of-parts or product for use; or the use, according to clause 38, wherein the subject has severe or very severe COPD based on the GOLD classification system.

[0417] 40. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 39, wherein the subject has had greater than or equal to 2 exacerbations in the 12 months prior to treatment. [70558W001]

[0418] 41. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 40, wherein the IL-33 binding protein is administered to the subject intravenously or subcutaneously and the TSLP binding protein is administered to the subject intravenously or subcutaneously.

[0419] 42. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 41, wherein the subject is a human subject.

[0420] 43. The method; the combination, kit-of-parts or product for use; or the use, according to any one of clauses 29 to 42, wherein the IL-33 binding protein and TSLP binding protein are administered simultaneously, concurrently or sequentially.

[0421] Further embodiments of the present disclosure are provided for in the below numbered paragraphs:

[0422] 1. A combination of antigen binding proteins comprising an interleukin 33 (IL-33) binding protein and an interleukin 5 (IL-5) binding protein.

[0423] 2. A kit-of-parts comprising an IL-33 binding protein and an IL-5 binding protein.

[0424] 3. A product comprising an IL-33 binding protein and an IL-5 binding protein for simultaneous, separate, or sequential use in prevention or therapy.

[0425] 4. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein the IL-33 binding protein comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6; b) CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16; c) CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26; or d) CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36.

[0426] 5. The combination, the kit-of-parts, or the product according to paragraph 4, wherein the IL-33 binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6.

[0427] 6. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein the IL-33 binding protein comprises a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and / or a VL region [70558W001]

[0428] that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 8; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 17 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 18; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 27 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 28; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 37 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 38.

[0429] 7. The combination, the kit-of-parts, or the product according to paragraph 6, wherein the IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8.

[0430] 8. The combination, the kit-of-parts, or the product for use according to any preceding paragraph, wherein the IL-33 binding protein comprises a) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 9 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 10; b) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 19 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 20; c) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 29 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 30; or d) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 39 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 40.

[0431] 9. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein the IL-33 binding protein comprises a) a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10; b) a heavy chain as shown in SEQ ID NO: 19 and a light chain as shown in SEQ ID NO: 20; c) a heavy chain as shown in SEQ ID NO: 29 and a light chain as shown in SEQ ID NO: 30; or d) a heavy chain as shown in SEQ ID NO: 39 and a light chain as shown in SEQ ID NO: 40.

[0432] 10. The combination, the kit-of-parts, or the product according to paragraph 8 or 9, wherein the IL- 33 binding protein comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10.

[0433] 11. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein the IL-5 binding protein comprises a) a VH region that is at least 90%, at least 92%, at [70558W001]

[0434] least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 89 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 90; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 93 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 94; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 97 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 98; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 101 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 102.

[0435] 12. The combination, the kit-of-parts, or the product according to paragraph 11, wherein the IL-5 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 89 and a VL region that is 100% identical to SEQ ID NO: 90.

[0436] 13. The combination, the kit-of-parts, or the product for use according to any preceding paragraph, wherein the IL-5 binding protein comprises a) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 91 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 92; b) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 95 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 96; c) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 99 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 100; or d) a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 103 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 104.

[0437] 14. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein the IL-5 binding protein comprises a) a heavy chain as shown in SEQ ID NO: 91 and a light chain as shown in SEQ ID NO: 92; b) a heavy chain as shown in SEQ ID NO: 95 and a light chain as shown in SEQ ID NO: 96; c) a heavy chain as shown in SEQ ID NO: 99 and a light chain as shown in SEQ ID NO: 100; or d) a heavy chain as shown in SEQ ID NO: 103 and a light chain as shown in SEQ ID NO: 104.

[0438] 15. The combination, the kit-of-parts, or the product according to paragraph 13 or 14, wherein the IL-5 binding protein comprises a heavy chain as shown in SEQ ID NO: 91 and a light chain as shown in SEQ ID NO: 92. [70558W001]

[0439] 16. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said IL-5 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 83; CDRH2 of SEQ ID NO: 84 and CDRH3 of SEQ ID NO: 85; and CDRL1 of SEQ ID NO: 86; CDRL2 of SEQ ID NO: 87; and CDRL3 of SEQ ID NO: 88.

[0440] 17. The combination, the kit-of-parts, or the product according to any preceding paragraph, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8 and wherein said IL-5 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 89 and a VL region that is 100% identical to SEQ ID NO: 90.

[0441] 18. The combination, the kit-of-parts, or the product according to any preceding paragraph, further comprising a pharmaceutically acceptable excipient.

[0442] 19. A method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of an IL-33 binding protein and a therapeutically effective amount of an IL-5 binding protein to the subject.

[0443] 20. A method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the combination, the kit- of-parts, or the product according to any one of paragraphs 1 to 18.

[0444] 21. A method of decreasing hospital admissions in a subject with COPD comprising administering to said subject a therapeutically effective amount of the combination, the kit-of-parts, or the product, according to any one of paragraphs 1 to 18, optionally wherein said hospital admissions are as a result of the subject experiencing acute exacerbation episodes.

[0445] 22. A method of decreasing the annualized rate of moderate-to-severe AECOPD events in a subject said method comprising administering to said subject a therapeutically effective amount of the combination, the kit-of-parts, or the product, according to any one of paragraphs 1 to 18.

[0446] 23. A method of improving pre- and / or post-bronchodilator FEV1 in a subject with COPD said method comprising administering to said subject a therapeutically effective amount the combination, the kit-of-parts, or the product, according to any one of paragraphs 1 to 18. [70558W001]

[0447] 24. The combination, the kit-of-parts, or the product according to according to any one of paragraphs 1 to 18 for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD).

[0448] 25. Use of the combination, the kit-of-parts, or the product according to any one of paragraphs 1 to 18, in the manufacture of a medicament for use in the prevention or treatment of COPD and / or for use in decreasing acute exacerbations of COPD (AECOPD) in a subject.

[0449] 26. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 25, wherein the subject is eligible for treatment with the combination, the kit-of-parts, or the product regardless of the subjects' blood eosinophil count.

[0450] 27. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 25, wherein the subject has a blood eosinophil count of between 10 cells per µL and 150 cells per µL, between 150 cells per µL and 300 cells per µL or greater than 300 cells per pL.

[0451] 28. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 27, wherein the subject has mild, moderate, severe, or very severe COPD based on the GOLD classification system.

[0452] 29. The method; the combination, kit-of-parts or product for use; or the use, according to paragraph 28, wherein the subject has severe or very severe COPD based on the GOLD classification system.

[0453] 30. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 29, wherein the subject has had greater than or equal to 2 exacerbations in the 12 months prior to treatment.

[0454] 31. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 30, wherein the IL-33 binding protein is administered to the subject intravenously or subcutaneously and the IL-5 binding protein is administered to the subject intravenously or subcutaneously.

[0455] 32. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 31, wherein the subject is a human subject.

[0456] 33. The method; the combination, kit-of-parts or product for use; or the use, according to any one of paragraphs 19 to 32, wherein the IL-33 binding protein and the IL-5 binding protein are administered simultaneously, concurrently or sequentially.

[0457] The invention is further illustrated by the following non-limiting examples. [70558W001]

[0458] EXAMPLES

[0459] Example 1 - Mechanistic Inference of ECLIPSE data

[0460] The aim of this experiment was to uncover molecular mechanisms linking IL5, TSLP, and IL33 to COPD phenotype.

[0461] The ECLIPSE study was a longitudinal observational study of 2164 COPD subjects and a smaller number of smoking controls (337) and nonsmoking controls (245) followed regularly for three years (Hurst JR etal N Engl J Med. 2010 Sep 16;363(12):1128-38).

[0462] In a subset of ~150 patients, blood and sputum transcriptomics were profiled via microarray readout. Patients were classified into different severity states following GOLD classification. Based on the transcriptomic differences in sputum, severe-state COPD patients (GOLD3 and GOLD4) were compared against mild-state COPD patients (GOLD2) to uncover molecular mechanisms describing relations of IL5, TSLP, and IL33 to COPD severity.

[0463] Further, based on their transcriptomics and mechanistic profile, patients were attempted to be further stratified.

[0464] Method Details: Workflow contained the following steps:

[0465] 1. Preprocessed microarray-derived differential expression (DE) profiles from sputum samples (e.g., GOLD3 vs GOLD2 patients) were loaded for analysis.

[0466] 2. Gene activity estimation was performed in R Package (using causaIR) wherein for gene activity estimate (delta = 1, threshold: alpha = 0.05).

[0467] 3. Mechanistic inference from multi-omics data (MIMO) analysis was performed in R Package (using cbmimo) starting from IL5, TSLP, IL33, and respective known receptors and ending at differentially expressed genes (DEGs, threshold: alpha = 0.01, fold-change = >50%).

[0468] 4. Enriched nodes downstream of IL5, TSLP, IL33 were identified using node set enrichment analysis (NSEA) as implemented in R package cbmimo.

[0469] 5. Enriched nodes were compared and commonalities / differences downstream of respective start-points were identified. [70558W001]

[0470] Results:

[0471] FIG. 1, Panel A illustrates a Venn diagram showing that in a data agnostic setting, IL-5, TSLP and IL-33 show large numbers of overlapping pathways and nodes towards differentially expressed genes (DEGs). However, following addition of omics readout data to the causal network during mechanistic inference from multi-omics data (MIMO) analysis, IL-5 and TSLP were identified as having more extensive overlap in paths and nodes towards DEGs as shown in FIG. 1, Panel B.

[0472] Despite starting from different receptors, IL-5 and TSLP were identified to share a common downstream signaling cascade via JAK1 / 2 and STAT3 / STAT5 (FIG. 2, Panel A), while IL-33 was identified to utilize distinct IRAK / STAT3 / MAPK cascade (FIG. 2, Panel B). TSLP and especially IL-5 showed strong mechanistic links to NFkB-related inflammation signaling through STAT5.

[0473] As a result of this work, targeting both IL-33 and TSLP / IL-5 may offer the opportunity to coblockade separate inflammatory signaling pathways resulting in an improved anti-inflammatory response in COPD patients.

[0474] Example 2: IL-33 and TSLP have genetic validation as targets in COPD

[0475] An analysis of genetic variance in IL-33 and TSLP expression as a proxy of pharmacological inhibition of IL-33 and TSLP was conducted using subject-level data from the UK Biobank study. For each gene, a gene risk score (GRS) was developed. Each GRS was constructed from select genetic variants associated with baseline blood eosinophil count in UK Biobank (Table 4). The IL-33 and TSLP GRSs were separately calculated in individual participants within the UK Biobank cohort study. The GRS was calculated as the sum of the number of selected genetic variants carried by a participant, each weighted by their effect size on blood eosinophil count. This cohort sample was then partitioned firstly into halves after ranking subjects according to one of the GRS (e.g., IL-33) and then subsequently into quartiles based on the other GRS (e.g., TSLP). The quartile with individuals who were in the bottom half for both scores is referred to as the 'combined' group, the quartile with individuals in the top half for both scores is known as the 'control' group and the other two quartiles were used to predict effects of targeting each target individually (e.g., low IL-33 score but high TSLP score is known as the IL-33 group and vice versa for the TSLP group). Three subsamples were then generated by considering the 'control' quartile with each of the other [70558W001]

[0476] quartiles in turn and each of these subsamples were separately analysed to estimate the genetically predicted effects of lowering activity of IL-33, TSLP and both on COPD risk.

[0477] Following analysis of data from the UK Biobank, lower genetically determined IL-33 and TSLP activity is associated with reduced risk of COPD as shown in FIG. 3. Lower genetically determined activity of both TSLP and IL-33 may yield an additive effect with respect to decreasing risk of COPD based on calculated central effect estimates. This data suggests that co-blockade of both targets will result in improved / additive effects in COPD patients. This data supports a differentiated COPD development approach, targeting multiple pathways to reach the broadest group of patients and utilizing combination therapy to maximise efficacy.

[0478] Table 4. Tool variants used as genetic proxies for IL-33 and TSLP

[0479] Variant_ID Effect Effect size for association with blood Target

[0480] (GRCh38) allele eosinophil count

[0481] IL33 chr9:6197392: T: C C -0.0966281

[0482] IL33 chr9:6257919: TTAAA: T T 0.117562

[0483] IL33 chr9:6255967: G: C C -0.282863

[0484] TSLP chr5:111066174: T: C C 0.037858

[0485] TSLP chr5:111089365: G: C c 0.036134

[0486] TSLP chr5:111162175: GAT: G G -0.0225186

[0487]

[0488] Example 3: Affinity in solution of the first IL-33 binding protein to human and cynomolgus IL-33

[0489] The affinity of the first IL-33 binding protein (including CDRs from SEQ ID NOs: 7 and 8) for human and cynomolgus monkey IL-33 at room temperature (25°C) and 37°C was determined using an MSD-SET (MESOSCALE DISCOVERY Solution Equilibrium Titration) assay. Two anti-IL-33 antibodies [70558W001]

[0490] (in-house) were included in the assay as positive controls and a human IgGl isotype control (inhouse) was included as a negative control for non-specific binding.

[0491] Methods

[0492] Two identical 96 well polypropylene plates were prepared with biotinylated human IL-33 (in-house) at a constant concentration of 30pM and the antibodies to be tested titrated 1 in 3 from InM to 5x10-5nM across the plate, with a final 1 in 10 dilution to 5x10-6nM. All antibodies were tested in duplicate within the plate. Both plates were incubated for 24 hours, one at room temperature, the other at 37°C.

[0493] After 24 hours, the same antibodies (20nM in PBS) were coated on to two identical standard bind MSD plates (Mesoscale Discovery #L15XA) for 30 minutes at room temperature. Plates were then blocked with starting block blocking buffer for 30 minutes with shaking at 700 rpm, followed by three washes with wash buffer. The incubated solutions were added to the MSD plates (each incubation temperature on its own MSD plate) for 150 seconds with shaking at 700 rpm followed by one wash. Antigen captured on the plate was detected with SULFO-TAG -labeled streptavidin (Mesoscale Discovery #R32AD-1). The plates were washed three times with wash buffer and then read on the MSD Sector Imager instrument using lx Read Buffer T (Mesoscale Discovery #R92TC-1) with surfactant. The percent free antigen was plotted as a function of titrated antibody concentration in GraphPad Prism and fit to a quadratic equation.

[0494] To determine the affinity to cynomolgus monkey IL-33 (in-house), the assay was repeated with cynomolgus IL-33 at a constant concentration of 62.5pM and the antibodies titrated 1 in 3 from 12nM to 6x10-4nM with a final 1 in 10 dilution to 6x10-5nM.

[0495] Results

[0496] The affinity of the first IL-33 binding protein for human IL-33 is 3.3pM (range 1.8-6pM) at 25°C and 13.5pM (range 0-42pM) at 37°C. The affinity of the first IL-33 binding protein for cynomolgus IL-33 at 25°C is 27.5pM (range 4.6-43pM) and at 37°C is 56.5pM (range 30-98pM). See Table 5 for results. [70558W001]

[0497] The positive control antibodies (mAbl and mAb2) bound both human and cynomolgus IL-33, while the negative isotype control antibody showed no binding to IL-33. All the assay results met the acceptance criteria of R2>0.96.

[0498] All the samples were run in duplicate within the plates and the reported results are therefore an average of n=2. One of the first IL-33 binding protein replicates in the cynomolgus IL-33 25°C assay failed acceptance criteria due to an automation pipetting error. This plate was repeated and hence the result for this sample is an average of n=3.

[0499] Table 5. Affinity in solution of IL-33 antibodies to human and cynomolgus IL-33 by MSD-SET Lower Upper 95% 95% Temp Average KD

[0500] Antibody Antigen confidence confidence (°C) (pM)

[0501] interval interval (pM) (pM) human IL- 25 3.3 1.8 6 the first IL-33 binding 33 37 13.5 0 42 protein 25 27.5* 4.6 43 cyno IL-33

[0502] 37 56.5 30 98 human IL- 25 <3.0 0 2.6 33 37 9.65 0 17 Anti IL-33 control mAbl

[0503] 25 125 95 320 cyno IL-33

[0504] 37 565 130 990 human IL- 25 <3.0 0 1.6 33 37 <3.0 0 9 Anti IL-33 control mAb2

[0505] 25 61.5 20 100 cyno IL-33

[0506]

[0507] 37 140 48 240 Affinity values are an average of n=2 replicates, apart from (*) which is n=3

[0508] Affinity values of 0 are not possible, but these lower confidence interval values of zero are due to the limits set in the prism macro used to analyse the results.

[0509] Example 4

[0510] Methodology [70558W001]

[0511] Peripheral blood mononuclear cells (PBMCs) were isolated from human whole blood samples, collected from 2-4 healthy donors per independent experiment (denoted by 'ELN' number). PBMCs were stimulated with 1.52 nM recombinant human (rh)IL-33 and 2 nM recombinant human (rh)TSLP (R& D systems, 1398-TS-010 / CF), pre-complexed with monoclonal antibodies for 30 minutes at 37°C.

[0512] The monoclonal antibodies tested were as follows:

[0513] - Tezepelumab (SEQ ID Nos: 51-60, i.e., second TSLP binding protein)

[0514] - Control anti-IL33 mAb (SEQ ID Nos: 21-30, i.e., third IL-33 binding protein)

[0515] HU179-33 anti-TSLP (SEQ ID Nos: 41-50, i.e., first TSLP binding protein)

[0516] 22A06-458 anti-IL-33 (SEQ ID Nos: 1-10, i.e., first IL-33 binding protein)

[0517] For 22A06-458 mAb and HU179-33, the respective isotype control was an anti-RSV IgGl YTE, whereas for Tezepelumab and control anti-IL-33 mAb, the respective isotype control antibodies were anti-RSV IgG2 and anti-RSV IgG4. Following 48-hour stimulation at 37°C, 5% CO2, quantities of IL-5, IL-13 and TARC (CCL17) in the supernatant were determined using MSD kits (IL-5, IL-13 = K15067M-2, K15067M-4, K15010K-2; TARC = K15705D-2, K15067M-2, K151ULK-4), following manufacturer's instructions.

[0518] Analyte concentration (pg / mL) was interpolated from electrochemiluminescence (ECL) using Discovery Workbench Software (version 4.0.13). For each analyte, the calculated concentration of unstimulated samples was subtracted from all monoclonal antibody-treated samples and rhIL-33 and rhTSLP only treated samples for each donor. Then, to determine the percentage of response, the monoclonal antibody-treated samples were normalised to the rhIL-33 and rhTSLP only treated samples. The calculation was performed using Excel (version 2508). The formula for the percentage of maximum responses is as below:

[0519] Percentage (%) of response

[0520] _ | / _ Cal. Cone, of samp _le - Cal. Cone, of no mAb treated unstimulated samp _le \

[0521] 1 x 100 yCal. Cone, of no mAb treated stimulated sample — Cal. Cone, of no mAb treated unstimulated sample J

[0522] Following normalisation, the mean percentage of response at each monoclonal antibody concentration ± standard deviation (SD) within 15 donors were plotted in scatter plots using R (v4.4.1) and RStudio. [70558W001]

[0523] For comparisons between different mAb treatments at the three mAb concentrations tested, 5.56nM, 16.67nM and 50nM, separate mixed effects models were used to assess differences in percent response at each concentration. The effects of the individual monotherapy treatments were specified as separate binary variables with the combination treatment as the baseline and a nested random effect was included for donors within each independent experiment (denoted by ELN); therefore, the model was adjusted to take donor effects and the batch effect between independent experiments into consideration. Statistical significance was assessed using a null hypothesis of each of the monotherapy treatment effects being equal to zero (no difference from combination), using a f-test with Satterthwaite's correction for degrees of freedom. The threshold for significance was set at 5%, which was indicated by p-values. Estimated p-values were adjusted for multiple testing using Benjamini-Hochberg FDR correction and p-values less than 0.05 were considered as significant. These statistical comparisons were performed in R and RStudio.

[0524] Results:

[0525] 22A06-458 and HU179-33:

[0526] In the study of 22A06-458 and HU179-33, IL-5, IL-13 and TARC secretion were upregulated by hPBMCs following stimulation with rhIL-33 and rhTSLP for 48 hours (data not shown). Control antibody (anti-RSV IgGl YTE) exhibited no effect on rhIL-33 and rhTSLP-induced IL-5, IL-13 or TARC when tested at matched concentrations to 22A06-458 and HU179-33 (data not shown).

[0527] Statistical comparison of three mAb concentrations tested (50 nM, 16.67 nM, 5.56 nM) was performed. The percentage inhibition by 22A06-458 + HU179-33 combination treatment at the two highest monoclonal antibody (mAb) concentrations tested (50 nM, 16.67 nM) were significantly greater than HU179-33 individual treatment for both IL-5 ( <0.001, =0.024, respectively) and IL-13 release px 0.001, =0.007, respectively) (FIG 4). Additionally, the percentage inhibition by 22A06-458 + HU-179-33 combination treatment at the three mAb concentrations tested (50 nM, 16.67 nM, 5.56 nM) were significantly greater than 22A06-458 individual treatment for both IL-5 ( <0.001, all concentrations) and IL-13 release ( <0.001, all concentrations) (FIG 4).

[0528] 22A06-458 + HU179-33 combination treatment and HU179-33 individual treatment were observed to be comparable in their inhibition of TARC release (FIG 5). The level of inhibition of 22A06-458 mAb + HU179-33 combination treatment was significantly greater than the 22A06-458 individual [70558W001]

[0529] treatment at the three mAb concentrations tested (50nM, 16.67nM, 5.56nM) ( / xO. OOl, all concentrations) (FIG 5).

[0530] Control anti-IL-33 mAb and Tezeoelumab:

[0531] In the study of Control anti-IL-33 mAb and Tezepelumab, IL-5, IL-13 and TARC secretion were upregulated by hPBMCs following stimulation rhIL-33 and rhTSLP for 48 hours (data not shown). Control antibodies (anti-RSV IgG2 and anti-RSV IgG4) exhibited no effect on rhIL-33 and rhTSLP-induced IL-5, IL-13 or TARC production when tested at matched concentrations to control anti-IL-33 mAb and Tezepelumab (data not shown).

[0532] Statistical comparison of the three mAb concentrations tested (50nM, 16.67nM, 5.56nM) was performed. The percentage inhibition by Control anti-IL-33 mAb + Tezepelumab combination treatment was significantly greater than Tezepelumab individual treatment for both IL-5, at the three concentrations tested (50 nM, 16.67 nM, 5.56 nM), ( / xO. OOl, all conditions) and IL-13, at concentrations 5.56 nM and 16.67 nM only, p= 0.012, p <0.001, respectively) (FIG 6). Additionally, the percentage inhibition by Control anti-IL-33 mAb + Tezepelumab combination at concentrations of 5.56 nM and 16.67 nM was significantly greater than Control anti-IL-33 mAb individual treatment for both IL-5 ( = 0.007, =0.013, respectively) and IL-13 release ( =0.041, =0.008, respectively), but not at 50 nM (FIG 6).

[0533] Control anti-IL-33 mAb + Tezepelumab combination treatment and Tezepelumab individual treatment were observed to be comparable in their inhibition of TARC release (FIG 7). The level of inhibition of Control anti-IL-33 mAb + Tezepelumab combination treatment was significantly greater than Control anti-IL-33 mAb individual treatment at the three highest mAb concentrations tested (50nM, 16.67nM, 5.56nM) ( / xO.001, all concentrations) (FIG 7).

[0534] Conclusion

[0535] Anti-IL-33 and anti-TSLP molecules in combination were demonstrated to provide greater inhibition of IL-5 and IL-13, compared to anti-IL-33 or anti-TSLP treatment alone. Anti-IL-33 and anti-TSLP molecules in combination resulted in inhibition of TARC that was comparable to anti-TSLP alone, but greater than anti-IL-33 alone. These effects were observed for both anti-IL-33 and anti-TSLP molecule combinations, 22A06-458 + HU179-33 and Control anti-IL-33 + Tezepelumab. [70558W001]

[0536] Example 5: Proteomic Analysis (ECLIPSE study)

[0537] Methods:

[0538] The study design of the ECLIPSE study has been published previously (see for example Vestbo et al Eur Respirl 2008;31:869-873). The clinicaltrials.gov identifier is NCT0029552.

[0539] A total of 927 longitudinally collected sputum samples from the ECLIPSE study were profiled using Alamar NULISASeq Inflammation Panel 250. Alamar Biosciences provided the log normalized expression levels (NPQ) for all proteins in the panel. These were further filtered based on whether a particular protein was detected above limit of detection in at least 10% of the patients. This yielded a final list of 243 unique proteins for downstream analysis however the analysis presented herein focuses only on the TSLP and IL-33 proteins. There were no sample outliers detected / filtered based on control distributions and Principal Component Analysis (PCA). The present analysis leveraged samples from the " COPD only" cohort at either the screening visit or visit 1.

[0540] The NPQ values for IL-33 and TSLP proteins were extracted, independently ranked and patients having:

[0541] the top 34% ranks for both proteins were classified as "high" co-expression i.e. the top tertile.

[0542] - the bottom 34% ranks for both proteins were classified as "low" co-expression i.e. the bottom tertile

[0543] - remaining patients as "moderate" co-expression group.

[0544] Spearman correlation, regression slope and R2were calculated for TSLP NPQ values against IL33 NPQ values for the overall data as well as for the high and low co-expression groups.

[0545] Association between a number of clinical parameters (i.e. smoking status, GOLD stage (2-4 and ABE), FEV1 and Exacerbation rate) and the high and low co-expression groups were explored and tested via the non-parametric Wilcox test.

[0546] Results: [70558W001]

[0547] Sputum IL-33 and TSLP protein levels are highly correlated (r=0.7; px 0.001) as shown in FIG. 8.

[0548] In GOLD II participants, the high co-expression sub-group displays significantly reduced (p<0.01) average FEV1 (~8% less) compared to the low group. A numerically similar trend in GOLD III / IV participants was observed (see FIG. 9). Furthermore, the high co-expression sub-group linked with more frequent future exacerbation rate (see FIG. 10). Together this data supports the hypothesis that airway IL-33 / TSLP could jointly contribute to COPD lung function decline and future exacerbation rate. A weak association of the high co-expression group with smoking status was observed with former smokers having a statistically significant correlation (likely due to higher samples size - data not shown).

[0549] SEQUENCE LISTING

[0550] SEQ ID NO: Description and Sequence

[0551] 1 CDRH1 of first IL-33 binding protein (also referred to herein as 22A06-458 )

[0552] SYGMH

[0553] 2 CDRH2 of first IL-33 binding protein (also referred to herein as 22A06-458 )

[0554] EINPHGGSTS YAQKFKG

[0555] 3 CDRH3 of first IL-33 binding protein (also referred to herein as 22A06-458 )

[0556] PSAAYSHYLGIDL

[0557] 4 CDRL1 of first IL-33 binding protein (also referred to herein as 22A06-458 )

[0558] RASQGISSWLA

[0559] 5 CDRL2 of first IL-33 binding protein (also referred to herein as 22A06-458 )

[0560] AASRLQS

[0561] 6 CDRL3 of first IL-33 binding protein (also referred to herein as 22A06-458 )

[0562] QQANVFPLT

[0563] 7 VH of first IL-33 binding protein (also referred to herein as 22A06- 458 )

[0564] QVQLVQS GAEVKKPGAS VKVS CKAS GYTFI S YGMHWVRQAPGQGLEWMG EINPHGGSTS YAQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARPS AAYSHYLGIDLWGRGTLVTVSS

[0565]

[0566] [70558W001]

[0567] 8 VL of first IL-33 binding protein (also referred to herein as 22A06- 458 )

[0568] D I QMTQS PS SVSAS VGDRVT I TCRAS QGI S SWLAWYQQKPGKAPKLL I Y AASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANVFPLTFG GGTKVEIK

[0569] 9 HC of first IL-33 binding protein (also referred to herein as 22A06- 458 )

[0570] QVQLVQS GAEVKKPGAS VKVS CKAS GYTFI S YGMHWVRQAPGQGLEW MGEINPHGGSTSYAQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYY CARPSAAYSHYLGIDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPS SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNS TYRWS VLTVLHQDWLNGKE YKCKVSNKALPAP I EKTI S K AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK

[0571] 10 LC of first IL-33 binding protein (also referred to herein as 22A06- 458 )

[0572] D I QMTQS PS SVSAS VGDRVT I TCRAS QGI S SWLAWYQQKPGKAPKLL I YA ASRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANVFPLTFGG GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

[0573] 11 CDRH1 of second IL-33 binding protein

[0574] SYAMS

[0575] 12 CDRH2 of second IL-33 binding protein

[0576] GISAIDQSTYYADSVKG

[0577] 13 CDRH3 of second IL-33 binding protein

[0578] QKFMQLWGGGLRYPFGY

[0579] 14 CDRL1 of second IL-33 binding protein

[0580] SGEGMGDKYAA

[0581] 15 CDRL2 of second IL-33 binding protein

[0582] RDTKRPS

[0583] 16 CDRL3 of second IL-33 binding protein

[0584] GVIQDNTGV

[0585] 17 VH of second IL-33 binding protein

[0586] EVQLLES GGGLVQPGGS LRLS CAAS GFTFS S YAMSWVRQAPGKGLEWVS GISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQ KFMQLWGGGLRYPFGYWGQGTMVTVS S

[0587] 18 VL of second IL-33 binding protein

[0588]

[0589] [70558W001]

[0590] S YVLTQPPS VS VS PGQTAS I TCS GEGMGDKYAAWYQQKPGQS PVLVI YRD TKRPS GI PERFS GSNS GNTATLT I S GTQAMDEADYYCGVI QDNTGVFGGGT KLTVL

[0591] 19 HC of second IL-33 binding protein

[0592] EVQLLES GGGLVQPGGS LRLS CAAS GFTFS S YAMSWVRQAPGKGLEWVS GISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQ KFMQLWGGGLRYPFGYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPS SSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDS DGS FFL YS KLTVDKS RWQQGNVFS CS VMHEALHNHYTQKS L SLSPGK

[0593] 20 LC of second IL-33 binding protein SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDT KRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTK LTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSP VKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEK TVAPTECS

[0594] 21 CDRH1 of third IL-33 binding protein

[0595] GFTFSRSA

[0596] 22 CDRH2 of third IL-33 binding protein

[0597] ISGSGGRT

[0598] 23 CDRH3 of third IL-33 binding protein

[0599] AKDS YTTSWYGGMDV

[0600] 24 CDRL1 of third IL-33 binding protein

[0601] QGIFSW

[0602] 25 CDRL2 of third IL-33 binding protein

[0603] AAS

[0604] 26 CDRL3 of third IL-33 binding protein

[0605] QQANSVPIT

[0606] 27 VH of third IL-33 binding protein

[0607] EVQLVES GGNLEQPGGS LRLS CTAS GFTFS RSAMNWVRRAPGKGLEWVS GISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKD S YTTSWYGGMDVWGHGTTVTVS S

[0608] 28 VL of third IL-33 binding protein DIQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYA ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQG TRLEIK

[0609] 29 HC of third IL-33 binding protein

[0610]

[0611] [70558W001]

[0612] EVQLVES GGNLEQPGGS LRLS CTAS GFTFS RSAMNWVRRAPGKGLEWV S GI S GS GGRT YYADS VKGRFTI S RDNS KNTL YLQMNS LSAEDTAAYYCAKD SYTTSWYGGMDVWGHGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRW SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0613] 30 LC of third IL-33 binding protein DIQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYAAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQGTRLEI KRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC

[0614] 31 CDRH1 of fourth IL-33 binding protein

[0615] NYWIG

[0616] 32 CDRH2 of fourth IL-33 binding protein IIYPGNSDTRFSPSFQ

[0617] 33 CDRH3 of fourth IL-33 binding protein

[0618] HGTSSDYYGLDV

[0619] 34 CDRL1 of fourth IL-33 binding protein

[0620] QASQDIS

[0621] 35 CDRL2 of fourth IL-33 binding protein

[0622] DASNLET

[0623] 36 CDRL3 of fourth IL-33 binding protein

[0624] DDNFPLT

[0625] 37 VH of fourth IL-33 binding protein EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYWIGWVRQMPGKGLEWMGII YPGNSDTRFSPSFQGQVTISADKSITTAYLQWSSLKASDTAMYYCARHGTSS D YYGLDVWGQGTTVTVS S

[0626] 38 VL of fourth IL-33 binding protein

[0627] D I QMTQS PS S LSAS VGDRVT I TCQAS QD I SNYLNWYQQKPGKAPKLL I YDASN LETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQDDNFPLTFGGGTKVEIKR

[0628] 39 HC of fourth IL-33 binding protein

[0629] EVQLVQS GAEVKKPGES LKI S CKGS GYS FTNYWI GWVRQMPGKGLEWMG IIYPGNSDTRFSPSFQGQVTISADKSITTAYLQWSSLKASDTAMYYCARHG TSSDYYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSNFGTQ TYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNST

[0630]

[0631] [70558W001]

[0632] FRWS VLTWHQDWLNGKE YKCKVSNKGLPAP I EKT I S KTKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0633] 40 LC of fourth IL-33 binding protein

[0634] D I QMTQS PS S LSAS VGDRVT I TCQAS QD I SNYLNWYQQKPGKAPKLL I YDAS NLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQDDNFPLTFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC

[0635] 41 CDRH1 of first TSLP binding protein (also referred to herein as HU179-33)

[0636] NYLIE

[0637] 42 CDRH2 of first TSLP binding protein (also referred to herein as HU179-33)

[0638] VIDPGVGDTNYNENFKG

[0639] 43 CDRH3 of first TSLP binding protein (also referred to herein as HU179-33)

[0640] EDNTGTAFDY

[0641] 44 CDRL1 of first TSLP binding protein (also referred to herein as HU179-33)

[0642] KASQSVSSDVT

[0643] 45 CDRL2 of first TSLP binding protein (also referred to herein as HU179-33)

[0644] YVSEHYT

[0645] 46 CDRL3 of first TSLP binding protein (also referred to herein as HU179-33)

[0646] QQHHRFPLT

[0647] 47 VH of first TSLP binding protein (also referred to herein as HU179- 33)

[0648] EVQLVQS GAEVKKPGS S VKVS CKAS GYTFSNYL I EWVRQAPGQGLEWI GV IDPGVGDTNYNENFKGRATLTADKSTSTAYIELSSLRSEDTAVYYCAREDN TGTAFD YWGQGTTVTVS S

[0649] 48 VL of first TSLP binding protein (also referred to herein as HU179- 33)

[0650] SIVMTQTPLSLSVTPGQPASISCKASQSVSSDVTWYLQKPGQSPQLLIYY VS EHYTGVPDRFS GS GYGTDFTLKI S RVEAEDVGVYYCQQHHRFPLTFG QGTKLEIK

[0651] 49 HC of first TSLP binding protein (also referred to herein as HU179- 33)

[0652] EVQLVQSGAEVKKPGSSVKVSCKASGYTFSNYLIEWVRQAPGQGLEWIGVI DPGVGDTNYNENFKGRATLTADKSTSTAYIELSSLRSEDTAVYYCAREDNT

[0653]

[0654] [70558W001]

[0655] GTAFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITRE PEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0656] 50 LC of first TSLP binding protein (also referred to herein as HU179- 33)

[0657] SIVMTQTPLSLSVTPGQPASISCKASQSVSSDVTWYLQKPGQSPQLLIYYVSEH YTGVPDRFSGSGYGTDFTLKISRVEAEDVGVYYCQQHHRFPLTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0658] 51 CDRH1 of second TSLP binding protein

[0659] TYGMH

[0660] 52 CDRH2 of second TSLP binding protein

[0661] VIWYDGSNKHYADSVKG

[0662] 53 CDRH3 of second TSLP binding protein

[0663] APQWELVHEAFDI

[0664] 54 CDRL1 of second TSLP binding protein

[0665] GGNNLGSKSVH

[0666] 55 CDRL2 of second TSLP binding protein

[0667] DDSDRPS

[0668] 56 CDRL3 of second TSLP binding protein

[0669] QVWDSSSDHW

[0670] 57 VH of second TSLP binding protein

[0671] QMQLVES GGGWQPGRS LRLS CAAS GFTFRT YGMHWVRQAPGKGLEWVA VIWYDGSNKHYADSVKGRFTITRDNSKNTLNLQMNSLRAEDTAVYYCARAP QWELVHEAFD IWGQGTMVTVS S

[0672] 58 VL of second TSLP binding protein SYVLTQPPSVSVAPGQTARITCGGNNLGSKSVHWYQQKPGQAPVLWYDD SDRPSWIPERFSGSNSGNTATLTISRGEAGDEADYYCQVWDSSSDHWFG GGTKLTVL

[0673] 59 HC of second TSLP binding protein

[0674] QMQLVES GGGWQPGRS LRLS CAAS GFTFRT YGMHWVRQAPGKGLEWVAV IWYDGSNKHYADS VKGRFT I TRDNS KNTLNLQMNS LRAEDTAVYYCARAPQ WELVHEAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSNFGTQTYTCN VDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEV TCVWDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWH QDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQ

[0675]

[0676] [70558W001]

[0677] VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0678] 60 LC of second TSLP binding protein SYVLTQPPSVSVAPGQTARITCGGNNLGSKSVHWYQQKPGQAPVLWYDDS DRPSWIPERFSGSNSGNTATLTISRGEAGDEADYYCQVWDSSSDHWFGGG TKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS

[0679] 61 CDRH1 of third TSLP binding protein

[0680] SSAMH

[0681] 62 CDRH2 of third TSLP binding protein

[0682] SVSGSGAGTY YADSVKG

[0683] 63 CDRH3 of third TSLP binding protein

[0684] EGGSRGFDY

[0685] 64 CDRL1 of third TSLP binding protein

[0686] RASQDISNYL A

[0687] 65 CDRL2 of third TSLP binding protein

[0688] TASSLQS

[0689] 66 CDRL3 of third TSLP binding protein

[0690] QQYNLYPPT

[0691] 67 VH of third TSLP binding protein

[0692] EVQLLESGGG LVQPGGSLRL SCAASGFTFR SSAMHWVRQA PGKGLKWVSS VSGSGAGTYY ADSVKGRFTI SRDNPKNTLY LQMNSLRAED TAVYYCVKEG GSRGFDYWGQ GTLVTVSS

[0693] 68 VL of third TSLP binding protein

[0694] DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLAWFQQKP GKAPKSLIYT ASSLQSGVPS KFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNLYPPTFGQ GTKVEIK

[0695] 69 HC of third TSLP binding protein

[0696] EVQLLESGGG LVQPGGSLRL SCAASGFTFR SSAMHWVRQA PGKGLKWVSS VSGSGAGTYY ADSVKGRFTI SRDNPKNTLY LQMNSLRAED TAVYYCVKEGGSRGFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDYFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSWTVP SSSLGTQTYICNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKDTLMISRTPEV TCVWDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNSTYRWSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVYTLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLDSDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK

[0697] 70 LC of third TSLP binding protein

[0698] DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLAWFQQKP GKAPKSLIYTASSLQSGVPS KFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNLYPPTFGQGTKVEIKRTV AAPSVFIFPP

[0699]

[0700] [70558W001]

[0701] SDEQLKSGTA SWCLLNNFY PREAKVQWKVDNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQGLSSPVTKSFN RGEC

[0702] 71 CDRH1 of fourth TSLP binding protein

[0703] DYAMH

[0704] 72 CDRH2 of fourth TSLP binding protein

[0705] TFIPLLDTSDYAQKFQG

[0706] 73 CDRH3 of fourth TSLP binding protein

[0707] MGVTHSYVMDA

[0708] 74 CDRL1 of fourth TSLP binding protein

[0709] RASQPISISVH

[0710] 75 CDRL2 of fourth TSLP binding protein

[0711] FASQSIS

[0712] 76 CDRL3 of fourth TSLP binding protein

[0713] QQTFSLPYT

[0714] 77 VH of fourth TSLP binding protein QVQLVQSGAEVKKPGASVKVSCKASGYIFTDYAMHWVRQAPGQGLEWMGTFIPLLDTSDYAQKF QGRVTMTADTS TS TAYMELRS LRS DDTAVYYCARMGVTHS YVMDAWGQGTLVTVS S

[0715] 78 VL of fourth TSLP binding protein EIVLTQSPGTLSLSPGERATLSCRASQPISISVHWYQQKPGQAPRLLIYFASQSISGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQTFSLPYTFGQGTKVEIK

[0716] 79 HC of fourth TSLP binding protein

[0717] QVQLVQSGAE VKKPGASVKV SCKASGYIFT DYAMHWVRQA PGQGLEWMGTFIPLLDTSDY AQKFQGRVTM TADTSTSTAY MELRSLRSDD TAVYYCARMGVTHS YVMDAW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVKDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQTYICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKPKDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQVYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPVLDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK

[0718] 80 LC of fourth TSLP binding protein

[0719] EIVLTQSPGT LSLSPGERAT LSCRASQPIS ISVHWYQQKP GQAPRLLIYFASQSISGIPD RFSGSGSGTD FTLTISRLEP EDFAVYYCQQ TFSLPYTFGQGTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SWCLLNNFY PREAKVQWKVDNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQGLSSPVTKSFN RGEC

[0720] 81 Human IL-33 (Uniprot: 095760)

[0721] MKPKMKYS TNKI S TAKWKNTAS KALCFKLGKS QQKAKEVCPMYFMKLRS GLMI KKEAC YF RRETTKRPSLKTGRKHKRHLVLAACQQQS TVECFAFGI S GVQKYTRALHDS S ITGISPIT EYLASLSTYNDQS ITFALEDES YEIYVEDLKKDEKKDKVLLS YYESQHPSNESGDGVDGK MLMVTLSPTKDFWLHANNKEHSVELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFI GVKDNHLALIKVDSSENLCTENILFKLSET

[0722] 82 Human TSLP (Uniprot: Q969D9)

[0723]

[0724] [70558W001] MFPFALLYVLSVSFRKIFILQLVGLVLTYDFTNCDFEKIKAAYLSTISKDLITYMSGTKS TEFNNTVSCSNRPHCLTEIQSLTFNPTAGCASLAKEMFAMKTKAALAIWCPGYSETQINA TQAMKKRRKRKVTTNKCLEQVSQLQGLWRRFNRPLLKQQ

[0725] 83 CDRH1 of first IL-5 binding protein

[0726] GSSVH

[0727] 84 CDRH2 of first IL-5 binding protein

[0728] VIWASGGTDYNSALMS

[0729] 85 CDRH3 of first IL-5 binding protein

[0730] DPPSGLLRLDY

[0731] 86 CDRL1 of first IL-5 binding protein

[0732] KS S QS LLNS GNQKNYLA

[0733] 87 CDRL2 of first IL-5 binding protein

[0734] GASTRES

[0735] 88 CDRL3 of first IL-5 binding protein

[0736] QNVHSFPFT

[0737] 89 VH of first IL-5 binding protein QVTLRESGPALVKPTQTLTLTCTVSGFSLTGSSVHWVRQPPGKGLEWLGVIWAS GGTDYNSALMSRLSISKDTSRNQWLTMTNMDPVDTATYYCARDPPSGLLRLDY WGRGTLVTVSS

[0738] 90 VL of first IL-5 binding protein DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLI YGASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVHSFPFTFGGG TKLEIKR

[0739] 91 HC of first IL-5 binding protein QVTLRESGPALVKPTQTLTLTCTVSGFSLTGSSVHWVRQPPGKGLEWLGVIWASGGTDYN SALMS RLSISKDTSRNQWLTMTNMDPVDTATYYCARDPPSGLLRLDYWGRGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK

[0740] 92 LC of first IL-5 binding protein DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGAST RES GVPDRFS GS GS GTDFTLT I S S LQAEDVAVYYCQNVHS FPFTFGGGTKLE I KRTVAA PSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS T YS LS S TLTLS KAD YEKHKVYACEVTHQGLS S PVTKS FNRGEC

[0741] 93 VH of second IL-5 binding protein QVTLRESGPALVKPTQTLTLTCTVSGFSLTS YSVHWVRQPPGKGLEWLGVIWASGGTD YNSALMSRLSISKDTSRNQWLTMTNMDPVDTATYYCARDPPSSLLRLDYWGRGTPV TVSS

[0742]

[0743] [70558W001]

[0744] 94 VL of second IL-5 binding protein DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVHSFPFTFGGGTKLEIK

[0745] 95 HC of second IL-5 binding protein QVTLRESGPALVKPTQTLTLTCTVSGFSLTS YSVHWVRQPPGKGLEWLGVIWASGGTDY NSALMSRLSISKDTSRNQWLTMTNMDPVDTATYYCARDPPSSLLRLDYWGRGTPVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRWSVLTVLHQDWLNGKEY

[0746] 96 LC of second IL-5 binding protein DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGAST RES GVPDRFS GS GS GTDFTLT I S S LQAEDVAVYYCQNVHS FPFTFGGGTKLE I KRTVAA PSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS T YS LS S TLTLS KAD YEKHKVYACEVTHQGLS S PVTKS FNRGEC

[0747] 97 VH of third IL-5 binding protein VQLVQSGAEVKKPGASVKVSCKASGYTFTS YVIHWVRQRPGQGLAWMGYINPYNDGTKY NERFKGKVTITSDRSTSTVYMELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLV TVSS

[0748] 98 VL of third IL-5 binding protein DIQMTQSPSSLSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYTLPYTFGQGTKVEIK

[0749] 99 HC of third IL-5 binding protein EVQLVQSGAEVKKPGASVKVSCKASGYTFTS YVIHWVRQRPGQGLAWMGYINPYNDGTK YNERFKGKVTITSDRSTSTVYMELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALP

[0750] 100 LC of third IL-5 binding protein DIQMTQSPSSLSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYTLPYTFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0751] 101 VH of fourth IL-5 binding protein EVQLVESGGGLVQPGGSLRLSCAVSGLSLTSNSVNWIRQAPGKGLEWVGLIWSNGDTD YNSAI KS RFT I S RDTS KS TVYLQMNS LRAEDTAVYYCARE YYGYFD YWGQGTLVTVS S

[0752] 102 VL of fourth IL-5 binding protein DIQMTQSPSSLSASVGDRVTITCLASEGISSYLAWYQQKPGKAPKLLIYGANSLQTGV PSRFSGSGSATDYTLTISSLQPEDFATYYCQQSYKFPNTFGQGTKVEVK

[0753] 103 HC of fourth IL-5 binding protein

[0754]

[0755] [70558W001] EVQLVESGGGLVQPGGSLRLSCAVSGLSLTSNSVNWIRQAPGKGLEWVGLIWSNGDTD YNSAI KS RFT I S RDTS KS TVYLQMNS LRAEDTAVYYCARE YYGYFD YWGQGTLVTVS S ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG

[0756] 104 LC of fourth IL-5 binding protein DIQMTQSPSSLSASVGDRVTITCLASEGISSYLAWYQQKPGKAPKLLIYGANSLQTGV PSRFSGSGSATDYTLTISSLQPEDFATYYCQQSYKFPNTFGQGTKVEVKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL S S TLTLS KAD YEKHKVYACEVTHQGLS S PVTKS FNRGEC

[0757] 105 Human I L - 5

[0758] IPTEIPTSALVKETLALLSTHRTLLIANETLRIPVPVHKNHQLCTEEIFQGIGTLESQT VQGGTVERLFKNLS L I KKYI DGQKKKCGEERRRVNQFLD YLQEFLGVMNTEWI I ES

[0759]

Claims

[70558W001]CLAIMSWe claim,1. A combination of antigen binding proteins comprising an interleukin 33 (IL-33) binding protein and a thymic stromal lymphopoietin (TSLP) binding protein.

2. The combination of claim 1, wherein the IL-33 binding protein comprises the following 6 CDRs:a) CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6; b) CDRH1 of SEQ ID NO: 11; CDRH2 of SEQ ID NO: 12 and CDRH3 of SEQ ID NO: 13; and CDRL1 of SEQ ID NO: 14; CDRL2 of SEQ ID NO: 15; and CDRL3 of SEQ ID NO: 16; c) CDRH1 of SEQ ID NO: 21; CDRH2 of SEQ ID NO: 22 and CDRH3 of SEQ ID NO: 23; and CDRL1 of SEQ ID NO: 24; CDRL2 of SEQ ID NO: 25; and CDRL3 of SEQ ID NO: 26; or d) CDRH1 of SEQ ID NO: 31; CDRH2 of SEQ ID NO: 32 and CDRH3 of SEQ ID NO: 33; and CDRL1 of SEQ ID NO: 34; CDRL2 of SEQ ID NO: 35; and CDRL3 of SEQ ID NO: 36.

3. The combination according to claim 2, wherein the IL-33 binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6.

4. The combination according to any preceding claim, wherein the IL-33 binding protein comprises a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 7 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 8; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 17 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 18; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 27 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 28; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 37 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 38.

5. The combination according to claim 4, wherein the IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and a VL region that is 100% identical to SEQ ID NO: 8.

6. The combination according to any preceding claim, wherein the IL-33 binding protein comprises a) a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10; b) a[70558W001]heavy chain as shown in SEQ ID NO: 19 and a light chain as shown in SEQ ID NO: 20; c) a heavy chain as shown in SEQ ID NO: 29 and a light chain as shown in SEQ ID NO: 30; or d) a heavy chain as shown in SEQ ID NO: 39 and a light chain as shown in SEQ ID NO: 40.

7. The combination according to claim 6, wherein the IL-33 binding protein comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10.

8. The combination according to any preceding claim, wherein the IL-33 binding protein comprises a modification which extends the half-life of the binding protein compared to the unmodified binding protein, optionally wherein the modification which extends the half-life of the binding protein compared to the unmodified binding protein is an M252Y substitution, an S254T substitution, and a T256E substitution according to EU numbering.

9. The combination according to any preceding claim, wherein the IL-33 binding protein binds to IL-33 with an affinity (KD) of less than 100pM, optionally wherein affinity (KD) is measured using surface plasmon resonance (SPR) at 37°C.

10. The combination according to any preceding claim, wherein the TSLP binding protein comprises the following 6 CDRs: a) CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46; b) CDRH1 of SEQ ID NO: 51; CDRH2 of SEQ ID NO: 52 and CDRH3 of SEQ ID NO: 53; and CDRL1 of SEQ ID NO: 54; CDRL2 of SEQ ID NO: 55; and CDRL3 of SEQ ID NO: 56; c) CDRH1 of SEQ ID NO: 61; CDRH2 of SEQ ID NO: 62 and CDRH3 of SEQ ID NO: 63; and CDRL1 of SEQ ID NO: 64; CDRL2 of SEQ ID NO: 65; and CDRL3 of SEQ ID NO: 66; or d) CDRH1 of SEQ ID NO: 71; CDRH2 of SEQ ID NO: 72 and CDRH3 of SEQ ID NO: 73; and CDRL1 of SEQ ID NO: 74; CDRL2 of SEQ ID NO: 75; and CDRL3 of SEQ ID NO: 76.

11. The combination according to claim 10, wherein the TSLP binding protein comprises the following 6 CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

12. The combination according to any preceding claim, wherein the TSLP binding protein comprises a) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 47 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 48; b) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 57 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 58; c) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 67 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100%[70558W001]identical to SEQ ID NO: 68; or d) a VH region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 77 and / or a VL region that is at least 90%, at least 92%, at least 94%, at least 96%, at least 98% or 100% identical to SEQ ID NO: 78.

13. The combination according to claim 12, wherein theTSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and a VL region that is 100% identical to SEQ ID NO: 48.

14. The combination according to any preceding claim, wherein the TSLP binding protein comprises a) a heavy chain as shown in SEQ ID NO: 49 and a light chain as shown in SEQ ID NO: 50; b) a heavy chain as shown in SEQ ID NO: 59 and a light chain as shown in SEQ ID NO: 60; c) a heavy chain as shown in SEQ ID NO: 69 and a light chain as shown in SEQ ID NO: 70; or d) a heavy chain as shown in SEQ ID NO: 79 and a light chain as shown in SEQ ID NO: 80.

15. The combination according to claim 13, wherein the TSLP binding protein comprises a heavy chain as shown in SEQ ID NO: 49 and a light chain as shown in SEQ ID NO: 50.

16. The combination according to any preceding claim, wherein the TSLP binding protein comprises a modification which extends the half-life of the binding protein compared to the unmodified binding protein, optionally wherein the modification which extends the half-life of the binding protein compared to the unmodified binding protein is an M252Y substitution, an S254T substitution, and a T256E substitution according to EU numbering.

17. The combination according to any preceding claim, wherein the TSLP binding protein binds to human TSLP with an affinity (KD) of less than 100pM, optionally wherein affinity (KD) is measured using surface plasmon resonance (SPR) at 37°C.

18. The combination according to any preceding claim, wherein said IL-33 binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 1; CDRH2 of SEQ ID NO: 2 and CDRH3 of SEQ ID NO: 3; and CDRL1 of SEQ ID NO: 4; CDRL2 of SEQ ID NO: 5; and CDRL3 of SEQ ID NO: 6 and wherein said TSLP binding protein comprises the following six CDRs: CDRH1 of SEQ ID NO: 41; CDRH2 of SEQ ID NO: 42 and CDRH3 of SEQ ID NO: 43; and CDRL1 of SEQ ID NO: 44; CDRL2 of SEQ ID NO: 45; and CDRL3 of SEQ ID NO: 46.

19. The combination according to any preceding claim, wherein said IL-33 binding protein comprises a VH region that is 100% identical to SEQ ID NO: 7 and / or a VL region that is 100% identical to SEQ ID NO: 8 and wherein said TSLP binding protein comprises a VH region that is 100% identical to SEQ ID NO: 47 and / or a VL region that is 100% identical to SEQ ID NO: 48.

20. The combination according to any preceding claim, wherein said IL-33 binding protein comprises a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO:[70558W001]9 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 10, and wherein said TSLP binding protein comprises a heavy chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 49 and a light chain that is at least 90%, at least 95%, or is 100% identical to SEQ ID NO: 50.

21. The combination according to any preceding claim, wherein said combination is a pharmaceutical combination product further comprising a pharmaceutically acceptable excipient.

22. The combination according to claim 21, wherein said pharmaceutical combination product is presented in a form adapted for simultaneous, concurrent or sequential administration.

23. The combination according to claim 21 or claim 22, wherein said IL-33 binding protein and said TSLP binding protein are presented as separate compositions.

24. The combination according to claim 21 or claim 22, wherein said IL-33 binding protein and said TSLP binding protein are in admixture with each other.

25. A method of preventing or treating chronic obstructive pulmonary disease (COPD) and / or decreasing acute exacerbations of COPD (AECOPD) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of the combination according to any preceding claim.

26. A method of decreasing hospital admissions in a subject with COPD comprising administering to said subject a therapeutically effective amount of the combination according to any one of claims 1 to 24, optionally wherein said hospital admissions are as a result of the subject experiencing acute exacerbation episodes.

27. A method of decreasing the annualized rate of moderate-to-severe AECOPD events in a subject said method comprising administering to said subject a therapeutically effective amount of the combination according to any one of claims 1 to 24.

28. A method of improving pre- and / or post-bronchodilator FEV1 in a subject with COPD said method comprising administering to said subject a therapeutically effective amount the combination according to any one of claims 1 to 24.

29. The method according to any one of claims 25 to 28, wherein the subject is eligible for treatment with the combination regardless of the subjects' blood eosinophil count.

30. The method according to any one of claims 25 to 29, wherein the subject has a blood eosinophil count of between 10 cells per µL and 150 cells per µL, between 150 cells per µL and 300 cells per µL or greater than 300 cells per pL.[70558W001]31. The method according to any one of claims 25 to 30, wherein the IL-33 binding protein is administered to the subject intravenously or subcutaneously and the TSLP binding protein is administered to the subject intravenously or subcutaneously.

32. The method according to any one of claims 25 to 31, wherein the IL-33 binding protein and the TSLP binding protein are administered simultaneously, concurrently or sequentially.

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