Antibodies and methods targeting interleukin-19

Abstract

The present invention provides compounds and methods targeting human interleukin-19, including therapeutic antibodies, pharmaceutical compositions, and methods of use thereof that are useful in the field of immune-mediated diseases including psoriasis, atopic dermatitis, asthma, psoriatic arthritis, rheumatoid arthritis, axial spondyloarthritis, inflammatory bowel disease, and colitis.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals. More specifically, the present invention relates to antibodies directed against human interleukin-19 (IL-19), pharmaceutical compositions comprising such antibodies, and methods of using such antibodies. The antibodies and methods of the present invention are expected to be useful in the field of autoimmune and chronic inflammatory diseases (collectively referred to herein as immune-mediated diseases), specifically, psoriasis (PsO), atopic dermatitis (AD), asthma, psoriatic arthritis (PsA), rheumatoid arthritis (RA), axial spondyloarthritis (AxSpA), inflammatory bowel disease (IBD), colitis, and other diseases, including their treatment.

Background Art

[0002] Interleukin-19 (IL-19) is a cytokine reported to belong to the interleukin-10 cytokine family (including IL-10, 20, 22, 24, and 26, and cytokines encoded by some viruses). IL-19 is involved in the IL-20R complex signaling pathway and is reported to be expressed in epithelial cells including resting monocytes, macrophages, B cells, and keratinocytes. Furthermore, studies have reported the involvement of IL-19 in immune-mediated diseases (for example, Konrad et al., Scientific Reports 9, Art. No. 5211 (2019) and Steiner et al., J. Immunol. 2017; 199: 2570-2584 (Sept. 2017)).

[0003] Autoimmune diseases are a form of immune-mediated diseases that result from the body producing an immune response against its own tissues. Autoimmune diseases are often chronic, can be debilitating, and even life-threatening. PsO is a chronic autoimmune disease with systemic symptoms including PsA, cardiovascular disease, metabolic syndrome, and mood disorders. AD affects the axial and / or peripheral skeleton, along with many other forms of chronic autoimmune diseases such as asthma, PsO, PsA, RA, IBD, colitis, and AxSpA.

[0004] Current FDA-approved treatments for immune-mediated diseases include corticosteroids, which are often used to treat acute inflammation, and biologic products that target TNFα, interleukin-12, -17, and -23. These treatments have demonstrated efficacy in reducing symptoms in some patients, but a percentage of patients remain non-responsive or lose their response to currently available treatments. Therefore, additional therapies targeting different human targets and pathways for the treatment of immune-mediated diseases are still needed.

[0005] IL-19 antibodies are known in the art (International Publication No. WO 2019 / 143585), but to date, no approved IL-19 antibody therapeutics exist. Further, for example, non-specific binding to serum proteins has proven to be an issue in the field of IL-19 antibodies. Thus, there remains an unmet need for antibodies, pharmaceutical compositions, and methods targeting human IL-19 that are useful for the treatment of immune-mediated diseases such as AD, asthma, PsO, RA, IBD, colitis, AxSpA, PsA, etc. Such IL-19 antibodies should possess favorable therapeutic properties, including being a potent neutralizer (i.e., antagonist) of human IL-19, having high binding affinity for human IL-19, and low non-specific binding, including non-specific binding to serum proteins. Such IL-19 antibodies should also possess a therapeutically acceptable pharmacokinetics (Pk) profile and demonstrate low immunogenicity. Such IL-19 antibodies should also be suitable for commercial manufacture, including high levels of solubility and low levels of aggregation. The present disclosure provides IL-19 antibodies that address these needs for use in the treatment of immune-mediated diseases. SUMMARY OF THE INVENTION

[0006] Accordingly, in certain embodiments, the present invention provides an antibody against human IL-19. According to some embodiments, the antibody of the present invention antagonizes human IL-19. Embodiments of the present invention are a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, the amino acid sequence of HCDR1 is SEQ ID NO: 7, the amino acid sequence of HCDR2 is SEQ ID NO: 8, the amino acid sequence of HCDR3 is SEQ ID NO: 9 or SEQ ID NO: 10, the amino acid sequence of LCDR1 is SEQ ID NO: 2, the amino acid sequence of LCDR2 is SEQ ID NO: 3, and the amino acid sequence of LCDR3 is SEQ ID NO: 4, and provides an antibody comprising the HCVR and LCVR. According to some embodiments, the antibody of the present invention also includes an antibody comprising a CDR having an amino acid sequence having at least 95% homology to the amino acid sequences of the CDRs herein.

[0007] According to some embodiments, the amino acid sequence of HCDR3 is SEQ ID NO: 9. According to some such embodiments, the amino acid sequence of the HCVR is SEQ ID NO: 11, and the amino acid sequence of the LCVR is SEQ ID NO: 5. According to some embodiments, the antibody of the present invention also includes an antibody comprising an LCVR and an HCVR having amino acid sequences having at least 95% homology to the amino acid sequences of the LCVR and HCVR herein.

[0008] According to some embodiments, the amino acid sequence of HCDR3 is SEQ ID NO: 10. According to some such embodiments, the amino acid sequence of HCVR is SEQ ID NO: 13, and the amino acid sequence of LCVR is SEQ ID NO: 5. According to some embodiments, the antibodies of the present invention also include antibodies comprising an LCVR and an HCVR having amino acid sequences with at least 95% homology to the amino acid sequences of LCVR and HCVR herein.

[0009] According to some embodiments of the antibodies of the present invention, there are a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 12 or 14, and the amino acid sequence of the LC is SEQ ID NO: 6, including the HC and the LC. In some such embodiments, the amino acid sequence of the HC is SEQ ID NO: 12. In some embodiments, the amino acid sequence of the HC is SEQ ID NO: 14. According to some embodiments, the antibodies of the present invention also include antibodies comprising an HC and an LC having amino acid sequences with at least 95% homology to the amino acid sequences of HC and LC herein.

[0010] A further embodiment of the present invention includes a nucleic acid comprising a sequence encoding SEQ ID NO: 6, 12, or 14. Additional embodiments include a vector comprising a first nucleic acid sequence encoding SEQ ID NO: 12 or 14 and a second nucleic acid sequence encoding SEQ ID NO: 6. Additional embodiments also include a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 12 or 14 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO: 6. Still further embodiments include a cell comprising one or more vectors of the present invention. Furthermore, the present invention provides a process for producing an antibody, which includes culturing the cells of the present disclosure under conditions such that the antibody is expressed and recovering the expressed antibody from the culture medium.

[0011] Embodiments of the invention further include a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR includes complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, the LCVR includes CDRs LCDR1, LCDR2, and LCDR3, the amino acid sequence of HCDR1 is SEQ ID NO: 21, the amino acid sequence of HCDR2 is SEQ ID NO: 22, the amino acid sequence of HCDR3 is SEQ ID NO: 23, the amino acid sequence of LCDR1 is SEQ ID NO: 16, the amino acid sequence of LCDR2 is SEQ ID NO: 17, and the amino acid sequence of LCDR3 is SEQ ID NO: 18, and an antibody that binds to mouse IL-19 and includes the HCVR and LCVR. According to some embodiments, the amino acid sequence of the HCVR is SEQ ID NO: 24, and the amino acid sequence of the LCVR is SEQ ID NO: 19. According to some embodiments, the antibody of the invention includes a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 25, and the amino acid sequence of the LC is SEQ ID NO: 20. According to some embodiments, the antibody of the invention also includes an antibody having an amino acid sequence having at least 95% homology to the amino acid sequences herein.

[0012] Another embodiment of the present invention is a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR includes complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and the LCVR includes CDRs LCDR1, LCDR2, and LCDR3, the amino acid sequence of HCDR1 is SEQ ID NO: 33, the amino acid sequence of HCDR2 is SEQ ID NO: 34, the amino acid sequence of HCDR3 is SEQ ID NO: 35, the amino acid sequence of LCDR1 is SEQ ID NO: 28, the amino acid sequence of LCDR2 is SEQ ID NO: 29, and the amino acid sequence of LCDR3 is SEQ ID NO: 30, and includes an antibody that binds to murine IL-19. According to some embodiments, the amino acid sequence of the HCVR is SEQ ID NO: 36, and the amino acid sequence of the LCVR is SEQ ID NO: 31. According to some embodiments, the antibody of the present invention is a heavy chain (HC) and a light chain (LC), and includes an antibody that includes an HC having an amino acid sequence of SEQ ID NO: 37 and an LC having an amino acid sequence of SEQ ID NO: 32. According to some embodiments, the antibody of the present invention also includes an antibody having an amino acid sequence having at least 95% homology to the amino acid sequences herein. Further, according to some embodiments, the antibody of the present invention that binds to murine IL-19 does not complete binding to murine IL-19.

[0013] A further embodiment of the present invention includes a nucleic acid sequence encoding SEQ ID NO: 26 or 27. Additional embodiments include a vector that includes a first nucleic acid sequence encoding SEQ ID NO: 26 and a second nucleic acid sequence encoding SEQ ID NO: 27. Alternatively, an embodiment of the present invention includes a nucleic acid sequence encoding SEQ ID NO: 38 or 39. Additional embodiments include a vector that includes a first nucleic acid sequence encoding SEQ ID NO: 38 and a second nucleic acid sequence encoding SEQ ID NO: 39.

[0014] Still further embodiments include a cell that includes one or more vectors of the present invention. Further, the present invention provides a process for producing an antibody, which includes culturing the cell of the present invention under conditions such that the antibody is expressed, and recovering the expressed antibody from the culture medium.

[0015] According to some embodiments, provided herein is a pharmaceutical composition comprising an antibody of the invention and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0016] Further provided herein is a method of treating AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, or PsA, the method comprising administering to a patient in need thereof an effective amount of an antibody of the invention or a pharmaceutical composition of the disclosure.

[0017] Embodiments of the invention include an antibody of the invention for use in therapy. According to some embodiments, provided herein is an antibody of the invention for use in the treatment of AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, or PsA. Further provided herein is an antibody of the invention for use in the manufacture of a medicament for the treatment of AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, or PsA.

[0018] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Embodiments of antibodies include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, bispecific or multispecific antibodies, or conjugate antibodies. The antibody may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0019] Exemplary antibodies of the present disclosure are immunoglobulin G (IgG)-type antibodies composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) crosslinked via inter-chain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains contains a variable region of about 100 to 125 or more amino acids that is primarily involved in antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains contains a constant region that is primarily involved in effector functions. Each heavy chain is composed of a heavy-chain variable region (VH) and a heavy-chain constant region. Each light chain is composed of a light-chain variable region (VL) and a light-chain constant region. The IgG isotype can be further divided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

[0020] The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed with more conserved regions called framework regions (FRs). The CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen-binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this specification, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3", and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3". The CDRs contain most of the residues that form specific interactions with the antigen.The assignment of amino acid residues to CDRs can be performed according to well-known schemes, including those described in Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987), Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27: 209-212).

[0021] Embodiments of the present disclosure also include, as used herein, Fab, Fab’, F(ab’) 2 , antibody fragments or antigen-binding fragments that include at least a portion of an antibody that retains the ability to specifically interact with an antigen or an epitope of an antigen, such as Fv fragments, scFv antibody fragments, scFab, disulfide-bonded Fv (sdFv), Fd fragments, and the like.

[0022] The antibody of the present invention is a monoclonal antibody. A monoclonal antibody is an antibody derived from a single copy or clone, including, for example, any eukaryote, prokaryote, or phage clone, and is not defined by the method by which it is produced. Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology, such as CDR grafting, or a combination of such techniques or other techniques known in the art.

[0023] Methods for producing and purifying antibodies are well known in the art and can be found, for example, in Harlow and Lane (1988), Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring harbor, N.Y., chapters 5-8 and 15, ISBN 0-87969-314-2. For example, a mouse or rabbit, including a transgenic mouse or rabbit known in the art, may be immunized with human IL-19 or a portion thereof, and the resulting antibody can be recovered, screened, purified, and the amino acid sequence can be determined using conventional methods well known in the art.

[0024] In certain embodiments of the present invention, the antibody, or the nucleic acid encoding the antibody, is provided in isolated form. As used herein, the term "isolated" refers to a protein, polypeptide, or nucleic acid that does not contain, or substantially does not contain, other macromolecular species found in the cellular environment.

[0025] The antibodies of the present invention can be prepared and purified using known methods. For example, cDNA sequences encoding HC (e.g., the amino acid sequence represented by SEQ ID NO: 12 or 14) and LC (e.g., the amino acid sequence represented by SEQ ID NO: 6) can be cloned and engineered into a GS (glutamine synthetase) expression vector. The engineered immunoglobulin expression vector can then be stably transfected into CHO cells. As will be understood by those skilled in the art, mammalian expression of the antibody will typically result in glycosylation at the highly conserved N-glycosylation site of the Fc region. Stable clones can be verified for expression of antibodies that specifically bind to human IL-19 (e.g., represented by a recombinantly produced peptide comprising SEQ ID NO: 1). Positive clones can be expanded in serum-free culture medium for antibody production in a bioreactor. The medium in which the antibody is secreted can be purified by conventional techniques. For example, the medium can be conveniently applied to a Protein A or G Sepharose FF column equilibrated with a compatible buffer such as phosphate buffered saline. The column is washed to remove non-specific binding components. The bound antibody is eluted, for example, by a pH gradient, and the antibody fractions are detected, for example, by SDS-PAGE and then pooled. The antibody can be concentrated and / or sterile filtered using common techniques. Soluble aggregates and multimers can be effectively removed by common techniques including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The product can be immediately frozen, for example, at -70 °C or lyophilized.

[0026] The antibodies of the present invention can be used for the treatment of patients. More specifically, the antibodies of the present invention are expected to be useful for treating immune-mediated diseases or disorders, including AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, and PsA. As used interchangeably herein, "treatment" and / or "treating" and / or "treat" are intended to refer to any process that may slow down, interfere with, inhibit, control, stop, or reverse the progression of the disorders described herein, but does not necessarily indicate complete elimination of all symptoms of the disorder. Treatment includes administration of an antibody of the present invention, or a pharmaceutical composition thereof, for the treatment of a disease or condition in a human who would benefit from a reduction in IL-19 activity, including (a) inhibiting further progression of the disease, i.e., suppressing its onset, or (b) alleviating the disease, i.e., causing regression of the disease or disorder, reducing its symptoms or complications, or reducing the "spread" of the disease symptoms.

[0027] As used interchangeably herein, the terms "patient", "subject", and "individual" refer to a human. In certain embodiments, the patient is further characterized by a disease, disorder, or condition (e.g., an immune-mediated disease) that would benefit from a reduction in IL-19 activity. In other embodiments, the patient is further characterized as being at risk of developing an immune-mediated disease, disorder, or condition that would benefit from a reduction in IL-19 activity.

[0028] As used herein, the terms "bind" and "binds" mean the ability of a protein or molecule to form a chemical bond or an attractive interaction with another protein or molecule, resulting in close proximity of the two proteins or molecules, as determined by conventional methods known in the art.

[0029] As used herein, the term "epitope" refers to the amino acid residues of an antigen that are bound by an antibody. An epitope can be a linear epitope, a conformational epitope, or a hybrid epitope.

[0030] The term "epitope" can be used with respect to a conformational epitope. A conformational epitope can, according to some embodiments, be used to describe the region of an antigen covered by an antibody (e.g., the footprint of the antibody when bound to the antigen). In some embodiments, a conformational epitope can describe the amino acid residues of an antigen that are within a particular proximity (e.g., within a particular number of angstroms) of the amino acid residues of the antibody.

[0031] The term "epitope" can also be used with respect to a functional epitope. A functional epitope can, according to some embodiments, be used to describe the amino acid residues of an antigen that interact with the amino acid residues of an antibody in a manner that contributes to the binding energy between the antigen and the antibody.

[0032] Epitopes can be determined according to different experimental techniques, also called "epitope mapping techniques." It is understood that the determination of an epitope can vary based on the different epitope mapping techniques used and can also vary depending on the different experimental conditions used, for example, due to conformational changes or cleavage of the antigen induced by particular experimental conditions. Epitope mapping techniques that are known in the art include, but are not limited to, X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, site-directed mutagenesis, species swap mutagenesis, alanine scanning mutagenesis, hydrogen-deuterium exchange (HDX), and cross-blocking assays (e.g., Rockberg and Nilvebrant, Epitope Mapping Protocols: Methods in Molecular Biology, Humana Press, 3rd ed. 2018).

[0033] The antibodies of the present invention can be prepared by methods well known in the art and can be incorporated into pharmaceutical compositions comprising the antibodies of the present invention and one or more pharmaceutically acceptable carriers and / or diluents (e.g., Remington, The Science and Practice of Pharmacy, 22nd Edition, Loyd V., Ed., Pharmaceutical Press, 2012, which provides an overview of formulation techniques generally known to practicing physicians). Suitable carriers for the pharmaceutical compositions include any material that retains the activity of the molecule when combined with the antibodies of the present invention and is non-reactive with the patient's immune system.

[0034] The pharmaceutical compositions containing the antibodies of the present invention can be administered to patients at risk of or presenting with the diseases or disorders described herein by a parental route (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal). The pharmaceutical compositions of the present invention contain an "effective" amount or "therapeutically effective" amount (used interchangeably herein) of the antibodies of the present invention. An effective amount refers to the amount (in terms of dosage and duration and means of administration) necessary to achieve the desired therapeutic result. The effective amount of the antibody can vary depending on factors such as the individual's medical condition, age, sex, and weight, as well as the ability of the antibody to induce the desired response in the individual. The effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the antibodies of the present invention.

[0035] When used in the present disclosure in relation to two or more amino acid sequences, percent homology is measured using a sequence comparison algorithm (e.g., BLASTP and BLASTN, or other algorithms available to those skilled in the art), or by visual inspection, and refers to the percentage of identical amino acid residues in two or more sequences that are compared and aligned for maximum correspondence. Depending on the application, percent homology can exist over the region of the sequences being compared, e.g., over a functional domain, or over the entire length of the two sequences being compared. By way of example, the percent homology of a sequence can be compared to a reference sequence. For example, when using a sequence comparison algorithm, the test sequence and the reference sequence can be input into a computer (optionally, subsequence coordinates can be further specified along with the parameters of the sequence algorithm program). The sequence comparison algorithm then calculates the percent sequence identity or homology of the test sequence to the reference sequence based on the parameters of the specified program. Exemplary sequence alignment and / or homology algorithms are available through Smith & Waterman, Adv. Appl. Math. 2:482 (1981), Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), GAP, BESTFIT, FASTA, and TFASTA (the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or are available by visual inspection (generally, see Ausubel et al.). An example of an algorithm suitable for determining percent sequence identity and percent sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990).Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

Brief Description of the Drawings

[0036] The features and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description in conjunction with the accompanying drawings.

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Examples

[0037] Expression of the exemplary anti-IL-19 antibody The exemplified anti-IL-19 antibodies of the present invention are shown in Table 1. The cDNA sequences encoding the heavy and light chains of the exemplified anti-IL-19 antibodies of the present disclosure can be cloned and engineered into a GS (glutamine synthetase) expression vector for recombinant expression in competent cell lines such as CHO cells. The relationships of the various regions of the exemplified anti-IL-19 antibodies are as follows (amino acid numbering applies linear numbering, the amino acid assignment to the variable domain is based on the International Immunogenetics Information System® available at www.imgt.org, and the amino acid assignment to the CDR domain is based on the well-known North numbering rule except for HCDR2 with the C-terminus based on the well-known Kabat numbering rule).

[0038]

Table 1

[0039] The exemplified antibodies of the present disclosure are identified as having high binding affinity and being chemically and physically stable, including aggregation and solubility consistent with parental administration for therapy. The exemplified antibodies of the present disclosure are also identified as having low immunogenicity (including low non-specific binding and / or serum binding) and having pharmacokinetic properties consistent with parental administration for the treatment of immune-mediated diseases.

[0040] Binding affinity The binding of the exemplified IL-19 antibodies of the invention to biotinylated human IL-19 (having the amino acid sequence set forth in SEQ ID NO: 1) is evaluated using the Meso Scale Discovery Solution Equilibrium Titration (MSD-SET) assay measured by SECTOR (registered trademark) Imager 6000 (Meso Scale Diagnostics).

[0041] Unless otherwise specified, all reagents and materials are from Meso Scale Diagnostics (Rockville, Maryland). Recombinant human IL-19 reagent is biotinylated using the EZ-link sulfo-NHS-Biotin kit (Thermo catalog number A39257). Briefly, 20 pM biotinylated human IL-19 is mixed with a 3-fold dilution series of the antibody samples (mAb 1 and mAb 2) exemplified in the present invention at a 1:1 ratio to obtain a final concentrate of 10 pM biotinylated human IL-19 and an 11-point 3-fold antibody gradient from 1 nM to 0.017 pM. The mix is incubated at 37 °C for 72 hours. An MSD 96-well plate (Multi-array 96 well plate, catalog number L15XA-3) is coated overnight at 4 °C with 30 μL of the exemplified antibody at 20 nM in phosphate buffered saline (PBS) per well. The plate is then washed three times with 150 μL of wash buffer (0.05% Tween-20 in PBS, VWR catalog number 9005-64-5) per well and blocked with 150 μL of blocking buffer (PBS + 3% blocker A buffer, catalog number R93BA-1) at 37 °C for 45 minutes. After three wash cycles, 50 μL of the IL-19 and antibody mix per sample is transferred to each well and incubated at 37 °C for 150 seconds with shaking (700 rpm). After sample discard and three wash cycles, 100 μL of the detection antibody (1 μg / mL MSD Sulfo-tag streptavidin antibody, catalog number R32AD1) is added to each well and incubated at 37 °C for 3 minutes with shaking. After washing three times with the wash buffer, 150 μL of 1X Read Buffer T (catalog number R92TC-1) is added to the wells and analyzed with a SECTOR (registered trademark) Imager 6000 (Meso Scale Diagnostics) 5 minutes after buffer addition. The exemplified antibodies are tested in duplicate within each individual experiment and three independent experiments are performed.

[0042] Using an assay development toolkit graphed with normalized electrochemiluminescence (ECL) values, a sigmoid curve is fitted to the ECL response vs. log(IL-19 concentration) to determine the equilibrium K D . K D is determined as the "curve fitting" with 10 pM immobilized IL-19 ligand. The reported average K D value is calculated from three independent experiments, and the data variability is represented by the standard deviation (SD) of the three independent runs.

[0043]

Table 2

[0044] Table 2 shows that the exemplified anti-IL-19 antibodies, mAb1 and mAb2, possess low picomolar binding affinity for human IL-19 in vitro.

[0045] Neutralization of IL-19 in vitro The antibodies of the present invention are expected to neutralize IL-19. Neutralization of IL-19 activity by the antibodies of the present invention can be evaluated, for example, by an IL-19 / IL-19 receptor (IL20Ra / IL20Rb) dimerization assay format as described below.

[0046] Briefly, U20S cells (DiscoveRx, catalog number 93-1027C3) expressing IL20Ra and IL20Rb are cultured in Assay Complete Cell Plating Media (DiscoveRx, catalog number 93-0563R5A). Sub-confluent cells are removed using Assay Complete Cell Detachment Reagent (DiscoveRx, catalog number 92-0009), pelleted, washed, resuspended in Assay Complete Cell Plating Reagent, and seeded at 2,500 cells per well in 100 μl per well in a white well clear bottom 96-well plate. The cells are cultured for 4 hours and then treated with 10 μl per well of antibody and 11× mix of IL-19. Each antibody is diluted in DiscoveRx Protein Dilution Buffer (DiscoveRx, catalog number 92-0023M), and the starting concentration of the antibody at 10 μg / ml (1×) and titrations of 1:3 for dose response are mixed with either 22× human (SEQ ID NO: 1) or cynomolgus monkey (SEQ ID NO: 15) IL-19 (1× is equal to 100 ng / ml) diluted in DiscoveRx Protein Dilution Buffer. The antibody and ligand mixtures are pre-incubated for 20 minutes, assay medium is used for the “untreated” control, and an isotype control antibody is used as the negative control. The cells are then incubated overnight at 37°C. The PathHunter Flash Detection Kit X (DiscoveRx, catalog number 93-0247) is used for luminescence readout counted at 0.1–1 second / well according to the manufacturer's instructions (Perkin Elmer Victor3). Statistical analysis is performed using GraphPad Prism version 9. The percent inhibition from each run in triplicate is calculated and averaged. The data are reported as the IC50 and 95% confidence interval (95%CI, symmetric) of a sigmoid curve fit (four parameters). Inhibition of human and cynomolgus monkey IL-19-induced receptor dimerization signals by the exemplary anti-IL-19 antibodies is shown in Table 3.

[0047]

Table 3

[0048] Neutralization of IL-19-induced phosphorylated STAT3 signaling in vitro IL-19 neutralization in vitro can be further evaluated essentially as described below. A431 squamous epithelial cells (ATCC#CRL-1555) express the IL-19 receptor (IL20Ra / IL20Rb). The interaction of IL-19 with its receptor induces phosphorylation of STAT3 in A431 squamous epithelial cells. Briefly, A431 cells are grown in growth medium [HyClone#sh30284.01, 10% HI FBS (Gibco#10082147), and 1× PenStrep (Gibco#15140-122)]. Cells are dissociated in 0.05% trypsin-PBS and plated in a 96-well plate (Falcon#353072) at 30,000 cells / 100 μl of medium in serum-free medium (Opti-MEM (Gibco#31985-070), 0.5% BSA (Gibco#15260-037), and 1× PenStrep). The cells are then incubated overnight at 37°C. Ab 1 or Ab 2, or an isotype control, is prepared at a final starting concentration of 20 nM and serially diluted 2-fold for an 8-point titration. The antibody is pre-incubated for 20 minutes with either human (SEQ ID NO: 1) or cynomolgus IL-19 (SEQ ID NO: 15) (100 ng / ml). The cells are then treated and stimulated with the antibody:IL-19 mixture for 15 minutes. Subsequently, the medium is removed, and Phospho-STAT3 (Tyr705) Kit (Meso Scale Diagnostics, LLC#K150SVD) is used according to the manufacturer's protocol to determine the phosphorylation of STAT3 (Note: After removing the medium, the cells may be frozen before phosphorylation determination). Phospho-STAT3 activation is determined by chemiluminescence induction and expressed as relative luminescent units (RLU) using a Meso Scale Diagnostics SECTORImager. Statistical analysis is performed using GraphPad Prism version 9. The percent inhibition of triplicate runs is calculated and averaged. The data are reported as the IC50 and 95% confidence interval (95% CI, symmetric) of a sigmoid curve fit (four parameters).

[0049] Table 4 shows the reduction of human and cynomolgus monkey IL-19-induced phosphor-STAT3 signals by the exemplified anti-IL-19 antibodies.

[0050]

Table 4

[0051] Tables 3 and 4 show that the exemplified anti-IL-19 antibodies, Ab 1 and Ab 2, neutralize both human and cynomolgus monkey IL-19 in vitro.

[0052] In vivo target engagement Target engagement in vivo can be evaluated essentially as described below. Briefly, the total plasma IL-19 concentration (free IL-19 and IL-19 bound to the exemplified IL-19 antibodies) is determined substantially as described herein. Biotinylated IL19 antibody is coated on streptavidin plates. The exemplified Ab 2 sample is diluted 1:4 in dilution buffer to a concentration of 10 μg / mL. A ruthenium-labeled anti-IgG4 antibody that binds to Ab 2 is used as the detection antibody.

[0053] The baseline plasma IL-19 levels of four cynomolgus monkeys are evaluated and measured below the limit of detection (about 20 pg / mL). Then, two cynomolgus monkeys are administered Ab 2 IV and two cynomolgus monkeys are administered Ab 2 subcutaneously. Then, the total plasma IL-19 concentration is measured. The total plasma IL-19 concentration showed an increase over time and reached a peak at 336 hours (1651.0 pg / mL and 4467.5 pg / mL for IV and 1382.0 pg / mL and 2127.6 pg / mL for SC). These results show that the exemplified IL-19 antibodies of the present disclosure associate with IL-19 in vivo and target engagement is maintained over time.

[0054] Exemplary antibody pharmacokinetics in vivo The pharmacokinetic parameters of the exemplified IL-19 antibodies of the present disclosure can be evaluated essentially as described herein. Briefly, male Sprague-Dawley rats are administered a single IV or SC dose of 5 mg / kg of Ab1 or Ab2 in PBS (pH 7.4) at a volume of 1 mL / kg. Blood is collected from each animal at 1, 6, 12, 24, 48, 96, 120, 168, 240, 336, 504, and 672 hours after IV administration, or at 3, 6, 12, 24, 48, 96, 120, 168, 240, 336, 504, and 672 hours after SC administration, and processed to serum.

[0055] The serum concentrations of Ab1 and Ab2 are determined by plate-based total human IgG ELISA. Goat anti-human IgG F(ab’) 2 antibody is coated onto the ELISA plate at 1 mg / mL as the capture reagent. After incubation with serum standards, controls, or samples, Ab1 or Ab2 bound to the plate is detected using mouse anti-human IgG4 pFc’ horseradish peroxidase (1:10,000 dilution). Pharmacokinetic parameters are calculated for each animal (N = 3) using non-compartmental analysis (NCA), and where appropriate, the parameters are summarized by mean and standard deviation (SD). NCA and summary statistical calculations are performed using Phoenix WinNonlin 8.1 or Excel. As shown in Table 5, both Ab1 and Ab2 exhibit an extended pharmacokinetic profile.

[0056]

Table 5

[0057] Immunogenicity analysis Dendritic cell (DC) internalization The dendritic cell (DC) internalization assay evaluates the internalization of molecules by CD14+ monocyte-derived dendritic cells. Briefly, according to the standard protocol, CD14+ monocytes are isolated from peripheral blood mononuclear cells (PBMC), cultured, and differentiated into DC. PBMC are isolated from LRS-WBC using density gradient centrifugation with Ficoll (#17-1440-02, GE Healthcare) and Sepmate 50 (#15450, STEMCELL Technologies). CD14+ monocytes are isolated using positive selection with a CD14+ microbead kit (#130-050-201, Miltenyi Biotec) according to the manufacturer's manual. Then, the cells are cultured at 1 million / mL for 6 days with 1000 units / mL of GM-CSF and 600 units / mL of IL-4, and induced into immature dendritic cells (MDDC) in RPMI medium (complete RPMI medium or medium purchased from Life Technologies) supplemented with 10% FBS, 1 mM sodium pyruvate, 1× penicillin-streptomycin, 1× non-essential amino acids, and 55 μM 2-mercaptoethanol, containing L-glutamine and 25 mM HEPES. The medium is changed on the 2nd and 5th days. On the 6th day, the cells are gently collected with a cell scraper and used for the experiment. To obtain mature DC, the cells are treated with 1 μg / mL of LPS for 4 hours.

[0058] Normalize individual test molecules to 1 mg / mL in PBS and then further dilute to 8 μg / mL in complete RPMI medium. Dilute the detection probe, Fab-TAMRA-QSY7, to 5.33 μg / mL in complete RPMI medium. Mix the antibody and Fab-TAMRA-QSY7 in equal amounts and incubate for 30 minutes at 4 °C in the dark for complex formation. Resuspend MDDC in complete RPMI medium at 4 million / mL and seed 50 μL per well into a 96-well round-bottom plate to which 50 μL of the antibody / probe complex is added. Incubate the cells in a CO2 incubator at 37 °C for 24 hours. Wash the cells with 2% FBS PBS and resuspend in 100 μL of 2% FBS PBS containing the Cytox Green live / dead dye. Collect data on a BD LSR Fortessa X-20 and analyze with FlowJo. Gate on live single cells and record the percentage of TAMRA fluorescent positive cells as the readout. Use the normalized internalization index to enable comparison of molecules with data generated from different donors. The internalization signal is normalized against the IgG1 isotype (normalized internalization index = 0) and the internal positive control PC (normalized internalization index = 100) using the following equation: [Number] where X TAMRA , the IgG1 isotype TAMRA , and PC TAMRA are the percentages of the TAMRA positive populations of the test molecule X, the IgG1 isotype, and PC, respectively.

[0059] [Table 6] For the normalized internalization index, 0 - 15 is considered low, >15 - 30 is considered low - moderate, >30 - 60 is considered moderate, and >60 is considered to have a high risk of immunogenicity.

[0060] Table 6 shows that the exemplified anti-IL-19 antibodies, Ab1 and Ab2, possess a low DC internalization risk.

[0061] MHC-related peptide proteomics MHC-associated peptide proteomics (MAPP) profiles human leukocyte antigen class II (HLA-II)-presented peptides on human dendritic cells pre-treated with a test molecule to evaluate immunogenicity. Briefly, primary human dendritic cells from a panel of 10 normal human donors were prepared from buffy coats by isolation of CD-14 positive cells as described, and incubated at 37 °C, 5% CO 2 with 20 ng / ml of IL-4 and 40 ng / ml of GM-CSF in complete RPMI medium containing 5% Serum Replacement (Thermo Fisher Scientific, catalog number A2596101) for 3 days to differentiate into immature dendritic cells (Knierman et al., 2020). On day 4, 3 micromolar of the test antibody was added to approximately 5 × 10 6 cells, and after a 5-hour incubation, the fresh medium containing 5 μg / ml of LPS was replaced to transform the cells into mature dendritic cells. The next day, the mature cells were lysed in 1 mL of RIPA buffer containing protease inhibitors and DNAse. The lysate was stored at -80 °C until sample analysis.

[0062] Using an automated liquid handling system, HLA-II molecules are isolated from thawed lysates using biotinylated anti-pan HLA class II antibody (clone Tu39). The bound receptor-peptide complexes are eluted with 5% acetic acid, 0.1% TFA. The eluted HLA-II peptides are passed through a pre-washed 10k MWCO filter to remove high molecular weight proteins. The isolated HLA-II peptides are analyzed by nano LC / MS using a Thermo easy 1200 nLC-HPLC system equipped with a Thermo LUMOS mass spectrometer. For separation, a 75 μm × 7 cm YMC-ODS C18 column is used with a flow rate of 250 nl / min and a 65-minute gradient with 0.1% aqueous formic acid as solvent A and 80% acetonitrile containing 0.1% formic acid as solvent B. Mass spectrometry is performed in full scan mode with a resolution of 240,000, followed by a 3-second data-dependent MS / MS cycle consisting of ion trap type rapid scan with HCD and EThcD fragmentation.

[0063] Peptide identification is generated by an in-house proteomics pipeline (Higgs et al. 2008) using multiple search algorithms without enzymatic search parameters against a bovine / human database containing the test molecule sequences. Peptides identified from the test molecules are aligned against the parent sequences. A summary is created for all test molecules annotating the percent of donors presenting peptides with non-germline residues and the number of different regions of the test molecules presenting peptides with non-germline residues. An increase in the degree of non-germline peptide presentation is associated with an increased risk of immunogenicity.

[0064]

Table 7

[0065] Table 7 shows that the exemplified anti-IL-19 antibodies, Ab1 and Ab2, possess a low-risk MAPP profile.

[0066] T cell proliferation assay The T cell proliferation assay evaluates the ability of the exemplified antibodies to activate CD4+ T cells by inducing cell proliferation. Briefly, cryopreserved PBMC from 10 healthy donors are used, CD8+ T cells are depleted from the PBMC, and labeled with 1 μM Carboxyfluorescein Diacetate Succinimidyl Ester (CFSE). The PBMC are seeded at 4×10 6 cells / ml / well in AIM-V medium (Life Technologies, catalog number 12055-083) containing 5% CTS™ Immune Cell SR (Gibco, catalog number A2596101), and tested in triplicate with 2.0 mL containing different exemplified antibodies, DMSO control, medium control, and keyhole limpet haemocyanin (KLH, positive control). The cells are cultured and incubated at 37 °C for 7 days with 5% CO 2 ₂. On day 7, samples are stained with the following cell surface markers for viability detection by flow cytometry using a BD LSRFortessa™ equipped with a High Throughput Sampler (HTS): anti-CD3, anti-CD4, anti-CD14, anti-CD19, and DAPI. Data are analyzed using FlowJo® software (FlowJo, LLC, TreeStar) and the Cellular Division Index (CDI) is calculated. The CDI for each exemplified antibody is calculated by dividing the percentage of CFSE dim CD4+ T cells that have proliferated in the antibody-stimulated wells by the percentage of CFSE dim CD4+ T cells that have proliferated in the unstimulated wells. A CDI of 2.5 or greater is considered to represent a positive response. The percentage of donor frequency across all donors is evaluated.

[0067]

Table 8

[0068] Table 8 shows that the exemplary anti - IL - 19 antibodies, Ab1 and Ab2, possess a low - risk T - cell proliferation immunogenic profile.

[0069] Existing reactivity assay Existing reactivity assays evaluate the presence of reactivity derived from pre - existing anti - drug antibodies (PEA) in treatment - naive normal human sera and potentially other cross - reactive proteins. Briefly, diluted sera from a panel of at least 50 treatment - naive donors are captured overnight on plates coated with biotinylated exemplary antibodies. The next day, the captured reactive proteins are eluted with acid and then neutralized in the presence of biotinylated and ruthenylated exemplary antibodies. If anti - drug antibodies are present, complexes are formed with the exemplary antibodies. The complexes are captured by mesoscale plates coated with streptavidin, and the resulting signal is called the Tier 1 signal (represented as electrochemiluminescence). The Tier 1 signal is confirmed in Tier 2 by adding excess unlabeled exemplary antibody in the detection step, which suppresses the Tier 1 signal. The presence of pre - existing anti - drug antibodies is represented as the 90th percentile of Tier 2 inhibition.

[0070]

Table 9

[0071] Table 9 shows that the exemplary anti - IL - 19 antibodies, Ab1 and Ab2, possess a risk from low PEA reactivity.

[0072] Physicochemical properties of the exemplary antibody The exemplified antibodies, Ab1 and Ab2, exhibit characteristics of solubility, low aggregation, chemical stability, and physical stability that are essential for parenteral therapeutic administration.

[0073] Solubility: For convenient administration, a sufficiently high solubility is desirable. For example, a 1 mg / kg dose administered by a 1.0 mL injection to a 100 kg patient requires a solubility of 100 mg / ml. Additionally, it is also desirable to maintain the antibody in a monomeric state at high concentrations without high molecular weight (HMW) aggregation. The solubility of the exemplified antibodies is analyzed by concentrating 15 mg of the exemplified antibody to a volume of less than 100 μl using a 10K molecular weight cut-off filter (Amicon U.C. filter, Millipore, catalog number UFC903024). The final concentration of the sample was measured by UV absorbance at A280 using a Nanodrop 2000 (Thermo Scientific). Substantially following the above procedure, the exemplified antibodies exhibit a solubility exceeding 200 mg / ml (at pH 7.4 in PBS buffer). Additionally, only low levels of HMW (about 3.8 - about 4.35%) are present at high concentrations, and no phase separation is observed.

[0074] Chemical and physical stability: Chemical stability facilitates the development of drug formulations with sufficient shelf life. The chemical stability of the exemplified antibodies is evaluated by formulating the exemplified antibodies at a concentration of 100 mg / ml in a buffer solution at pH 6. The formulated samples are incubated at 4°C for 4 weeks and at 35°C in an accelerated degradation study. Changes in the antibodies reflecting chemical changes are evaluated using CE-SDS and aSEC following standard procedures. Substantially following the above procedure, the exemplified antibodies exhibit the chemical stability results shown in Table 10.

[0075]

Table 10

[0076] The results provided in Table 10 show that after 4 weeks of storage at 35°C, the exemplified antibodies have a percentage of main peak decrease of about 0.6 - 1.9%. Additionally, mass spectrometry shows only minimal degradation observed after 4 weeks of storage at 35°C (about 0.2% CDR PTM change in all CDR sequences), indicating that the exemplified antibodies have sufficient chemical stability to facilitate the development of a solution formulation with an appropriate shelf life.

[0077] IL-19 expression and activity in a psoriasiform mouse model Eight-week-old female BALB / c mice (Envigo, Inc., Indianapolis, IN) were maintained with free access to food and water. 30 mg of 3.75% imiquimod (IMQ) cream (Zyclara) (Bausch Health Companies Inc., Laval, Quebec, Canada) was applied daily to the shaved back (2×2 cm area) of the mice. The mice were randomly assigned to treatment groups of 6 mice each based on body weight. One day prior to IMQ application, an isotype control / vehicle, an anti-inflammatory positive control antibody, or an anti-mouse IL-19 Ab (“mAb4”, comprising the HCVR of SEQ ID NO: 36 and the LCVR of SEQ ID NO: 31) was administered subcutaneously to the mice. Clinical scores were given as 0 - 4 based on the absence, slight, moderate, marked, or severe changes in erythema, thickness, and scaling, with a maximum total score of 12. All mice were sacrificed on day 8.

[0078] Figure 1 shows the change in the clinical total score over time, comparing vehicle-treated mice, anti-inflammatory Ab-treated mice, and naive mice. This study was used for further genetic analysis to evaluate the IL-19 mRNA levels in this model. Figures 2A and 2B represent the clinical total scores over time (Figure 2A) and the area under the curve (Figure 2B) for a single study evaluating the efficacy of mAb4 in this model. The mAb4 at a dose of 10 mg / kg improved the total clinical score by 25% and reduced the final day clinical score by 46% compared to the isotype control. However, the mice in the high-treatment group at 20 mg / kg had no improvement in the total clinical score compared to the isotype control.

[0079] This study indicates that anti-IL-19 antibodies have the potential to treat psoriatic skin diseases. In this regard, the results show that the antibodies of the present invention reduce inflammation in a mouse inflammation model.

[0080] Expression and activity of IL-19 in an atopic dermatitis-like mouse model Balb / cJ mice at 6 - 8 weeks of age were anesthetized by inhalation of isoflurane (5%), the thickness of both ears was measured using a digital caliper, and recorded for baseline ear measurements. On day 1, 10 μL of MC903 (Tocris Bioscience) was pipetted onto both the dorsal and ventral sides of each ear (40 μL in total). After application of MC903, the mice were kept under anesthesia until the treated area dried. Ear measurements were recorded two or three times a week. The thickness (inflammation) of the left and right ears was averaged for each mouse daily, the change in thickness was calculated, and recorded between measurements. The standard protocol has a total of 4 inoculations performed on days 1, 4, 6, and 8. On days 0 and 7, mice were administered either 10 mg / kg of isotype control Ab, an anti - inflammatory agent as a positive control, or anti - mouse IL - 19 Ab (「mAb 3」, containing the HCVR of SEQ ID NO: 24 and the LCVR of SEQ ID NO: 19). The ears were prepared for culture by manually separating the dermal layer using forceps and placing them in RPMI culture medium. IL - 19 levels in ear cultures were measured by an in - house developed ELISA using mAb3 and mAb4 that do not compete with each other for binding. IL - 4 and IL - 13 levels from ear cultures were evaluated using a custom U - Plex Biomarker MSD Group 1 according to the manufacturer's protocol (Meso Scale Discovery). Data analysis and statistical significance were performed using GraphPad Prism Version 9.

[0081] The results in Figure 3 compare the isotype control to normal uninoculated and untreated mice up to the peak of inflammation on day 14. The isotype control has no effect on the inflammatory response measured by ear thickness using a precision electronic caliper. The untreated and uninoculated controls show no inflammatory response. Treatment with a known anti-inflammatory agent administered weekly at 10 mg / kg for two weeks (days 0 and 7) significantly reduces the inflammatory effect of MC903 inoculation and persists until day 21 (Figure 3). These studies were used for further genetic analysis to evaluate IL-19 mRNA levels in this model. Figure 4 shows that IL-19 protein levels in the ear are significantly elevated during MC903-induced inflammation compared to the naive group, confirming the elevation of IL-19 in this model of skin inflammation.

[0082] Figure 5 shows the efficacy of "mAb 3" containing HCVR of SEQ ID NO: 24 and LCVR of SEQ ID NO: 19 in this model. mAb3 significantly reduced ear thickness on days 11 and 13 compared to isotype control-treated mice. In addition, isotype-treated mice had increased secretion of IL-4 and IL-13 from the ear compared to naive untreated mice (Figures 6A and 6B). mAb3 reduced both IL-4 and IL-13 secretion in ear cultures compared to the isotype group. This indicates that mAb3 not only reduces ear inflammation but also reduces Th2 cytokine production in this AD-like mouse model of inflammation. The results show that the antibodies of the present invention reduce inflammation in a mouse inflammation model.

[0083] Expression and activity of IL-19 in a contact dermatitis mouse model C57BL / 6J mice at 6 - 8 weeks of age were anesthetized by inhalation of isoflurane (5%), and the thickness of both ears was measured using a digital caliper and recorded for baseline ear measurements. Twenty - four hours after inoculation, or on day 7, the ears were measured again. On day 0, under inhalation of 5% isoflurane anesthesia, the ventral sides of all mice were shaved. DBP: 100 μl of fluorescein isothiocyanate isomer I (FITC; Sigma) in acetone was applied to the shaved area. The mice were kept under anesthesia until the solution dried. On day 1, the procedure of administration and application of FITC in DBP: acetone was repeated. On day 5, the mice were treated with either an isotype control Ab or an anti - mouse antibody, mAb4 (containing HCVR of SEQ ID NO: 36 and LCVR of SEQ ID NO: 31). On day 6, after baseline measurements, the mice were inoculated with 10 μL of FITC in DBP: acetone solution and applied to both sides of both ears at a total of 40 μL per mouse. The ears were prepared for culture by manually separating the dermis layer using forceps and placing them in RPMI culture medium. The IL - 19 levels in the ear cultures were measured by ELISA developed in - house using mAb3 and another anti - mouse IL - 19 Ab that do not compete with each other for binding. Data analysis and statistical significance were performed using GraphPad Prism Version 9.

[0084] The results in Figure 7 compare the isotype control with naive mice and inoculated mice treated with an anti - inflammatory agent until the peak of inflammation on day 7. The isotype control has no effect on the inflammatory response measured by ear thickness using a precision electronic caliper. Naive uninoculated controls do not show an inflammatory response. Treatment with an anti - inflammatory agent administered at 10 mg / kg 24 hours before inoculation significantly reduces the inflammatory effect of FITC inoculation. In addition, Figure 8 shows that the IL - 19 protein level is elevated in FITC - inoculated mice compared to naive mice, confirming the elevation of IL - 19 in this model of skin inflammation.

[0085] Figures 9 and 10 show the results of comparing two separate studies using mAb4 in this model. In Figure 9, both high-dose (20 mg / kg) and medium-dose (10 mg / kg) mAb4 significantly reduced ear thickness compared to the isotype treatment group (21% inhibition), while the low-dose (3 mg / kg) did not significantly reduce ear thickness (11% inhibition). In the repeat study (Figure 10), mAb4 significantly reduced ear thickness at the high dose (20% inhibition) compared to the isotype control group, but not at the medium dose (10 mg / kg) and low dose (3 mg / kg). Overall, this indicates that high-dose (30 mg / kg) mAb4 reduces the inflammation induced in this contact dermatitis model. The results show that the antibody of the present invention reduces inflammation in the mouse inflammation model.

[0086] IL-19 gene expression in an in vivo model of skin inflammation To evaluate changes in IL19 gene expression in these mouse models of skin inflammation, tissue RNA levels were evaluated using qPCR and NanoString analysis. Isolation of RNA from the selected tissues was performed using Qiagen RNeasy (catalog number 74181) and the spin protocol, following the protocol proposed by the manufacturer for animal tissues.

[0087] Gene expression levels were determined by two-step TaqMan RT-PCR using a custom 96-marker gene expression panel and the Viia-7 platform (Applied Biosystems). RNA pre-purified from mouse tissues was first reverse transcribed into cDNA using the Qiagen QuantiTect Reverse Transcription kit according to the method recommended by the manufacturer. The resulting cDNA was diluted 1:10 for downstream applications. RT-PCR was performed according to the method recommended by the manufacturer for the Applied Biosystems TaqMan Custom Plate. Gene expression levels were determined by NanoString using the "Mouse Cancer Immune Profiling Panel" according to the protocol recommended by the manufacturer. Pre-purified RNA was diluted to 20 ng / ul in RNase-free water and a total of 100 ng (in 5 ul) was used to prepare the NanoString cartridge. Raw mRNA counts were normalized using nSolver Advanced Analysis software (version 2.0.115) according to the data processing method recommended by the manufacturer. All mRNA counts were first scaled against the in-sample binding density control, then the experimental genes were further normalized against the housekeeping gene indicators, followed by dynamic housekeeping gene selection for the entire dataset to minimize the housekeeper variance. The normalized gene counts were then compared.

[0088] IL19 gene expression was evaluated by qRT-PCR or NanoString and was found to be elevated in mouse models of skin inflammation representative of atopic dermatitis and psoriasis (Figures 1 and 3). The increase in IL19 gene expression strongly correlated with measurements of disease pathology in tissues such as the increase in ear thickness in an atopic dermatitis-like model (Figure 11) and the clinical total score of psoriasis (Figure 12). Additionally, treatment significantly reduced IL19 gene expression in proportion to the changes in histopathology observed in the same tissues (Figures 1 and 3). In the atopic dermatitis-like model, IL19 mRNA was the single most upregulated transcript observed by differential expression analysis of the genes evaluated in this study (Figure 13). Collectively, these findings indicate that IL19 gene expression is strongly associated with tissue inflammation in skin diseases.

[0089] Preparation of anti-mouse IL-19 antibodies (mAb 3 and mAb 4) Rabbits are immunized with mouse IL-19. Spleen cells are obtained and a library derived from the spleen cells is constructed by amplifying the variable heavy chain (VH) and variable light chain (VL) genes and combining them into single-chain Fabs for expression using yeast cell surface display. mAb 3 and mAb 4 are obtained after panning the library with mouse IL-19. The sequences of the clones are determined and used to construct expression plasmids for recombinant IgG expression.

[0090] Both mAb3 and mAb4 are expressed as recombinant rabbit IgG after co-transfection into CHO cells and purification using MabSelect (protein A) resin.

[0091] Sequence listing SEQ ID NO: 1 (human IL-19) MKLQCVSLWLLGTILILCSVDNHGLRRCLISTDMHHIEESFQEIKRAIQAKDTFPNVTILSTLETLQIIKPLDVCCVTKNLLAFYVDRVFKDHQEPNPKILRKISSIANSFLYMQKTLRQCQEQRQCHCRQEATNATRVIHDNYDQLEVHAAAIKSLGELDVFLAWINKNHEVMFSA

[0092] SEQ ID NO: 2 (LCDR1 of the exemplary Ab 1 and Ab 2) RASQDIRSDFG

[0093] SEQ ID NO: 3 (LCDR2 of the exemplary Ab 1 and Ab 2) YAASSLQS

[0094] SEQ ID NO: 4 (LCDR3 of the exemplary Ab 1 and Ab 2) LQDYNYPWT

[0095] SEQ ID NO: 5 (LCVR of the exemplary Ab 1 and Ab 2) AIQLTQSPSSLSASVGDRVTITCRASQDIRSDFGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPWTFGQGTKVEIK

[0096] SEQ ID NO: 6 (LC of the exemplary Ab 1 and Ab 2) AIQLTQSPSSLSASVGDRVTITCRASQDIRSDFGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0097] SEQ ID NO: 7 (HCDR1 of the exemplary Ab 1 and Ab 2) KASGYTFTGYYLH

[0098] SEQ ID NO: 8 (HCDR2 of the exemplary Ab 1 and Ab 2) WINPNSGGTNYAQKFQG

[0099] SEQ ID NO: 9 (HCDR3 of the exemplary Ab 1) ARDIVVLPPAIGFDY

[0100] SEQ ID NO: 10 (HCDR3 of the exemplary Ab 2) ARDIVVLPPAIGFDL

[0101] SEQ ID NO: 11 (HCVR of the exemplary Ab 1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYLHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIVVLPPAIGFDYWGQGTLVTVSS

[0102] SEQ ID NO: 12 (HC of the exemplary Ab 1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYLHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIVVLPPAIGFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0103] SEQ ID NO: 13 (HCVR of the exemplary Ab 2) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYLHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIVVLPPAIGFDLWGQGTLVTVSS

[0104] SEQ ID NO: 14 (HC of the exemplary Ab 2) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYLHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIVVLPPAIGFDLWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0105] SEQ ID NO: 15 (cynomolgus monkey IL-19) MKLQCVSLWLLGTILMLCSVDNHGLRRCLISTDMDHIEDSFQEIKRAIQAKDTFPNVTILSTLETLQIIKPLDVCCVTKNLLAFYVDRVFKDHQEPNPKILRKISSIANSFLYMQKTLRQCQEQRQCHCRQEATNVTRVIHDNYDQLEVRSAAVKSLGELDIFLAWIAKNHEVTSSAAAHHHHHHSGS

[0106] SEQ ID NO: 16 (LCDR1 of the exemplary Ab 3) QASESVYNKNWLS

[0107] SEQ ID NO: 17 (LCDR2 of the exemplary Ab 3) DSSDLAS

[0108] SEQ ID NO: 18 (LCDR3 of the exemplary Ab 3) GGSYTDTYV

[0109] SEQ ID NO: 19 (LCVR of the exemplary Ab 3) AQVLTQTPSSVSEPVGGTVTINCQASESVYNKNWLSWFQQKPGQPPKLLIYDSSDLASGVPSRFKGSGSGTHFTLTISDVQCGDAATYYCGGSYTDTYVFGGGTEVVVK

[0110] SEQ ID NO: 20 (LC of the exemplary Ab 3) AQVLTQTPSSVSEPVGGTVTINCQASESVYNKNWLSWFQQKPGQPPKLLIYDSSDLASGVPSRFKGSGSGTHFTLTISDVQCGDAATYYCGGSYTDTYVFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC

[0111] SEQ ID NO: 21 (HCDR1 of the exemplary Ab 3) GFDLSSTYYMS

[0112] SEQ ID NO: 22 (HCDR2 of the exemplary Ab 3) SIVTSGRSGASYYANWAKG

[0113] SEQ ID NO: 23 (HCDR3 of the exemplary Ab 3) DLPAPTDDRGL

[0114] SEQ ID NO: 24 (HCVR of the exemplary Ab 3) QQLEESGGGLAKPEGSLTLTCKTSGFDLSSTYYMSWVRQAPGKGLEWIASIVTSGRSGASYYANWAKGRFTISKTSSTTVTLQMTSLAAADTASYFCVRDLPAPTDDRGLWGPGTLVVVSS

[0115] SEQ ID NO: 25 (HC of the exemplary Ab 3) QQLEESGGGLAKPEGSLTLTCKTSGFDLSSTYYMSWVRQAPGKGLEWIASIVTSGRSGASYYANWAKGRFTISKTSSTTVTLQMTSLAAADTASYFCVRDLPAPTDDRGLWGPGTLVVVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK

[0116] SEQ ID NO: 26 (LC of the exemplary Ab 3) GCCCAAGTGCTGACCCAGACTCCATCCTCCGTGTCTGAACCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGAGTGTTTATAATAAGAACTGGTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATTCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACACTTCACTCTCACCATCAGCGACGTGCAGTGTGGCGATGCTGCCACTTATTACTGTGGAGGCAGTTATACTGATACCTATGTTTTCGGCGGAGGGACCGAAGTGGTGGTCAAAGGGGATCCAGTGGCCCCCACCGTGCTGATTTTCCCACCAGCCGCCGATCAGGTCGCCACCGGCACCGTGACAATCGTGTGCGTGGCCAACAAGTACTTCCCCGACGTGACCGTGACCTGGGAGGTGGACGGCACCACCCAGACCACCGGCATCGAGAACAGCAAGACCCCCCAGAATTCTGCCGACTGCACCTACAACCTGAGCAGCACCCTGACCCTGACCAGCACCCAGTACAACAGCCACAAAGAGTACACCTGTAAAGTCACCCAGGGCACCACCAGCGTGGTGCAGAGCTTCAACCGGGGCGACTGC

[0117] Sequence number 27 (HC of exemplified Ab 3)

[0118] Sequence number 28 (LCDR1 of exemplified Ab 4) SASASIYEYLS

[0119] Sequence number 29 (LCDR2 of exemplified Ab 4) GASVLTD

[0120] Sequence number 30 (LCDR3 of exemplified Ab 4) QSYNDGSSSGDAHV

[0121] Sequence number 31 (LCVR of exemplified Ab 4) DIVMTQTPASVEAAVGGTVTIKCSASASIYEYLSWYQQKPGQRPKLLIYGASVLTDGVSSRFKGSGSGTEFTLTISDLEAADAATYYCQSYNDGSSSGDAHVFGGGTEVVVK

[0122] Sequence number 32 (LC of exemplified Ab 4) DIVMTQTPASVEAAVGGTVTIKCSASASIYEYLSWYQQKPGQRPKLLIYGASVLTDGVSSRFKGSGSGTEFTLTISDLEAADAATYYCQSYNDGSSSGDAHVFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADNTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC

[0123] Sequence number 33 (HCDR1 of exemplified Ab 4) GFPLSSYGFS

[0124] Sequence number 34 (HCDR2 of exemplified Ab 4) YLDPVFGSTLSAHTVNG

[0125] Sequence number 35 (HCDR3 of exemplified Ab 4) GIGYVYYGYTYDL

[0126] Sequence number 36 (HCVR of exemplified Ab 4) QEQLKESGGGLVQPGGSLKLSCKASGFPLSSYGFSWVRQAPGKGLEWIGYLDPVFGSTLSAHTVNGRLTISSDNAQNTLYLQLNSLTAADTATYFCARGIGYVYYGYTYDLWGPGTLVTVSS

[0127] Sequence number 37 (HC of exemplified Ab 4) QEQLKESGGGLVQPGGSLKLSCKASGFPLSSYGFSWVRQAPGKGLEWIGYLDPVFGSTLSAHTVNGRLTISSDNAQNTLYLQLNSLTAADTATYFCARGIGYVYYGYTYDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK

[0128] Sequence number 38 (LC of exemplified Ab 4) GACATTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCTCGGCCAGCGCGAGCATTTACGAGTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATGGTGCGTCGGTTTTAACGGATGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGGCTGCCGATGCTGCCACTTACTACTGTCAAAGCTATAATGATGGTAGTAGTAGTGGCGATGCTCATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGGGATCCAGTGGCCCCCACCGTGCTGATTTTCCCACCAGCCGCCGATCAGGTCGCCACCGGCACCGTGACAATCGTGTGCGTGGCCAACAAGTACTTCCCCGACGTGACCGTGACCTGGGAGGTGGACGGCACCACCCAGACCACCGGCATCGAGAACAGCAAGACCCCCCAGAATTCTGCCGACAACACCTACAACCTGAGCAGCACCCTGACCCTGACCAGCACCCAGTACAACAGCCACAAAGAGTACACCTGTAAAGTCACCCAGGGCACCACCAGCGTGGTGCAGAGCTTCAACCGGGGCGACTGC

[0129] Sequence number 39 (HC of exemplified Ab 4)

Claims

**Claim 1** An antibody that binds to human IL-19 and comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, the LCVR comprises CDRs LCDR1, LCDR2, and LCDR3, the amino acid sequence of HCDR1 is SEQ ID NO: 7, the amino acid sequence of HCDR2 is SEQ ID NO: 8, the amino acid sequence of HCDR3 is SEQ ID NO: 9 or SEQ ID NO: 10, the amino acid sequence of LCDR1 is SEQ ID NO: 2, the amino acid sequence of LCDR2 is SEQ ID NO: 3, and the amino acid sequence of LCDR3 is SEQ ID NO:

4. **Claim 2** The antibody according to claim 1, wherein HCDR3 is SEQ ID NO:

9. **Claim 3** The antibody according to claim 2, wherein the amino acid sequence of the HCVR is SEQ ID NO: 11 and the amino acid sequence of the LCVR is SEQ ID NO:

5. **Claim 4** The antibody according to claim 1, wherein HCDR3 is SEQ ID NO:

10. **Claim 5** The antibody according to claim 4, wherein the amino acid sequence of the HCVR is SEQ ID NO: 13 and the amino acid sequence of the LCVR is SEQ ID NO:

5. **Claim 6** An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 12 or SEQ ID NO: 14 and the amino acid sequence of the LC is SEQ ID NO:

6. **Claim 7** The antibody according to claim 6, wherein the amino acid sequence of the HC is SEQ ID NO:

12. **Claim 8** The antibody according to claim 6, wherein the amino acid sequence of the HC is SEQ ID NO:

14. **Claim 9** A pharmaceutical composition comprising the antibody according to any one of claims 1 to 8 and one or more pharmaceutically acceptable carriers, diluents, or excipients. **Claim 10** A method of treating AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, or PsA, the method comprising administering to a patient in need thereof an effective amount of the antibody according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9. **Claim 11** The antibody according to any one of claims 1 to 8 for use in therapy. **Claim 12** The antibody according to any one of claims 1 to 8 for use in the treatment of AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, or PsA. **Claim 13** The antibody according to any one of claims 1 to 8 for use in the manufacture of a medicament for the treatment of AD, asthma, PsO, PsA, RA, AxSpA, IBD, colitis, or PsA.

14. A nucleic acid comprising a sequence encoding SEQ ID NO: 6, 12, or 14.

15. A vector comprising a first nucleic acid sequence encoding SEQ ID NO: 12 or 14 and a second nucleic acid sequence encoding SEQ ID NO:

6.

16. A cell comprising the vector according to claim 15.

17. A composition comprising a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 12 or 14 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

6.

18. A cell comprising the first vector and the second vector according to claim 17.

19. A process for producing an antibody, the process comprising culturing the cell according to claim 16 or 18 under conditions such that the antibody is expressed and recovering the expressed antibody from the culture medium.

20. An antibody produced by culturing the cell according to claim 16 or 18 under conditions such that the antibody is expressed and recovering the expressed antibody from the culture medium.

21. An antibody that binds to human IL-19 and comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, the LCVR comprises CDRs LCDR1, LCDR2, and LCDR3, the amino acid sequence of HCDR1 is SEQ ID NO: 21, the amino acid sequence of HCDR2 is SEQ ID NO: 22, the amino acid sequence of HCDR3 is SEQ ID NO: 23, the amino acid sequence of LCDR1 is SEQ ID NO: 16, the amino acid sequence of LCDR2 is SEQ ID NO: 17, and the amino acid sequence of LCDR3 is SEQ ID NO:

18.

22. The antibody according to claim 21, wherein the amino acid sequence of the HCVR is SEQ ID NO: 24 and the amino acid sequence of the LCVR is SEQ ID NO:

19.

23. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 25 and the amino acid sequence of the LC is SEQ ID NO:

20.

24. An antibody that binds to human IL-19 and comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, the LCVR comprises CDRs LCDR1, LCDR2, and LCDR3, the amino acid sequence of HCDR1 is SEQ ID NO: 33, the amino acid sequence of HCDR2 is SEQ ID NO: 34, the amino acid sequence of HCDR3 is SEQ ID NO: 35, the amino acid sequence of LCDR1 is SEQ ID NO: 28, the amino acid sequence of LCDR2 is SEQ ID NO: 29, and the amino acid sequence of LCDR3 is SEQ ID NO:

30. The antibody according to claim 24, wherein the amino acid sequence of the HCVR is SEQ ID NO: 36 and the amino acid sequence of the LCVR is SEQ ID NO:

31. An antibody comprising a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 37 and the amino acid sequence of the LC is SEQ ID NO:

32. The antibody according to any one of claims 21 to 26, wherein the antibody is an anti-mouse IL-19 antibody. ​ ​ ​

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