Compounds and methods targeting interleukin-19

Abstract

Provided are compounds and methods that target human interleukin-19, including therapeutic antibodies, pharmaceutical compositions, and diagnostic applications useful in the fields of immune-mediated diseases, including psoriasis, atopic dermatitis, psoriatic arthritis, bronchial asthma, and diabetic nephropathy. The present invention provides an antibody that comprises a specific light chain variable region (LCVR) and a specific heavy chain variable region (HCVR) and that binds to human IL-19.

Description

[Technical field]

[0001] The present invention belongs to the field of medicine. More specifically, the present invention relates to compounds, pharmaceutical compositions, and methods comprising antibodies against human interleukin-19 (IL-19). The compounds 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), in particular diseases such as psoriasis (Ps0), atopic dermatitis (AD), diabetic nephropathy (DN), bronchial asthma (BA), and psoriatic arthritis (PsA), including their treatment and associated diagnostic applications. [Background technology]

[0002] Interleukin-19 (IL-19) is a cytokine reported to belong to the interleukin-10 cytokine family (which includes IL-10, 20, 22, and 26, as well as several virally encoded cytokines). IL-19 is involved in the IL-20R complex signaling pathway and is reported to be expressed in resting monocytes, macrophages, B cells, and epithelial cells, including keratinocytes.

[0003] Autoimmune diseases result from the body generating an immune response against its own tissues. Autoimmune diseases are often chronic and can be debilitating and even fatal. Ps0 is a chronic autoimmune disease with systemic symptoms including psoriatic arthritis, cardiovascular disease, metabolic syndrome, and affective disorders. AD, along with many other forms of chronic autoimmune diseases such as Ps0, RA, AxSpA, and PsA, affect the axial and / or peripheral skeleton.

[0004] Current FDA-approved treatments for immune-mediated diseases include corticosteroids, often used to treat acute inflammation, as well as biologics targeting TNFα or interleukin-12 and 23. While these treatments have been shown to be effective in reducing symptoms in some patients, many of the patients remain non-responsive or lose response to currently available treatments. In autoimmune diseases such as Ps0, ixekizumab is an FDA-approved therapeutic antibody that targets IL-17A, with 90% of patients achieving a 75% reduction in Psoriasis Assessment Skin Lesion (PASI) score (e.g., PASI75). However, PASI assessment is dependent on subject inputs that may be difficult to assess in certain circumstances. To date, there are no objective, sensitive, reproducible blood-based biomarkers to assess and inform clinical management of Ps0, as well as other immune-mediated diseases such as AD, DN, and BA. Thus, there remains an unmet need for compounds, pharmaceutical compositions, and methods useful as therapeutics for and / or in diagnostic applications related to immune-mediated diseases such as Ps0, AD, BA, DN, etc. Summary of the Invention

[0005] Thus, in certain embodiments, the present invention provides an antibody against human IL-19. According to some embodiments, the present invention provides an antibody comprising 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, and the HCVR comprises CDRs, HCDR1, HCDR2, and HCDR3, selected from the group of CDR combinations provided in Tables 1, 2, or 3. In some embodiments, the LCVR comprises CDRs, LCDR1, LCDR2, and LCDR3, and the HCVR comprises CDRs, HCDR1, HCDR2, and HCDR3, having an amino acid sequence with at least 95% homology to an amino acid sequence selected from the group of CDR combinations provided in Tables 1, 2, or 3. According to certain embodiments, the present invention also provides an antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises CDRs, LCDR1, LCDR2, and LCDR3, and the HCVR comprises CDRs, HCDR1, HCDR2, and HCDR3, having at least 95% homology to an amino acid sequence selected from the group of CDR combinations provided in Tables 1, 2, or 3. a. LCVR having the amino acid sequence of SEQ ID NO: 66 and HCVR having the amino acid sequence of SEQ ID NO: 70; b. LCVR having the amino acid sequence of SEQ ID NO: 74 and HCVR having the amino acid sequence of SEQ ID NO: 78; c. LCVR having the amino acid sequence of SEQ ID NO: 82 and HCVR having the amino acid sequence of SEQ ID NO: 86; d. LCVR having the amino acid sequence of SEQ ID NO: 34 and HCVR having the amino acid sequence of SEQ ID NO: 38; e. LCVR having the amino acid sequence of SEQ ID NO: 42 and HCVR having the amino acid sequence of SEQ ID NO: 46; f. an LCVR having the amino acid sequence of SEQ ID NO:50 and an HCVR having the amino acid sequence of SEQ ID NO:54, and g. Also provided are antibodies comprising a LCVR and HCVR selected from: a LCVR having the amino acid sequence of SEQ ID NO:58; and a HCVR having the amino acid sequence of SEQ ID NO:62.

[0006] According to an even more specific embodiment, the present invention also comprises a. a LC having the amino acid sequence of SEQ ID NO:2 and a HC having the amino acid sequence of SEQ ID NO:6; b. a LC having the amino acid sequence of SEQ ID NO: 10 and a HC having the amino acid sequence of SEQ ID NO: 14; c. a LC having the amino acid sequence of SEQ ID NO: 18 and a HC having the amino acid sequence of SEQ ID NO: 22; d. LC having the amino acid sequence of SEQ ID NO:26 and HC having the amino acid sequence of SEQ ID NO:30; e. a LC having the amino acid sequence of SEQ ID NO: 310 and a HC having the amino acid sequence of SEQ ID NO: 311, and f. Also provided are antibodies comprising an LC and a HC selected from, or having amino acid sequences having at least 95% homology to, the amino acid sequences of: an LC having the amino acid sequence of SEQ ID NO:312 and an HC having the amino acid sequence of SEQ ID NO:313.

[0007] According to certain embodiments, the present invention provides human IL-19 neutralizing antibodies having an LCVR and an HCVR, wherein the LCVR comprises CDRs (LCDR1, LCDR2, and LCDR3) and the HCVR comprises CDRs (HCDR1, HCDR2, and HCDR3), which are selected from or have an amino acid sequence having at least 95% homology to the amino acid sequence of the CDR combinations provided in Tables 1, 2, or 3. In certain embodiments, the human IL-19 neutralizing antibodies of the present invention comprise: a. LCVR having the amino acid sequence of SEQ ID NO: 66 and HCVR having the amino acid sequence of SEQ ID NO: 70; b. LCVR having the amino acid sequence of SEQ ID NO: 74 and HCVR having the amino acid sequence of SEQ ID NO: 78; c. LCVR having the amino acid sequence of SEQ ID NO: 82 and HCVR having the amino acid sequence of SEQ ID NO: 86; d. LCVR having the amino acid sequence of SEQ ID NO: 34 and HCVR having the amino acid sequence of SEQ ID NO: 38; e. LCVR having the amino acid sequence of SEQ ID NO: 42 and HCVR having the amino acid sequence of SEQ ID NO: 46; f. an LCVR having the amino acid sequence of SEQ ID NO:50 and an HCVR having the amino acid sequence of SEQ ID NO:54, and g. The antibody comprises an LCVR and an HCVR selected from: an LCVR having the amino acid sequence of SEQ ID NO:58 and an HCVR having the amino acid sequence of SEQ ID NO:62.

[0008] According to an even more specific embodiment, the present invention also comprises a. a LC having the amino acid sequence of SEQ ID NO:2 and a HC having the amino acid sequence of SEQ ID NO:6; b. a LC having the amino acid sequence of SEQ ID NO: 10 and a HC having the amino acid sequence of SEQ ID NO: 14; c. a LC having the amino acid sequence of SEQ ID NO: 18 and a HC having the amino acid sequence of SEQ ID NO: 22; d. a LC having the amino acid sequence of SEQ ID NO:26 and a HC having the amino acid sequence of SEQ ID NO:30, and e. a LC having the amino acid sequence of SEQ ID NO: 310 and a HC having the amino acid sequence of SEQ ID NO: 311, and f. Also provided is a human IL-19 neutralizing antibody comprising an LC and a HC selected from, or having amino acid sequences having at least 95% homology to, the amino acid sequences of SEQ ID NO:312 and SEQ ID NO:313.

[0009] In embodiments, the antibody of the invention comprises an IgG1 heavy chain. According to some embodiments, the antibody further comprises a kappa light chain.

[0010] According to some aspects of the invention, human IL-19 antibodies, including human IL-19 neutralizing antibodies, are provided that bind to human IL-19 within an epitope region that includes at least one or more of the following amino acid residues of human IL-19 set forth in SEQ ID NO: 1: 95-102; 67-75; 125-136; 67-75 and 125-136; 90-100; 42-60; 90-107; 149-160; 42-60, 90-107 and 149-160 (as determined by my methods described herein). In one embodiment, the invention provides IL-19 antibodies that bind to human IL-19 within an epitope region of human IL-19 that binds to the antibodies provided herein.

[0011] According to some embodiments, the IL-19 antibodies of the present invention are useful for the treatment of immune-mediated diseases. In some more specific embodiments, the immune-mediated disease is at least one of Ps0, AD, PsA, BA, and / or DN. According to other embodiments of the present invention, the IL-19 antibodies of the present invention are useful for the diagnostic application of autoimmune diseases. In some more specific embodiments, the immune-mediated disease is at least one of Ps0, AD, and / or DN.

[0012] The present invention further provides a pharmaceutical composition comprising an IL-19 antibody of the present invention and one or more pharma- ceutically acceptable carriers, diluents, or excipients. Additionally, the present invention provides a method of treating immune-mediated diseases, such as Ps0, AD, and / or DN, comprising administering to a patient in need of treatment a pharmaceutical composition of the present invention.

[0013] In addition, the present invention provides a method of treating an immune-mediated disease, more specifically, a method of treating an immune-mediated disease, including Ps0, AD, PsA, BA, or DN, comprising administering to a patient in need of treatment an effective amount of an IL-19 antibody of the present invention.

[0014] The present invention also provides an IL-19 antibody of the present invention for use in therapy. More specifically, the present invention provides an IL-19 antibody of the present invention for use in treating immune-mediated diseases, including Ps0, AD, PsA, and DN. In one embodiment, the present invention provides the use of an IL-19 antibody of the present invention in the manufacture of a medicament for the treatment of one or more immune-mediated diseases, including Ps0, AD, PsA, BA, and DN.

[0015] According to some embodiments, the present invention provides a method for detecting IL-19 in a patient sample, comprising contacting the patient sample with a first antibody that binds to a first epitope region of IL-19, contacting the patient sample with a second antibody that binds to a second epitope region of IL-19 and has a detectable label, and detecting a signal provided by the detectable label. In some embodiments, the patient sample is one of blood, serum, or plasma. According to some more specific embodiments, the first epitope region of IL-19 overlaps with the second epitope region of IL-19. Moreover, in some embodiments, the contacting with the first and second antibodies occurs simultaneously. In some specific embodiments, the first antibody comprises a combination of LC and HC CDRs provided in Table 1, 2, or 3. In some embodiments, the first antibody comprises a combination of LC and HC CDRs that have 95% homology to the LC and HC CDRs provided in Table 1, 2, or 3. In some specific embodiments, the second antibody comprises a combination of LC and HC CDRs provided in Tables 1, 2, or 3. In some embodiments, the second antibody comprises a combination of LC and HC CDRs that have 95% homology to the LC and HC CDRs provided in Tables 1, 2, or 3. In more specific embodiments, the first and second antibodies are not bottled together.

[0016] According to some embodiments of the present invention, there is provided a method of quantifying IL-19 in a patient sample, comprising the steps of contacting the patient sample with a first antibody that binds to a first epitope region of IL-19, contacting the patient sample with a second antibody that binds to a second epitope region of IL-19 and that bears a detectable label, and detecting a signal provided by the detectable label. The method includes contacting the control standard with a first antibody that binds to the same first epitope region of IL-19 (used in contacting the patient sample), contacting the control standard with a second antibody that binds to the same second epitope region of IL-19 (used in contacting the patient sample) and has a detectable label, and detecting the signal provided by the detectable signal. In some embodiments, the patient sample is one of blood, serum, or plasma. According to some more specific embodiments, the first epitope region of IL-19 overlaps with the second epitope region of IL-19. Moreover, in some embodiments, the contacting with the first and second antibodies occurs simultaneously. In some specific embodiments, the first antibody comprises a combination of LC and HC CDRs provided in Table 1, 2, or 3. In some embodiments, the first antibody comprises a combination of LC and HC CDRs that have 95% homology to the LC and HC CDRs provided in Table 1, 2, or 3. In some specific embodiments, the second antibody comprises a combination of LC and HC CDRs provided in Tables 1, 2, or 3. In some embodiments, the second antibody comprises a combination of LC and HC CDRs that have 95% homology to the LC and HC CDRs provided in Tables 1, 2, or 3. In more specific embodiments, the first and second antibodies are not bottled together.

[0017] According to some embodiments, a method for diagnosing an immune-mediated disease is provided. Such a method includes contacting a patient sample with an IL-19 antibody and detecting binding between IL-19 in the patient sample and the antibody. According to some specific embodiments, the diagnostic method includes diagnosing the patient as having, at risk of, in need of treatment for, and / or at risk of symptoms associated with an immune-mediated disease if the presence of IL-19 in the patient sample is detected above the reference value. According to some more specific embodiments, such a method further includes determining the reference value, comprising contacting a control standard with a first antibody that binds to a first epitope region of IL-19 identical to that used in contacting the patient sample, contacting the control standard with a second antibody having a detectable label and that binds to a second epitope region of IL-19 identical to that used in contacting the patient sample, and detecting the signal provided by the detectable signal. In some embodiments, the first antibody comprises a combination of LC and HC CDRs provided in Table 1, 2, or 3. In some embodiments, the first antibody comprises a combination of LC and HC CDRs having 95% homology to the LC and HC CDRs provided in Tables 1, 2, or 3. Some embodiments of the methods of diagnosing immune-mediated diseases provided herein further comprise contacting the patient sample with a second IL-19 antibody that binds to a second epitope region of IL-19 and has a detectable label, and detecting the signal provided by the detectable label. In some specific embodiments, the IL-19 antibody comprises a combination of LC and HC CDRs provided in Tables 1, 2, and 3. In some embodiments, the second IL-19 antibody comprises a combination of LC and HC CDRs provided in Tables 1, 2, and 3. In some embodiments, the second antibody comprises a combination of LC and HC CDRs having 95% homology to the LC and HC CDRs provided in Tables 1, 2, and 3. According to specific embodiments, the first epitope region of IL-19 overlaps with the second epitope region of IL-19.According to certain embodiments, the first and second antibodies are not bottled together. According to further embodiments, the reference value is about 21 pg / mL. In further embodiments, the immune-mediated disease is one of Ps0, AD, PsA, BA, and DN.

[0018] In yet further embodiments, the present invention provides a method of treating an immune-mediated disease in a patient. Such a method includes contacting a patient sample with an IL-19 antibody and detecting binding between IL-19 in the patient sample and the antibody, and diagnosing the patient as having, at risk of, in need of treatment for, and / or at risk of symptoms associated therewith, if the presence of IL-19 in the patient sample is detected above the reference value. According to some more specific embodiments of the treatment methods provided herein, such a method further includes determining the reference value, which includes contacting a control standard with a first antibody that binds to a first epitope region of IL-19 identical to that used in contacting the patient sample, contacting the control standard with a second antibody having a detectable label and that binds to a second epitope region of IL-19 identical to that used in contacting the patient sample, and detecting the signal provided by the detectable signal. In some specific embodiments, the IL-19 antibody includes a combination of LC and HC CDRs provided in Tables 1, 2, and 3. In some embodiments, the IL-19 antibody comprises a combination of LC and HC CDRs having 95% homology to the LC and HC CDRs provided in Table 1, 2, or 3. According to some embodiments, the reference value is about 21 pg / mL. In embodiments, the immune-mediated disease is one of Ps0, AD, and DN. In some embodiments, the patient sample is one of blood, serum, or plasma. According to some embodiments, the method further comprises contacting the patient sample with a second IL-19 antibody that binds to a second epitope region of IL-19 and has a detectable label, and detecting the signal provided by the detectable signal. In still further embodiments, the second antibody comprises a combination of LC and HC CDRs provided in Table 1, 2, or 3. In some embodiments, the second antibody comprises a combination of LC and HC CDRs having 95% homology to the LC and HC CDRs provided in Table 1, 2, or 3. According to certain embodiments, the first and second antibodies are not bottled together. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] As used herein, an "antibody" is an immunoglobulin molecule that contains two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portion of each LC and HC contains a variable region of about 100-120 amino acids that is primarily responsible for antigen recognition via the CDRs housed therein. The CDRs are interspersed with more conserved regions called frame regions ("FRs"). Each LCVR and HCVR is composed of three CDRs and four FRs arranged from the amino-terminus to the carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the LC are referred to as "LCDR1, LCDR2, and LCDR3" and the three CDRs of the HC are referred to as "HCDR1, HCDR2, and HCDR3". The CDRs contain the majority of the residues that form specific interactions with the antigen. The functional ability of an antibody to bind a particular antigen is largely influenced by the six CDRs. The assignment of amino acids to the CDR domains within the LCVR and HCVR regions of the antibodies of the present invention is based on the well-known Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242 (1991)), and the North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)).

[0020] LCs are classified as kappa or lambda, each of which is characterized by a specific constant region known in the art. HCs are classified as gamma, mu, alpha, delta, or epsilon, which define the antibody's isotype as IgG, IgM, IgA, IgD, or IgE, respectively. The antibodies of the present invention include IgG HCs, which can be further classified into subclasses, e.g., IgG1, IgG2, IgG3, IgG4. The carboxy-terminal portion of each HC defines the constant region that is primarily responsible for effector function. Certain embodiments of the antibodies of the present invention may include one or more modifications in the constant region of each HC, e.g., that enhance or reduce effector function, which are known in the art.

[0021] The antibody of the present invention is a monoclonal antibody.A monoclonal antibody is an antibody that originates from a single copy or clone (including, for example, any eukaryotic, prokaryotic, or phage clone), not the method by which it is produced.Monoclonal antibody can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology, such as CDR grafting, or a combination of such technology or other technology known in the art.

[0022] 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, New York, chapters 5-8 and 15, ISBN 0-87969-314-2. For example, mice or rabbits can be immunized with human IL-19, and the resulting antibodies can be harvested, purified, and amino acid sequenced using conventional methods well known in the art. Similarly, phage libraries can be screened to screen thousands of Fab fragments for interaction with human IL-19, and the resulting interacting fragments can be harvested, purified, and amino acid sequenced using conventional methods well known in the art, from which initial lead antibodies can be constructed. According to possible embodiments, the antibodies of the present invention can be engineered to contain one or more human framework regions surrounding the CDRs derived from a non-human antibody. Human framework germline sequences can be obtained, for example, from ImMunoGeneTics (INGT) through their website (http: / / imgt.cines.fr) or from The Immunoglobulin Facts Book by Marie-Paule Lefranc and Gerard Lefranc, Academic Press, 2001, ISBN 012441351.

[0023] In certain embodiments of the invention, the antibody, or 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 is free or substantially free from other macromolecular species that are found within a cellular environment.

[0024] The antibody of the present invention can be used to treat patients. More specifically, the antibody of the present invention is expected to treat immune-mediated diseases or disorders, including Ps0, AD, PsA, BA, and DN. Although the antibody of the present invention is expected to be useful in treating Ps0, AD, and DN, such antibodies may also be useful in treating other immune-mediated diseases, including RA, AxSpA, and PsA, and / or immune-mediated diseases, specifically involving epithelial cell involvement. As used interchangeably herein, "treatment" and / or "treating" and / or "treat" are intended to refer to any process in which there may be a slowing, impeding, arresting, controlling, halting, or reversing the progression of the disorders described herein, but do not necessarily indicate a complete elimination of symptoms of all disorders. Treatment includes the administration of the antibodies of the invention for the treatment of a human disease or condition that would benefit from reduced IL-19 activity, and includes (a) inhibiting further progression of the disease, i.e., arresting its development, and (b) relieving the disease, i.e., causing regression of the disease or disorder or alleviating its symptoms or complications.

[0025] As used interchangeably herein, the terms "patient," "subject," and "individual" refer to a human. In certain embodiments, the patient is further characterized as having a disease, disorder, or condition (e.g., an autoimmune disorder) that would benefit from reduced IL-19 activity. In other embodiments, the patient is further characterized as being at risk for developing an immune-mediated disease, disorder, or condition that would benefit from reduced IL-19 activity.

[0026] As used herein, a patient "sample" refers to a human sample. Non-limiting sources of samples for use in the present invention include blood, plasma, serum, spinal fluid, lymphatic fluid, biopsy aspirates, peritoneal fluid, fluid extracts, solid tissues, skin, external sections of the respiratory, intestinal, and urogenital tracts, tears, saliva, milk, tumors, organs, cell cultures, and / or cell culture components.

[0027] As used herein, the term "bind (or binds)" refers to the interaction of an antibody with an epitope region of human IL-19. The term "epitope region" refers to specific amino acids comprising IL-19 that provide an antigenic determinant capable of specific binding to an IL-19 antibody. The amino acids of the epitope region provide chemically active surface groups on IL-19, form a specific three-dimensional structure of IL-19, and may provide specific charge characteristics. Binding may include interaction with the epitope region by either "conformational" or "linear" epitope binding of the antibody to human IL-19. Presented herein are exemplary embodiments of IL-19 antibodies that bind to linear epitopes of human IL-19, and other exemplary embodiments of IL-19 antibodies that bind to conformational epitopes. Conformational and non-conformational / linear epitopes may be distinguished in that binding to conformational epitope regions is lost in the presence of denaturing solvents, whereas linear epitope regions are not. In certain embodiments, the term "binds" (or binds) to human IL-19 refers to interactions with an epitope region comprising amino acid residues 95-102 of human IL-19, as determined by my methods described herein (residue numbering based on the exemplary human IL-19 of SEQ ID NO:1). In further embodiments, the term "binds" (or binds) to human IL-19 refers to interactions with an epitope region comprising amino acid residues 90-100 of human IL-19, as determined by my methods described herein (residue numbering based on the exemplary human IL-19 of SEQ ID NO:1). In another specific embodiment, the term "binds" (or binds to) human IL-19 refers to interaction with an epitope region comprising amino acid residues 67-75 of human IL-19, as determined by my method described in this disclosure (residue numbering based on the exemplary human IL-19 of SEQ ID NO:1).In another embodiment, the term "binds" (or binds) to human IL-19 refers to an interaction with an epitope region comprising amino acid residues 125-136 of human IL-19 as determined by my method described herein (residue numbering based on exemplary human IL-19 in SEQ ID NO:1). In another specific embodiment, the term "binds" (or binds) to human IL-19 refers to an interaction with an epitope region comprising amino acid residues 67-75 and 125-136 of human IL-19 as determined by my method described herein (residue numbering based on exemplary human IL-19 in SEQ ID NO:1). In a further embodiment, the term "binds" (or binds) to human IL-19 refers to an interaction with an epitope region comprising amino acid residues 42-60 of human IL-19 as determined by my method described herein (residue numbering based on exemplary human IL-19 in SEQ ID NO:1). In certain embodiments, the term "binds" (or binds) to human IL-19 refers to interactions with an epitope region comprising amino acid residues 90-107 of human IL-19 as determined by my methods described herein (residue numbering based on the exemplary human IL-19 in SEQ ID NO:1). In certain embodiments, the term "binds" (or binds) to human IL-19 refers to interactions with an epitope region comprising amino acid residues 149-160 of human IL-19 as determined by my methods described herein (residue numbering based on the exemplary human IL-19 in SEQ ID NO:1). In another specific embodiment, the term "binds" (or binds) to human IL-19 refers to interactions with an epitope region comprising amino acid residues 42-60, 90-107, and 149-160 of human IL-19 as determined by my methods described herein (residue numbering based on the exemplary human IL-19 in SEQ ID NO:1). It should be understood that there are known variations of human IL-19, resulting, for example, from splice variants.It is also understood that such known variants may result in altered residue numbering of the residues described herein (e.g., in the context of the residue numbering presented in SEQ ID NO:1). Although some variants may have altered residue numbering, the amino acids that comprise the epitope region remain the same. As used herein, the term "epitope region" refers to a distinct three-dimensional site of an antigen that is recognized either completely or partially by an antibody of the present invention.

[0028] The antibodies of the invention can be prepared by methods well known in the art and can be incorporated into pharmaceutical compositions comprising an antibody of the invention and one or more pharma- ceutically acceptable carrier(s) and / or diluent(s) (see, e.g., Remington, The Science and Practice of Pharmacy, 22(1), which provides an overview of formulation techniques generally known to the practicing physician). nd Edition, Loyd V., Ed., Pharmaceutical Press, 2012). Suitable carriers for pharmaceutical compositions include any material that retains the activity of the molecule when combined with the antibody of the present invention and is non-reactive with the patient's immune system. The pharmaceutical composition containing the antibody of the present invention can be administered by parental route (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal) to a patient at risk for or exhibiting a disease or disorder described herein. The pharmaceutical composition of the present invention contains an "effective" amount or a "therapeutically effective" amount (used interchangeably herein) of the antibody of the present invention. An effective amount refers to the amount (at the dosage and duration and by 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 elicit a desired response in the individual. An effective amount is also an amount in which any toxic or detrimental effects of the antibody of the present invention are outweighed by the therapeutically beneficial effects.

[0029] The term percent homology, as used in this disclosure, in the context of two or more amino acid sequences, refers to two or more sequences that have a certain percentage of amino acid residues that are identical when compared and aligned for maximum correspondence using a sequence comparison algorithm (e.g., BLASTP and BLASTN, or other algorithms available to those skilled in the art) or as determined by visual inspection. Depending on the application, the percent homology can be over a region of the sequences being compared, e.g., over a functional domain, or over the entire length of the two sequences being compared. As an example, the percent homology of a sequence can be compared to a reference sequence. For example, when using a sequence comparison algorithm, a test sequence and a reference sequence can be input into a computer (and subsequence coordinates can be further specified, if necessary, along with sequence algorithm program parameters). The sequence comparison algorithm then calculates the percent sequence identity or homology of the test sequence(s) to the reference sequence(s) based on the specified program parameters. 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 (Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally, Ausubel et al., infra). One example of an algorithm suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215: 403-410 (1990).Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0030] The present disclosure also relates to a method of clinical diagnosis, prognosis, or theranosis of a subject performed by a medical professional using the methods disclosed herein. The methods described herein can be performed, for example, by an individual, a medical professional, or a third party, such as a service provider that resolves genotype information from a subject. As described herein, a medical professional can initiate or change treatment after receiving information about the diagnostic methods of the present disclosure. For example, a medical professional may recommend a therapy or a change in therapy.

[0031] The antibodies of the present disclosure can be used to isolate, detect, and / or quantitate IL-19 by standard techniques, such as affinity chromatography, immunoprecipitation, immunohistochemistry, or ELISA-based assays. Such assays can be used to detect and / or evaluate the abundance and / or pattern of IL-19 expression for diagnostic, prognostic, or theranostic purposes, e.g., to monitor polypeptide levels in serum, plasma, blood, or tissues as part of a clinical trial procedure to determine the effectiveness of a given therapeutic regimen.

[0032] The IL-19 level or measurement provided by the assay of the present invention can be an absolute value (e.g., concentration in a biological sample) or a relative value (e.g., concentration compared to a reference). As used herein, when the detection method of IL-19 indicates that the level or concentration of IL-19 in a patient sample is higher than a reference value, IL-19 is referred to as "increased" in the patient sample. Conversely, when the level or concentration of IL-19 in a patient sample is lower than a reference value, or, for example, the IL-19 value measured in a previous patient sample, IL-19 is referred to as "decreased" in the patient sample.

[0033] As used herein, a "reference value" refers to a known or approximate concentration of IL-19 associated with a specific condition. The reference value concentration level may be an absolute or relative amount, a range of amounts, or a minimum, average, and / or median amount of IL-19. The reference value may also serve as a baseline for IL-19 against which values ​​obtained from patient samples are compared. According to some embodiments, the reference value may include a reference value of about 21 pg / mL.

[0034] As used herein, "control standard" refers to a sample that can be used to compare results obtained from patient samples in the methods of the present invention. A control standard is a cell, tissue, or a known protein concentration added to the medium. The concentration level of the control standard can be an absolute or relative amount of IL-19, a range of amounts, or a minimum, average, and / or median amount. A control standard can also serve as a baseline of IL-19 to which patient samples are compared. A control standard can include concentration values ​​from the same patient, or a known normal standard of IL-19. According to some embodiments, a control standard can include a reference value of about 21 pg / mL. Furthermore, in some embodiments, a control standard can represent IL-19 concentrations in the form of a standard curve.

[0035] As used herein, the term "capture antibody" or "first antibody" refers to an IL-19 antibody that can bind and capture IL-19 in a patient sample under suitable conditions such that the capture antibody-IL-19 complex can be separated from the remainder of the sample. In some embodiments, the capture antibody is immobilized. In some embodiments, the capture antibody is labeled with a detectable label. In some embodiments, the capture antibody is immobilized in a "sandwich" immunoassay, and the capture or first IL-19 antibody binds to a specific or first epitope region of IL-19. In such sandwich immunoassays, a "detection (or second) antibody" is also utilized. According to some embodiments, the detection or second antibody can specifically bind to the capture antibody and can be labeled with a detectable label. In some embodiments, the detection second antibody binds to IL-19 that has already been bound or captured by the capture or first antibody. In such embodiments, the detection antibody binds to IL-19 at the second epitope region and can be labeled with a detectable label.

[0036] As understood in the art, the antibodies of the present invention can be conjugated to a "detectable label" to facilitate its detection. As used herein, a detectable label is a moiety, composition, or technique that can be used to detect the binding of the detection antibody to the capture antibody-IL-19 complex. According to some embodiments, the detectable label can be directly or indirectly conjugated to the antibody (either for capture or detection, as the case may be). Examples of detectable labels include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase. Examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotnazinylamine fluorescein, dansyl chloride, or phycoerythrin. Examples of luminescent materials include luminol. Examples of bioluminescent materials include luciferase, luciferin, and aequorin. And examples of suitable radioactive materials include 125 I, 131 I, 35 S, or 3 H. The antibodies of the present invention may also be useful in pharmacogenomic analyses. Such embodiments can be used to identify individuals who may benefit from a particular or altered therapy and / or to monitor the effectiveness of a current treatment regimen.

[0037] As used interchangeably herein, the terms "diagnosis" or "diagnosing" refer to a method by which one of skill in the art can estimate and / or determine the probability ("likelihood") that a patient is or is not afflicted with a given disease or condition. In the context of the present invention, "diagnosing" a patient includes using the results of the assays of the present invention to identify or diagnose an autoimmune disease or an autoimmune disease and factors associated with the patient (i.e., the presence or occurrence of an autoimmune disease, or the need for treatment, or the effectiveness of treatment for the patient's autoimmune disease). According to the present invention, diagnosis may be based on a combination of other clinical signs that are understood by medical practitioners to arrive at a diagnosis. EXAMPLES

[0038] Expression of IL-19 antibodies The mouse-derived IL-19 antibodies of the present invention are produced using hybridoma methodology (e.g., as originally described by Kohler et al., Nature, 256:495 (1975)). Briefly, mice are immunized with recombinant human IL-19, and lymphocytes capable of producing antibodies that bind to human IL-19 are isolated and fused with myeloma cell lines using a suitable fusing agent to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). The hybridomas are seeded and grown in a suitable culture medium (preferably containing one or more substances that inhibit the survival of unfused myeloma cells). The binding specificity of the monoclonal antibodies produced by the hybridomas is then determined by in vitro binding assays (e.g., immunoprecipitation, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA)). Preferred hybridomas can be subcloned by limiting dilution procedures and grown by standard methods, including in vivo as ascites tumors in animals (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). Monoclonal antibodies secreted by the hybridomas (and or subclones) are purified according to conventional procedures, such as, for example, affinity chromatography (e.g., protein A or protein G-Sepharose) or ion exchange chromatography, hydroxyapatite chromatography, gel electrophoresis, dialysis, etc. Affinity maturation of antibodies can be performed according to methods known in the art.

[0039] The cDNA encoding the antibody of the present invention is sequenced using conventional procedures. The cDNA sequences encoding the heavy and light chains can be cloned and incorporated into a GS (glutamine synthetase) expression vector. The engineered immunoglobulin expression vector can then be stably transfected into CHO cells. As will be appreciated by those skilled in the art, mammalian expression of antibodies will typically result in glycosylation at the highly conserved N-glycosylation site in the Fc region. Stable clones can be verified for expression of an antibody that specifically binds to human IL-19. Positive clones can be grown into serum-free medium for antibody production in a bioreactor. The medium into 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-specifically bound components. The bound antibody is eluted, for example, by a pH gradient, and the antibody fraction is detected, such as by SDS-PAGE, and then pooled. The antibody may 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 may be immediately frozen, for example, at -70°C, or lyophilized. The CDR sequences of exemplary embodiments of the inventive mouse-derived IL-19 antibodies that are affinity-optimized as known in the art are provided in Table 1. [Table 1]

[0040] The rabbit-derived IL-19 antibody of the present invention is generated after obtaining antibody gene sequences directly from B cells. Briefly, rabbits are immunized with recombinant human IL-19, and mRNA is isolated from antigen-specific B cells enriched from PBMC. The nucleic acid sequences encoding the heavy and light chain variable regions from this library are then cloned into a cell-based display system. Functional binding fragments are isolated from the library, individual gene sequences are determined, and cloned for recombinant IgG expression and purified essentially as described above for mouse-derived IL-19 antibody. Table 2 provides the CDR sequences of exemplary embodiments of the rabbit-derived IL-19 antibody of the present invention that are affinity-optimized as known in the art. [Table 2]

[0041] The phage-derived IL-19 antibodies of the present invention are isolated from antibody phage libraries using common techniques as described above, as described in McCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991). The cDNA sequences encoding the heavy and light chains of the phage-derived antibodies of the present invention may be cloned and engineered into GS (glutamine synthetase) expression vectors for recombinant expression in competent cell lines such as CHO cells. The CDR sequences of exemplary embodiments of the phage-derived IL-19 antibodies of the present invention are provided in Table 3. [Table 3]

[0042] Binding kinetics and affinity Binding of exemplary IL-19 antibodies of the invention to recombinant human IL-19 (having the amino acid sequence set forth in SEQ ID NO:1) is measured using a Biolayer Interferometry (BLI) assay (using HBS-EP+ running buffer (GE Healthcare, 10 mM Hepes pH 7.4+150 mM NaCl+3 mM EDTA+0.05% surfactant P20) at 25° C.) measured on an Octet Red96® instrument available from ForteBio.

[0043] All reagents and materials are from ForteBio (Freemont, CA) except as noted. The antibodies to be analyzed are immobilized using an AMQ biosensor. Exemplary antibody samples of the invention (R_1, R_2, R_3, R_4, R_39, M_1, M_2, and M_5) are prepared at 5 μg / mL by dilution in running buffer. Recombinant human IL-19 is prepared at concentrations of 270, 90, 30, 10, 3.33, 1.11, 0.370, and 0 (blank) nM by dilution in running buffer. Each analysis consisted of (1) capturing the antibody sample on the biosensor for 300 seconds, (2) establishing a baseline by incubating the antibody-loaded biosensor with running buffer for 60 seconds, (3) incubating the antibody-loaded biosensor with serially diluted recombinant human IL-19 for 300 seconds to monitor the association phase, and (4) transferring the biosensor back into running buffer to monitor the dissociation phase.

[0044] Binding data were processed using standard double referencing and fitted to a 1:1 binding model using Data Analysis v9.0 evaluation software to determine association rates (k on , M -1 s -1 units), dissociation rate (k off , s -1 units), and R max Determine the K (unit: nm). D =k off / k on From the relationship, the equilibrium dissociation constant (K D) was calculated and is in units of moles. The results are provided in Table 4. [Table 4]

[0045] Epitope mapping For high-resolution linear epitope mapping, PEPperCHIP® peptide microarray linear epitope mapping of exemplary antibody M_1 against human IL-19 is performed according to the manufacturer's instructions. Briefly, exemplary antibody M-1 is incubated with a custom PEPperCHIP® peptide microarray containing overlapping 12-mer peptide fragments of human IL-19. Scan intensities are resolved using the manufacturer's software. For exemplary antibody M_1, PEPperCHIP® analysis revealed an epitope consisting of residues 95-102 (EPNPKILR) of SEQ ID NO:1. Other mouse- and rabbit-derived exemplary antibodies of the invention do not yield linear epitopes and demonstrate conformational epitope binding of human IL-19.

[0046] Hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS) is performed to map the epitope regions of recombinant human IL-19 protein of exemplary antibodies M_2, M_3, M_5, and R_39. Briefly, HDX-MS is performed on a Waters nanoACQUITY system equipped with HDX technology including a LEAP HDX robotic liquid handling system, and mass spectrometry is performed on a Waters Xevo G2-Tof mass spectrometer. Complexes of human IL-19 with exemplary antibodies M_2, M_3, M_5, and R_39 are prepared in a molar ratio of 1:1.2 in 10 mM sodium phosphate buffer, pH 7.4, containing 150 mM NaCl (1xPBS buffer). The complexes are incubated in 55 uL of D3000 containing 0.1xPBS at 15°C for various time amounts (0 s, 10 s, 1 min, 10 min, 60 min, 120 / 240 min). 2Deuterium exchange experiments are initiated by adding 5 ul of O buffer to 5 ul of human IL-19 or human IL-19 / antibody complex. The reaction is quenched for 2 min at 1 °C using an equal volume of 0.32 M TCEP, 0.1 M phosphate pH 2.5. 50 μL of the quenched reaction is injected onto an online pepsin column (Waters BEH Enzymate) at 14 °C for 4 min at a flow rate of 100 μL / min using 0.2% formic acid in water as the mobile phase. The resulting peptic peptides are then separated on a C18 column (Waters, Acquity UPLC BEH C18, 1.7 μm, 1.0 mm x 50 mm) with a Vanguard trap column using a 3-85% acetonitrile (containing 0.2% formic acid) gradient over 10 min at a flow rate of 50 μL / min. The separated peptides are sent to a Waters Xevo G2 time-of-flight (qTOF) mass spectrometer. The mass spectrometer was operated in the mass acquisition range of m / z 255.00 to 1950.00 with a scan time of 0.5 seconds. E , E.S.I. + The Xevo G2 was set to collect data in 50% ACN, 50% H mode. The Xevo G2 was calibrated with Glu-fibrinopeptide prior to use. All data acquired was in 50% ACN, 50% H mode. 2 The peptides are mass-corrected (m / z is 556.2771) using a 2 μg / ml solution of LeuEnk in 0.0, 1000, and 0.1% FA at a flow rate of 5 μl / min every 30 s. Peptides are initially identified by Waters Protein Lynx Global Server 3.02. Processing parameters are set at a low energy threshold of 100.0 counts, a high energy threshold of 50.0 counts, and an intensity threshold of 1500.0 counts. The resulting list of peptides is imported into Waters DynamX 3.0 software with thresholds of 5 ppm mass error and 20% fragment ions per peptide based on peptide length. The relative deuterium uptake of each peptide is determined by processing the MS data of the deuterated sample along with the non-deuterated control in DynamX.

[0047] With the described HDX-MS, sequence coverage of 90.9-94.8% of the human IL-19 protein is observed. When complexed with the exemplary antibodies, reduced deuterium incorporation is observed at residues of SEQ ID NO:1, as shown: M_2 and M_3: residues 67-75 (QIIKPLDVC) and 125-136 (RQCHCRQEATNA); M_5: residues 90-100 (FKDHQEPNPKI), and R_39: residues 42-60 (QEIKRAIQAKDTFPNVTIL), 90-107 (FKDHQEPNPKILRKISSI), and 149-160 (VHAAAIKSLGEL).

[0048] Binning experiment Binning experiments involve monoclonal antibodies competing with each other in a pairwise and combinatorial manner for binding to a specific antigen. A "bin" is a relative concept based on the epitope region represented within the panel of monoclonal antibodies being tested. When tested against other antibodies (or bins of antibodies) in the test panel, two antibodies belong to the same bin if they are not paired with each other and share the same blocking profile. Binning of the exemplary antibodies of the present invention can be performed by a cross-competition binning assay using Octet Red96® available from ForteBio according to the manufacturer's instructions. Briefly, to determine if two antibodies share overlapping epitope regions, the exemplary antibodies are labeled with biotin and captured on a streptavidin sensor tip. The coated biosensor tip is then incubated with recombinant human IL-19 to saturate the capture antibody binding sites. The capture antibody-antigen complex is then incubated with a detection antibody. If the detection antibody is able to bind, a change in wavelength is detected. Antibodies with identical binding profiles are grouped together in the same bin. The results are presented in Table 5. [Table 5]

[0049] Neutralization of IL-19 in vitro The antibodies of the invention are expected to neutralize IL-19. Neutralization of IL-19 activity by the antibodies of the invention may be assessed by one or more of the IL-19 / IL-19 receptor binding assay formats, as well as the IL-19 binding assay, for example, described below.

[0050] In one example, IL-19 is radiolabeled, for example with iodine-125 or tritium. Cells expressing an IL-19 receptor, such as IL-20R1 (e.g., primary human cells such as transformed keratinocytes that endogenously express the IL-19 receptor, or keratinocytes that express the IL-19 receptor) are used in the assay, which can be performed in a buffered medium, such as HBSS, containing calcium and magnesium as well as whole cells. Thus, cells can be incubated with labeled IL-19 in assay buffer for 1-6 hours at 4, 20, or 37 °C. The readout provides the amount of label bound to the cells after separation of unbound tracer, such as by filtration through a glass fiber filter. Alternatively, neutralization can be assessed by a proximity-based assay, such as with SPA beads. Additionally, neutralization assays utilizing non-radioactively labeled IL-19 protein can be used.

[0051] Such neutralization assays include pre-incubation (e.g., 1 hour) of the antibody being evaluated with labeled IL-19 (as well as a control sample not involving an antibody targeting IL-19) before addition to the binding assay. Concentrations of labeled IL-19 close to the 50% binding level (EC50) can be used, as well as various concentrations (e.g., when evaluating the antibody dose response, such as from about 100 micromolar to about 1 picomolar). Antibody inhibition evaluated over a range allows for the determination of potency (IC50).

[0052] According to another method for evaluating the neutralization of IL-19 by the antibody of the present invention, IL-19 protein is labeled with a fluorescent dye for flow cytometry (e.g., Alexa-647) and used to label cells such as human keratinocytes. Flow cytometry can then be used to measure binding. The neutralization of IL-19 by the antibody is evaluated by pre-incubating the antibody with labeled IL-19 (e.g., for 1 hour at 4°C) before adding the mixture to the cells (with staining performed for about 3 hours at 4°C). Concentrations of fluorescently labeled IL-19 close to the 50% binding level (EC50) can be used, as well as various concentrations (e.g., when evaluating the dose response of the antibody, such as about 100 micromolar to about 1 picomolar). The antibody inhibition of the binding of labeled IL-19 to its receptor can be reflected by measuring the loss of labeled cells, and the potency (IC50) of the antibody can be determined.

[0053] Alternatively, biophysical assays such as biolayer interferometry (BLI) can be used to evaluate the neutralization of IL-19 by the antibodies of the present invention. Binding of the analyte in solution to the ligand immobilized on the surface of the biosensor tip increases the optical thickness of the biosensor tip and generates a wavelength shift (expressed in nm). According to such an assay, the IL-19 receptor (i.e., IL-20R1) is expressed in a membrane-free manner (e.g., in an Fc-fusion, e.g., IL20Rbeta Fc chimeric protein from R&D Systems catalog 1788-IR-050). AMQ or anti-rabbit conjugate biosensors (ForteBio) are used to immobilize the anti-IL-19 antibodies of interest (M_1, M_2, M_3, M_5, and R_39). The immobilized antibody is then incubated with recombinant human IL-19 protein diluted to 100 nM using HBS-EP+ running buffer (GE Healthcare, 10 mM Hepes pH 7.4 + 150 mM NaCl + 3 mM EDTA + 0.05% surfactant P20) for 240-300 seconds. Human IL-19 is assessed by binding to the anti-IL-19 antibody followed by incubation for 240-300 seconds with human IL-20R beta Fc fusion protein. The ability of the antibody to block or neutralize binding of the IL-19 ligand to the soluble receptor is observed as a minimal (<0.025 nm) increase in wavelength during this step of the assay. The results are provided in Table 6. [Table 6]

[0054] Another method for assessing neutralization of IL-19 by the antibodies of the invention includes adding such antibodies preincubated with human IL-19 to human keratinocytes. Exogenous IL-19 to human keratinocytes induces expression of additional IL-19 as well as other inflammatory molecules such as IL-8, CCL20, and S100A7. After preincubation of the antibody and IL-19 (e.g., 1 hour at 4°C), the antibody-IL-19 mixture is added to cultured human keratinocytes. The cells are then cultured for 1-48 hours, and one or more of IL-19, IL-8, CCL20, and S100A7 (or other molecules expressed downstream of IL-19) in the supernatant is measured, for example, by ELISA (alternatively, the mRNA of the downstream molecule can be measured). Antibody-inhibited IL-19 function indicates reduced expression of the downstream molecule by cultured keratinocytes.

[0055] The PathHunter® eXpress IL20RA / IL20RB Dimerization Assay (DiscoverX product code 93-1027E3) is used to evaluate the ability of the exemplary antibodies to block binding of human IL-19 recombinant protein in a cell-based assay format. This assay detects ligand-induced dimerization of the two subunits of a receptor-dimer pair. Cells are designed to co-express one receptor subunit fused to an enzyme donor and a second dimer partner fused to an enzyme acceptor. Binding of an agonist to one receptor subunit induces it to interact with its dimer partner, forcing the complementation of the two enzyme fragments, resulting in the formation of a functional enzyme that hydrolyzes a substrate and generates a chemiluminescent signal. Briefly, cells are seeded at 2500 cells per well and incubated at 37°C / 5% CO. 2 After 4 hours of incubation at 4°C / 5% CO, human IL-19 recombinant protein premixed with various concentrations of exemplary antibodies (M_1 and M_5) ranging from 10 to 0.00001 μg / ml, including a buffer only control, is added. Human IL-19 recombinant protein with or without the exemplary antibody mix is ​​then incubated with the cells at 37°C / 5% CO 2The cells are incubated at 4° C. overnight. Substrate buffer is added to the cells and incubated in the dark at room temperature for 1 hour prior to luminescence detection. The concentrations of exemplary antibodies that result in 50% inhibition of signal (IC50) and maximum signal inhibition percentage (% inhibition) are tabulated for eight experiments with standard error of the mean (SEM) shown below. Results are provided in Table 7. [Table 7]

[0056] IL-19 assay Psoriasis vulgaris is currently measured based on the assessment of total body surface area (BSA) scale, and / or the assessment of the degree of erythema, thickness and extent of psoriatic lesions (PASI). However, given the subjective input required by these methods, they may not be linear depending on the severity of skin lesions. No single blood-derived marker capable of assessing overall psoriasis activity has been identified. Thus, a more objective and reproducible method for determining severity is desirable. The present invention provides a sensitive and specific assay for measuring IL-19 levels in patient samples such as blood, serum, and plasma. As shown herein, the IL-19 assay of the present invention provides an accurate diagnostic tool for treatment response (i.e., predictive biomarker), disease recurrence (i.e., prognostic biomarker), disease onset, and disease severity in patients with moderate to severe Ps0.

[0057] According to exemplary embodiments, a sandwich ELISA assay for sensitive detection of IL-19 is provided herein. The assay utilizes an exemplary IL-19 antibody of the present invention, e.g., as described in Table 1, 2, or 3. According to exemplary embodiments, a first IL-19 antibody (selected from Table 1, 2, or 3) is utilized as an IL-19 capture antibody, and a second IL-19 antibody (selected from Table 1, 2, or 3) is utilized as an IL-19 reporter antibody. In some embodiments, the first and second IL-19 antibodies are selected from distinct epitope bins (e.g., in a specific embodiment, exemplary IL-19 antibody M_1 is paired with exemplary IL-19 antibody M_2). According to some embodiments, 1 milligram of a first IL-19 antibody (capture antibody) is biotinylated using the Pierce Biotinylation Kit (Cat. No.) and 1 milligram of a second IL-19 antibody (reporter antibody) is labeled with ruthenium using the MesoScale Discovery (MSD) kit for electrochemiluminescence (ECL) detection. According to such embodiments, the labeled antibodies are evaluated using MALDI-TOF to ensure suitable labeling, then diluted in 50% glycerol and stored at -20°C prior to use.

[0058] Streptavidin-coated 96-well MSD plates are washed three times with TBST (Tris-buffered saline containing 10 mmol / L Tris pH 7.40, 150 mmol / L NaCl with 1 mL Tween 20 / L) and then blocked with TBS-T+1% BSA for 1 hour at room temperature. The plates are washed again and then the wells are incubated with biotinylated IL-19 capture antibody (1 mg / L) for 1 hour. The plates are then washed again before testing patient samples.

[0059] During testing of patient samples, a standard curve is generated using 50 µL of recombinant human IL-19 control standard (serialized diluted IL-19 recombinant protein ranging from 100 to 0.0001 ng / L in assay buffer of 50 mmol / L HEPES, pH 7.40, 150 mmol / L NaCl, 10 µL / L Triton X-100, 5 mmol / L EDTA, and 5 mmol / L EGTA, as well as a zero blank). Data from 10 separate standard curves prepared as described herein are analyzed using a 10 -1 pg / mL~10 5 The dynamic range of IL-19 in pg / mL is shown (providing high sensitivity and wide dynamic range in the therapeutic and diagnostic assays provided herein). Patient samples (which may include blood, serum, or plasma according to the present invention) are diluted 1:4 in assay buffer and added to each well. The plate is incubated overnight at 4°C. After incubation, the wells are aspirated and washed three times with TBST. 50 μL of ruthenium-labeled IL-19 detection antibody (0.5 mg / L) is then added to the wells for incubation at room temperature for 1 hour. After incubation, the wells are aspirated and washed three times with TBST. 150 μl of 2X MSD read buffer is then added. Ruthenium electrochemiluminescence in the wells is detected using an MSD Sector 6000 plate reader. Data is analyzed and calibration curve fitting of the IL-19 MSD immunoassay is performed using MesoScale Discovery software. SAS® software version 9.4 (PROC MIXED) uses the unstructured covariance matrix and log 10 A mixed-effects model with transformed IL-19 concentrations (SAS version 9.4 for UNIX, SAS Institute Inc.: Cary, NC, 2016) is used to evaluate the effect of treatment on IL-19 levels. Statistical analyses are generated using the R version 3.3.3 statistical computing environment (www.R-project.org, Vienna, Austria, 2017) with the ggplot and pROC packages.

[0060] IL-19 serum concentrations in Ps0 patients versus healthy groups A study of IL-19 levels in the serum of 125 Ps0 patients prior to treatment was compared to IL-19 serum levels of 36 healthy volunteer samples. Using an IL-19 assay essentially as described above, the serum IL-19 concentration (pg / ml) of each patient sample is measured with a capture antibody selected from bin 1 (specifically, an exemplary IL-19 antibody M_1), and a detection antibody selected from bin 2 (specifically, an exemplary IL-19 antibody M_2). The geometric mean of serum IL-19 concentrations of healthy volunteers (n=36) is measured at 11 pg / mL (range 4-51 pg / mL, and 95% confidence level below 21 pg / mL), while the geometric mean of serum IL-19 concentrations of Ps0 patients (pre-treatment) (n=112) is measured at 87 pg / mL. Thus, the present invention provides an IL-19 blood-based assay that allows for the diagnosis of Ps0 patients.

[0061] PS0 study in anti-IL-17 treatment group A study of IL-19 levels in the serum of 125 Ps0 patients treated with the therapeutic antibody ixekizumab targeting IL-17 is conducted. The study includes five treatment arms of doses of 10 mg (n=24), 25 mg (n=23), 75 mg (n=26), or 150 mg (n=28) ixekizumab or placebo (n=24). Administration of all treatment doses is subcutaneous, with doses administered starting at week 0 and every two weeks thereafter through week 16 (inclusive). Using the IL-19 assay described above, with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1), and a detection antibody selected from bin 5 (specifically, exemplary IL-19 antibody M_2), each patient's serum IL-19 concentration (pg / ml) is measured at weeks 0 (pretreatment administration), 2, and 12. Serum IL-19 concentration levels, PASI percent change, and PASI 75 responses are provided in Tables 8-10.

[0062] As shown, 36 of 41 (87.8%) patients with ≥5-fold reduction in IL-19 from weeks 0 to 2 achieved PASI 75 or higher by week 16 (whereas only 24 of 56 (42.9%) patients with <5-fold reduction in IL19 from weeks 0 to 2 achieved a PASI 75 response by week 16). Additionally, 37 of 42 (88%) patients with ≥5-fold reduction in IL-19 from weeks 0 to 9 achieved PASI 75 or higher by week 12 (whereas only 22 of 53 (41.5%) patients with <5-fold reduction in IL19 from weeks 0 to 16 achieved a PASI 75 response by week 16 (data reflect two patients who withdrew from weeks 2 to 12). No significant changes in IL-19 concentrations were observed during the 16-week study period for the placebo treatment group. [Table 8] Table 8 provides data showing IL-19 measured in treatment groups over 16 weeks of treatment with placebo or various ixekizumab doses. [Table 9] Table 9 provides the number of patients by treatment group who achieved PASI 75 by week 16. [Table 10]

[0063] Table 10 presents the correlation between IL-19 serum levels and PASI in psoriasis patients after 16 weeks of placebo or various ixekizumab treatments (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects). The improvement in PASI 100 at 16 weeks was noted following a prior reduction in circulating IL-19 to near-normal concentrations after 2 weeks of treatment.

[0064] The data provided in Tables 8-10 demonstrate that the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of Ps0 patients treated with IL-17 antibodies.

[0065] PS0 study in anti-TNFα treatment group A study of IL-19 levels in the serum of 35 Ps0 patients who were complete responders when treated with the FDA-approved TNFα antagonist entanercept was conducted. Treatment groups are compared with 50 mg etanercept (n=35) or placebo administered every other week. Administration of both treatment groups is subcutaneous. Using the IL-19 assay described above, serum IL-19 concentrations (pg / ml) of each patient are measured at weeks 0 (pretreatment administration), 1, 4, and 12 with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1) and a detection antibody selected from bin 2 (specifically, exemplary IL-19 antibody M_2). IL-19 levels are evaluated for prognostic value with improvement in PASI at weeks 4 and 12. Serum IL-19 concentration levels are presented in Table 11. Prognostic values ​​at week 4 showing the correlation between IL-19 serum levels and PASI in psoriasis patients (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects) are presented in Table 12. Prognostic values ​​at week 12 showing the correlation between IL-19 serum levels and PASI in psoriasis patients (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects) are presented in Table 13. [Table 11] [Table 12] [Table 13]

[0066] As noted above, patients treated with TNF antagonists experienced, on average, a median decrease in serum IL-19 of over 40 pg / mL after 1 week and a median decrease in serum IL-19 of over 70 pg / mL at week 4. The data provided in Tables 11-13 demonstrate that the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of Ps0 patients treated with TNFα antibodies.

[0067] PS0 study in anti-IL-23 treatment group A study of IL-19 levels in the serum of Ps0 patients treated with the therapeutic antibody mirikizumab targeting IL-23 is conducted. Eight treatment arms are evaluated: 5 mg, 20 mg, 60 mg, 120 mg, 200 mg, 350 mg, 600 mg of mirikizumab or placebo. Administration of each treatment arm is on day 0 as a single subcutaneous dose. Using the IL-19 assay described above, serum IL-19 concentrations (pg / ml) of each patient are measured during visits 2-12 with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1), and a detection antibody selected from bin 2 (specifically, exemplary IL-19 antibody M_2). IL-19 levels are also evaluated for prognostic value with improvement in PASI during visits 2-12. Serum IL-19 concentration levels are presented in Table 14. Comparison of serum levels at week 8 is presented in Table 15. And the prognostic values ​​at week 8 showing the correlation of IL-19 serum levels and PASI in psoriasis patients (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects) are presented in Table 16. The reduction in serum IL-19 correlating with the improvement in PASI score showing the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of Ps0 patients treated with IL-23 antibodies. [Table 14] [Table 15] [Table 16]

[0068] Ps0 study in JAK1 and JAK2 kinase inhibitor treatment groups A study of IL-19 levels in the serum of Ps0 patients treated with the therapeutic selective JAK1 and JAK2 inhibitor baricitinib is conducted. Treatment groups of 2 mg, 4 mg, 8 mg, and 10 mg of baricitinib or placebo are evaluated. Each treatment group is administered orally once daily. Using the IL-19 assay described above, serum IL-19 concentrations (pg / ml) of each patient are measured at baseline and after each treatment with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1) and a detection antibody selected from bin 2 (specifically, exemplary IL-19 antibody M_2). IL-19 levels are also evaluated for prognostic value with improvement in PASI. Serum IL-19 concentration levels are presented in Table 17. PASI prognostic data (week 12) showing the correlation between IL-19 serum levels and PASI in psoriasis patients (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects) are presented in Table 18. The data show that the reduction in serum IL-19 correlating with the improvement in PASI scores indicating the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of Ps0 patients treated with JAK1 and JAK2 inhibitors. [Table 17] [Table 18]

[0069] AD study in JAK1 and JAK2 kinase inhibitor treatment groups A study of IL-19 levels in serum of 123 patients with moderate to severe atopic dermatitis treated with the therapeutic selective JAK1 and JAK2 inhibitor baricitinib is conducted. Treatment groups of 2 mg and 4 mg baricitinib or placebo are compared. Each treatment group is orally administered once daily. Using the IL-19 assay described above, serum IL-19 concentrations (pg / ml) of each patient are measured at baseline (before treatment), and at weeks 4 and 16 with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1) and a detection antibody selected from bin 2 (specifically, exemplary IL-19 antibody M_2). IL-19 levels are evaluated for prognostic value with improvement in EASI score. Serum IL-19 concentration levels are presented in Table 19. The prognostic value of EASI (week 16) showing correlation of IL-19 serum levels in AD patients (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects) is presented in Table 20. The data show that baseline IL-19 concentrations in AD patients were found to be elevated compared to normal (geometric mean of AD patients was 34 pg / mL). The data also show that the reduction in serum IL-19 at weeks 4 and 16 correlating with improvement in EASI score at week 16 showing the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of Ps0 patients treated with JAK1 and JAK2 inhibitors. [Table 19] [Table 20]

[0070] IL-19 serum concentrations in patients with renal failure and diabetes IL-19 levels are measured in healthy donors (n=20), renal failure patients (n=16), diabetic patients without renal failure (n=20), and diabetic patients with renal failure (n=21). Using the IL-19 assay described above, baseline serum IL-19 concentrations (pg / ml) for each patient are measured with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1) and a detection antibody selected from bin 2 (specifically, exemplary IL-19 antibody M_2). The data show that IL-19 levels are significantly elevated in renal failure patients (40±6pg / mL), diabetic patients without renal failure (17±3pg / mL), and diabetic patients with renal failure (46±9pg / mL) compared to healthy donors (8±1pg / mL). Thus, the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of diabetic and renal failure patients.

[0071] PsA study in anti-IL-17 treatment group A study of IL-19 levels in the serum of 309 PsA patients treated with the therapeutic antibody ixekizumab targeting IL-17 will be conducted. The study will include three treatment arms: (i.) an anti-IL-17 treatment arm, receiving 160 mg of ixekizumab at baseline followed by 80 mg doses every 2 weeks thereafter for 12 weeks (n=103), (ii.) an anti-IL-17 treatment arm, receiving 160 mg of ixekizumab at baseline followed by 80 mg doses every 4 weeks thereafter for 12 weeks (n=107), or (iii.) placebo (n=105). Administration of all treatment doses will be subcutaneous. Using the IL-19 assay described above, with a capture antibody selected from bin 1 (specifically, exemplary IL-19 antibody M_1) and a detection antibody selected from bin 2 (specifically, exemplary IL-19 antibody M_2), each patient's serum IL-19 concentration (pg / ml) is measured at weeks 0 (pre-treatment administration), 4, and 12. Serum IL-19 concentration levels are presented in Table 21. PASI prognostic values ​​at weeks 4 and 12 showing the correlation of IL-19 serum levels and PASI in patients (21 ng / L represents the upper limit of the normal range for IL-19 in healthy subjects) are presented in Tables 22 and 23, respectively. [Table 21] [Table 22] [Table 23]

[0072] Table 21 shows that baseline IL-19 levels in psoriatic arthritis patients are increased compared to the reference values ​​in healthy volunteers (represented by the shaded grey area). Placebo treatment does not result in significant changes in IL-19 over the 12-week study. However, both ixekizumab treatment groups show a reduction in IL-19 to near-normal levels after 4 weeks, and this reduction is sustained over 12 weeks of treatment. Tables 22 and 23 show the relationship between IL-19 levels and 12-week PASI scores in PsA patients in either placebo or ixekizumab treatment groups after 4 or 12 weeks. Improvement in PASI 100 at 12 weeks correlated with a reduction in circulating IL-19 concentrations to near-normal levels, with the majority of poor PASI responders in the placebo group. The data provided in Tables 21-23 show that the IL-19 assay of the present invention provides a valuable tool for the diagnosis and therapeutic prognosis of PsA patients treated with IL-17 antibodies.

[0073] Sequence Listing SEQ ID NO:1 (human IL-19) MKLQCVSLWLLGTILILCSVDNHGLRRCLISTDMHHIEESFQEIKRAIQAKDTFPNVTILSTLETLQIIKPLDVCCVTKNLLAFYVDRVFKDHQEPNPKILRKISSIANSFLYMQKTLRQCQEQRQCHCRQEATNATRVIHDNYDQLEVHAAAIKSLGELDVFLAWINKNHEVMFSA

[0074] SEQ ID NO:2 (LC of mouse-derived IL-19 Ab 1 ("M_1")) DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLSSYNQKNYLAWYQQKPGQSPKLLVYFASTRPPGVPDRFIGSGSGSDFTLTISSVQAEDLADYFCQQHERLPITFGAGTKL ELKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0075] SEQ ID NO:3 (LCDR1 of mouse-derived IL-19 Ab 1) KSSQSLLSSYNQKNYLA

[0076] SEQ ID NO: 4 (LCDR2 of mouse-derived IL-19 Ab 1) FASTRPP

[0077] SEQ ID NO:5 (LCDR3 of mouse-derived IL-19 Ab 1) QQHERLPIT

[0078] SEQ ID NO:6 (HC of mouse-derived IL-19 Ab 1 ("M_1")) EVQLQQSGPVLVKPGASVKMSCKASGYKFTDYFVGWVKQSHGKSLEWIGYVDPENGYTRCNQKFKGKATLTVDKSSSTAYMELNSLTSEDSAVYYCARYDYDWAWFTNWG QGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDC GCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTI SKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK

[0079] SEQ ID NO: 7 (HCDR1 of mouse-derived IL-19 Ab 1) GYKFTDYFVG

[0080] SEQ ID NO:8 (HCDR2 of mouse-derived IL-19 Ab 1) YVDPENGYTRCNQKFKG

[0081] SEQ ID NO: 9 (HCDR3 of mouse-derived IL-19 Ab 1) YDYDWAWFTN

[0082] SEQ ID NO:10 (LC of mouse-derived IL-19 Ab 2 ("M_2")) DIVLTQSPESLAVSLGQRATISCRASESVDNYGISFIHWYQQKPGQPPKLLIYRASNLKSGIPARFSGRGSRTDFTLTINPVETDDVATYYCQQINKDPLTFGAGTKLE LKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0083] SEQ ID NO: 11 (LCDR1 of mouse-derived IL-19 Ab 2) RASESVDNYGISFIH

[0084] SEQ ID NO: 12 (LCDR2 of mouse-derived IL-19 Ab 2) RASNLKS

[0085] SEQ ID NO: 13 (LCDR3 of mouse-derived IL-19 Ab 2) QQINKDPLT

[0086] SEQ ID NO: 14 (HC of mouse-derived IL-19 Ab 2 ("M_2")) LVQLQQSDAELVKPGASLKISCKVSGYTFTDHALHWMKQRPEQGLEWIGYIYPRDGSTKYNEKFKGKATLTADRSSSTAYMELNSLTSEDSAVYFCARGWDFAMDYWGQG TSVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCG CKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTI SKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK

[0087] SEQ ID NO: 15 (HCDR1 of mouse-derived IL-19 Ab 2) GYTFTDHALH

[0088] SEQ ID NO: 16 (HCDR2 of mouse-derived IL-19 Ab 2) YIYPRDGSTKYNEKFKG

[0089] SEQ ID NO: 17 (HCDR3 of mouse-derived IL-19 Ab 2) GWDFAMDY

[0090] SEQ ID NO: 18 (LC of mouse-derived IL-19 Ab 3 ("M_3")) DIKMTQSPSSMYASLGERVTITCKASQDINSYLSWFQQKPGKSPKTLIYRANRLVDGVPSRFSGSGSGQDYSLTISSLEYEDMGIYFCLQYDDFPYTFGGGTKLEIK RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0091] SEQ ID NO: 19 (LCDR1 of mouse-derived IL-19 Ab 3) KASQDINSYLS

[0092] SEQ ID NO: 20 (LCDR2 of mouse-derived IL-19 Ab 3) RANRLVD

[0093] SEQ ID NO: 21 (LCDR3 of mouse-derived IL-19 Ab 3) LQYDDFPYT

[0094] SEQ ID NO:22 (HC of mouse-derived IL-19 Ab 3 ("M_3")) QIQLVQSGPELKKPGETVKISCKASGYTFTTYGMSWVKQAPGKGLKWMVWINTYSGVPTYVDDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARRDEGFAYWGQGT LVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGC KPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPMHQDWLNGKEFKCRVNSAAFPAPIEKTIS KTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK

[0095] SEQ ID NO: 23 (HCDR1 of mouse-derived IL-19 Ab 3) GYTFTTYGMS

[0096] SEQ ID NO: 24 (HCDR2 of mouse-derived IL-19 Ab 3) WINTYSGVPTYVDDFKG

[0097] SEQ ID NO: 25 (HCDR3 of mouse-derived IL-19 Ab 3) RDEGFAY

[0098] SEQ ID NO:26 (LC of mouse-derived IL-19 Ab 4 ("M_4")) DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLSSYNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPDRFIGSGSGSDFTLTISSVQAEDLADYFCQQHYSTPLTFGAGTKL ELKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0099] SEQ ID NO: 27 (LCDR1 of mouse-derived IL-19 Ab 4) KSSQSLLSSYNQKNYLA

[0100] SEQ ID NO: 28 (LCDR2 of mouse-derived IL-19 Ab 4) FASTRES

[0101] SEQ ID NO: 29 (LCDR3 of mouse-derived IL-19 Ab 4) QQHYSTPLT

[0102] SEQ ID NO:30 (HC of mouse-derived IL-19 Ab 4 ("M_4")) EVQLQQSGPVLVKPGASVKMSCKASGYTFTDYYMNWVKQSHGKSLEWIGFINPYNDDTRCNQKFKGKATLTVDKSSSTAYMELNSLTSEDSAVYYCARYDGYWAWFAYWG QGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDC GCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTI SKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK

[0103] SEQ ID NO: 31 (HCDR1 of mouse-derived IL-19 Ab 4) GYTFTDYYMN

[0104] SEQ ID NO: 32 (HCDR2 of mouse-derived IL-19 Ab 4) FINPYNDDTRCNQKFKG

[0105] SEQ ID NO: 33 (HCDR3 of mouse-derived IL-19 Ab 4) YDGYWAWFAY

[0106] SEQ ID NO:34 (LCVR of rabbit-derived IL-19 Ab 1 ("R_1")) AIDMTQTPASVSEPVGGTVTIKCQASQSISSYLAWYQQKPGQPPKLLIYSASTLASGVPSRFRGSGSGREFTLTISDLECADAATYYCQCHYHGSSYWDNSFGGGTEVVVK

[0107] SEQ ID NO: 35 (LCDR1 of rabbit-derived IL-19 Ab 1) QASQSISSYLA

[0108] SEQ ID NO: 36 (LCDR2 of rabbit-derived IL-19 Ab 1) SASTLAS

[0109] SEQ ID NO: 37 (LCDR3 of rabbit-derived IL-19 Ab 1) QCHYHGSSYWDNS

[0110] SEQ ID NO:38 (HCVR of rabbit-derived IL-19 Ab 1 ("R_1")) QQLEESGGGLVQPEGSLTLTCTASGFSFSSSYWICWVRQAPGKGLEWLACIDTGVSGDTYYANWAEGRFTISKTSSTTVTLQMTSLTAADTATYFCARDIFGSAIDNSLWGPGTLVTVSS

[0111] SEQ ID NO: 39 (HCDR1 of rabbit-derived IL-19 Ab 1) GFSFSSSYWIC

[0112] SEQ ID NO: 40 (HCDR2 of rabbit-derived IL-19 Ab 1) CIDTGVSGDTYYANWAEG

[0113] SEQ ID NO: 41 (HCDR3 of rabbit-derived IL-19 Ab 1) DIFGSAIDNSL

[0114] SEQ ID NO: 42 (LCVR of rabbit-derived IL-19 Ab 2 ("R_2")) ADVVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYDASKLASGVPSRFKGSGSGTQFTLTISDLECADAATYYCQCHYHGSSYWDNSFGGGTEVVVK

[0115] SEQ ID NO: 43 (LCDR1 of rabbit-derived IL-19 Ab 2) QASESIGNALA

[0116] SEQ ID NO: 44 (LCDR2 of rabbit-derived IL-19 Ab 2) DASKLAS

[0117] SEQ ID NO: 45 (LCDR3 of rabbit-derived IL-19 Ab 2) QCHYHGSSYWDNS

[0118] SEQ ID NO: 46 (HCVR of rabbit-derived IL-19 Ab 2 ("R_2")) QQLEESGGGLVQPEGSLTLTCTASGFSFSSSYWICWVRQAPGKGLEWLACIDTGVSGDTYYANWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARDIFGSAIDNSLWGPGTLVTVSS

[0119] SEQ ID NO: 47 (HCDR1 of rabbit-derived IL-19 Ab 2) GFSFSSSYWIC

[0120] SEQ ID NO: 48 (HCDR2 of rabbit-derived IL-19 Ab 2) CIDTGVSGDTYYANWAKG

[0121] SEQ ID NO: 49 (HCDR3 of rabbit-derived IL-19 Ab 2) DIFGSAIDNSL

[0122] SEQ ID NO:50 (LCVR of rabbit-derived IL-19 Ab 4 ("R_3")) ADVVMTQTPSSVEAAVGGTVTIKCQASQSIGSSLAWYQQKPGQRPKLLIYGASTLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQCHYHGSSYWDNSFGGGTEVVVK

[0123] SEQ ID NO:51 (LCDR1 of rabbit-derived IL-19 Ab 3) QASQSIGSSLA

[0124] SEQ ID NO:52 (LCDR2 of rabbit-derived IL-19 Ab 3) GASTLAS

[0125] SEQ ID NO:53 (LCDR3 of rabbit-derived IL-19 Ab 3) QCHYHGSSYWDNS

[0126] SEQ ID NO:54 (HCVR of rabbit-derived IL-19 Ab 4 ("R_3")) QCQSLEESGGGLVEPEGSLTLTCKASGFSFSSSYWICWVRQAPGKGLEWIACTDTFSGDTYYASWAKGRFTISKTSSTTVTLRMTSLTDADTATYFCARDIFGTAVHISLWGPGTLVTVSS

[0127] SEQ ID NO:55 (HCDR1 of rabbit-derived IL-19 Ab 3) GFSFSSSYWIC

[0128] SEQ ID NO:56 (HCDR2 of rabbit-derived IL-19 Ab 3) CTDTFSGDTYYASWAKG

[0129] SEQ ID NO:57 (HCDR3 of rabbit-derived IL-19 Ab 3) DIFGTAVHISL

[0130] SEQ ID NO:58 (LCVR of rabbit-derived IL-19 Ab 5 ("R_4")) ADVVMTQTPSSVSEPVGGTVTIKCQASQSIYSYLSWYQQKPGQPPKLLIYEASKLASGVPSRFKGSGSGTQFTLTISGVECADAATYYCQQGYSSSNVDNTFGGGTEVVVT

[0131] SEQ ID NO:59 (LCDR1 of rabbit-derived IL-19 Ab 4) QASQSIYSYLS

[0132] SEQ ID NO: 60 (LCDR2 of rabbit-derived IL-19 Ab 4) EASKLAS

[0133] SEQ ID NO: 61 (LCDR3 of rabbit-derived IL-19 Ab 4) QQGYSSSNVDNT

[0134] SEQ ID NO:62 (HCVR of rabbit-derived IL-19 Ab 5 ("R_4")) QCQSVEESGGRLVTPGTPLTLTCTVSGIDLSIYAMGWVRQAPGKGLEYIGIIDTTGTAYYARWAKGRFTISKTSATVALKITSPTTEDTATYFCARDSGSLYYGSYALWGPGTLVTVSS

[0135] SEQ ID NO: 63 (HCDR1 of rabbit-derived IL-19 Ab 4) GIDLSIYAMG

[0136] SEQ ID NO: 64 (HCDR2 of rabbit-derived IL-19 Ab 4) IIDTTGTAYYARWAKG

[0137] SEQ ID NO: 65 (HCDR3 of rabbit-derived IL-19 Ab 4) DSGSLYYGSYAL

[0138] SEQ ID NO:66 (LCVR of phage-derived IL-19 Ab 1 ("P_1")) EIVMTQSPGTLSLSPGERATLSCRASQSISSGYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFATYYCLQFKSFPLTFGQGTKLEIKR

[0139] SEQ ID NO: 67 (LCDR1 of phage-derived IL-19 Ab 1) RASQSISSGYLA

[0140] SEQ ID NO: 68 (LCDR2 of phage-derived IL-19 Ab 1) GASSRAT

[0141] SEQ ID NO: 69 (LCDR3 of phage-derived IL-19 Ab 1) LQFKSFPLT

[0142] SEQ ID NO:70 (HCVR of phage-derived IL-19 Ab 1 ("P_1")) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDGGDYGDMGYWGQGTLVTVSS

[0143] SEQ ID NO: 71 (HCDR1 of phage-derived IL-19 Ab 1) GGTFSSYAIS

[0144] SEQ ID NO: 72 (HCDR2 of phage-derived IL-19 Ab 1) GIIPIFGTANYAQKFQG

[0145] SEQ ID NO: 73 (HCDR3 of phage-derived IL-19 Ab 1) DGGDYGDMGY

[0146] SEQ ID NO:74 (LCVR of phage-derived IL-19 Ab 2 ("P_2")) EIVMTQSPDSLAVSLGERATINCKSSQSVLYRSNSKSYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPGSFGPGTKVEIKR

[0147] SEQ ID NO: 75 (LCDR1 of phage-derived IL-19 Ab 2) KSSQSVLYRSNSKSYLA

[0148] SEQ ID NO: 76 (LCDR2 of phage-derived IL-19 Ab 2) WASTRES

[0149] SEQ ID NO: 77 (LCDR3 of phage-derived IL-19 Ab 2) QQYYSTPGS

[0150] SEQ ID NO:78 (HCVR of phage-derived IL-19 Ab 2 ("P_2")) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISQSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHPERGSRRGPYYYYMDVWGKGTTVTVSS

[0151] SEQ ID NO: 79 (HCDR1 of phage-derived IL-19 Ab 2) GFTFSSYAMS

[0152] SEQ ID NO:80 (HCDR2 of phage-derived IL-19 Ab 2) AISQSGGSTYYADSVKG

[0153] SEQ ID NO: 81 (HCDR3 of phage-derived IL-19 Ab 2) HPERGSRRGPYYYYMDV

[0154] SEQ ID NO:82 (LCVR of phage-derived IL-19 Ab 3 ("P_3")) DIQLTQSPSSLSASLGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYYDYSPWAFGQGTKLEIKR

[0155] SEQ ID NO: 83 (LCDR1 of phage-derived IL-19 Ab 3) RASQGISSWLA

[0156] SEQ ID NO: 84 (LCDR2 of phage-derived IL-19 Ab 3) AASTLQS

[0157] SEQ ID NO: 85 (LCDR3 of phage-derived IL-19 Ab 3) QQYYDYSPWA

[0158] SEQ ID NO:86 (HCVR of phage-derived IL-19 Ab 3 ("P_3")) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGLSLLYYDLSENYFDYWGQ GTTVTVSS

[0159] SEQ ID NO: 87 (HCDR1 of phage-derived IL-19 Ab 3) GFTFSSYAMS

[0160] SEQ ID NO: 88 (HCDR2 of phage-derived IL-19 Ab 3) AISGSGGSTYYADSVKG

[0161] SEQ ID NO: 89 (HCDR3 of phage-derived IL-19 Ab 3) GLSLLYYDLSENYFDY

[0162] SEQ ID NO: 90 (LCDR1 of rabbit-derived IL-19 Ab 5) QASQSIYSYLS

[0163] SEQ ID NO: 91 (LCDR2 of rabbit-derived IL-19 Ab 5) EASKLAS

[0164] SEQ ID NO: 92 (LCDR3 of rabbit-derived IL-19 Ab 5) QQGYSSSNVDNT

[0165] SEQ ID NO: 93 (HCDR1 of rabbit-derived IL-19 Ab 5) GIDLSIYAMG

[0166] SEQ ID NO: 94 (HCDR2 of rabbit-derived IL-19 Ab 5) IIDTTGTAYYARWAKG

[0167] SEQ ID NO: 95 (HCDR3 of rabbit-derived IL-19 Ab 5) DSGSLYYGSYAL

[0168] SEQ ID NO: 96 (LCDR1 of rabbit-derived IL-19 Ab 6) QASESIYSSLA

[0169] SEQ ID NO: 97 (LCDR2 of rabbit-derived IL-19 Ab 6) GASTLAS

[0170] SEQ ID NO: 98 (LCDR3 of rabbit-derived IL-19 Ab 6) QCHYHGSSYWDNS

[0171] SEQ ID NO: 99 (HCDR1 of rabbit-derived IL-19 Ab 6) GFSFSSSYWIC

[0172] SEQ ID NO: 100 (HCDR2 of rabbit-derived IL-19 Ab 6) CTDTFSGDTYYASWAKG

[0173] SEQ ID NO: 101 (HCDR3 of rabbit-derived IL-19 Ab 6) DIFGTAVHISL

[0174] SEQ ID NO: 102 (LCDR1 of rabbit-derived IL-19 Ab 7) QASESIYSSLA

[0175] SEQ ID NO: 103 (LCDR2 of rabbit-derived IL-19 Ab 7) GASTLAS

[0176] SEQ ID NO: 104 (LCDR3 of rabbit-derived IL-19 Ab 7) QCHYHGSSYWDNS

[0177] SEQ ID NO: 105 (HCDR1 of rabbit-derived IL-19 Ab 7) GFSFSSSYWIC

[0178] SEQ ID NO: 106 (HCDR2 of rabbit-derived IL-19 Ab 7) CTDTFSGDTYYASWAKG

[0179] SEQ ID NO: 107 (HCDR3 of rabbit-derived IL-19 Ab 7) DIFGTAVHISL

[0180] SEQ ID NO: 108 (LCDR1 of rabbit-derived IL-19 Ab 8) QASQSIGSSLA

[0181] SEQ ID NO: 109 (LCDR2 of rabbit-derived IL-19 Ab 8) GASTLAS

[0182] SEQ ID NO: 110 (LCDR3 of rabbit-derived IL-19 Ab 8) QCHYHGSSYWDNS

[0183] SEQ ID NO: 111 (HCDR1 of rabbit-derived IL-19 Ab 8) GFSFSSSYWIC

[0184] SEQ ID NO: 112 (HCDR2 of rabbit-derived IL-19 Ab 8) CTDTFSGDTYYASWAKG

[0185] SEQ ID NO: 113 (HCDR3 of rabbit-derived IL-19 Ab 8) DIFGTAVHISL

[0186] SEQ ID NO: 114 (LCDR1 of rabbit-derived IL-19 Ab 9) QASESIYSSLA

[0187] SEQ ID NO: 115 (LCDR2 of rabbit-derived IL-19 Ab 9) GASTLAS

[0188] SEQ ID NO: 116 (LCDR3 of rabbit-derived IL-19 Ab 9) QCHYHGSSYWDNS

[0189] SEQ ID NO: 117 (HCDR1 of rabbit-derived IL-19 Ab 9) GFSFSSSYWIC

[0190] SEQ ID NO: 118 (HCDR2 of rabbit-derived IL-19 Ab 9) CTDTFSGDTYYASWAKG

[0191] SEQ ID NO: 119 (HCDR3 of rabbit-derived IL-19 Ab 9) DIFGTAVHISL

[0192] SEQ ID NO: 120 (LCDR1 of rabbit-derived IL-19 Ab 10) QASQSISSYLA

[0193] SEQ ID NO: 121 (LCDR2 of rabbit-derived IL-19 Ab 10) GASTLAS

[0194] SEQ ID NO: 122 (LCDR3 of rabbit-derived IL-19 Ab 10) QCHYHGSSYWDNS

[0195] SEQ ID NO: 123 (HCDR1 of rabbit-derived IL-19 Ab 10) GFSFSSSYWIC

[0196] SEQ ID NO: 124 (HCDR2 of rabbit-derived IL-19 Ab 10) CTDTFSGDTYYASWAKG

[0197] SEQ ID NO: 125 (HCDR3 of rabbit-derived IL-19 Ab 10) DIFGTAVHISL

[0198] SEQ ID NO: 126 (LCDR1 of rabbit-derived IL-19 Ab 11) QASQSISSYLA

[0199] SEQ ID NO: 127 (LCDR2 of rabbit-derived IL-19 Ab 11) GASTLAS

[0200] SEQ ID NO: 128 (LCDR3 of rabbit-derived IL-19 Ab 11) QSAVYSSSSGYGVP

[0201] SEQ ID NO: 129 (HCDR1 of rabbit-derived IL-19 Ab 11) GFSLSSYDMS

[0202] SEQ ID NO: 130 (HCDR2 of rabbit-derived IL-19 Ab 11) IIDSIGSIWYANWAKG

[0203] SEQ ID NO: 131 (HCDR3 of rabbit-derived IL-19 Ab 11) ESGPINTDYDL

[0204] SEQ ID NO: 132 (LCDR1 of rabbit-derived IL-19 Ab 12) QTSESFYSNNILS

[0205] SEQ ID NO: 133 (LCDR2 of rabbit-derived IL-19 Ab 12) EASKLAS

[0206] SEQ ID NO: 134 (LCDR3 of rabbit-derived IL-19 Ab 12) QSAIYDGSYIVT

[0207] SEQ ID NO: 135 (HCDR1 of rabbit-derived IL-19 Ab 12) GFSLSSYDMS

[0208] SEQ ID NO: 136 (HCDR2 of rabbit-derived IL-19 Ab 12) IIDSIGSIWYANWAKG

[0209] SEQ ID NO: 137 (HCDR3 of rabbit-derived IL-19 Ab 12) ESGPINTDYDL

[0210] SEQ ID NO: 138 (LCDR1 of rabbit-derived IL-19 Ab 13) QASQSISSYLA

[0211] SEQ ID NO: 139 (LCDR2 of rabbit-derived IL-19 Ab 13) GASTLAS

[0212] SEQ ID NO: 140 (LCDR3 of rabbit-derived IL-19 Ab 13) QSAVYSSSSGYGVP

[0213] SEQ ID NO: 141 (HCDR1 of rabbit-derived IL-19 Ab 13) GFSLSSYDMS

[0214] SEQ ID NO: 142 (HCDR2 of rabbit-derived IL-19 Ab 13) IIDSIGSIWYANWAKG

[0215] SEQ ID NO: 143 (HCDR3 of rabbit-derived IL-19 Ab 13) ESGPINTDYDL

[0216] SEQ ID NO: 144 (LCDR1 of rabbit-derived IL-19 Ab 14) QASQSISSYLA

[0217] SEQ ID NO: 145 (LCDR2 of rabbit-derived IL-19 Ab 14) GASTLAS

[0218] SEQ ID NO: 146 (LCDR3 of rabbit-derived IL-19 Ab 14) QSAVYSSSSGYGVP

[0219] SEQ ID NO: 147 (HCDR1 of rabbit-derived IL-19 Ab 14) GFSLSSYDMS

[0220] SEQ ID NO: 148 (HCDR2 of rabbit-derived IL-19 Ab 14) IIDSIGSIWYANWAKG

[0221] SEQ ID NO: 149 (HCDR3 of rabbit-derived IL-19 Ab 14) ESGPINTDYDL

[0222] SEQ ID NO: 150 (LCDR1 of rabbit-derived IL-19 Ab 15) QASESISSYLA

[0223] SEQ ID NO: 151 (LCDR2 of rabbit-derived IL-19 Ab 15) GASTLAS

[0224] SEQ ID NO: 152 (LCDR3 of rabbit-derived IL-19 Ab 15) QGYFGDYIYG

[0225] SEQ ID NO: 153 (HCDR1 of rabbit-derived IL-19 Ab 15) GFSLTSYAMS

[0226] SEQ ID NO: 154 (HCDR2 of rabbit-derived IL-19 Ab 15) IIGSPGTTGYATWAKG

[0227] SEQ ID NO: 155 (HCDR3 of rabbit-derived IL-19 Ab 15) GWFYYGMAL

[0228] SEQ ID NO: 156 (LCDR1 of rabbit-derived IL-19 Ab 16) PXQEHLTP

[0229] SEQ ID NO: 157 (LCDR2 of rabbit-derived IL-19 Ab 16) GASTLAX

[0230] SEQ ID NO: 158 (LCDR3 of rabbit-derived IL-19 Ab 16) QGYFGDYIYG

[0231] SEQ ID NO: 159 (HCDR1 of rabbit-derived IL-19 Ab 16) GFSLTSYAMS

[0232] SEQ ID NO: 160 (HCDR2 of rabbit-derived IL-19 Ab 16) IIGSPGTTGYATWAKG

[0233] SEQ ID NO: 161 (HCDR3 of rabbit-derived IL-19 Ab 16) GWFYYGMAL

[0234] SEQ ID NO: 162 (LCDR1 of rabbit-derived IL-19 Ab 17) QASESISSYLA

[0235] SEQ ID NO: 163 (LCDR2 of rabbit-derived IL-19 Ab 17) GASTLAS

[0236] SEQ ID NO: 164 (LCDR3 of rabbit-derived IL-19 Ab 17) QGYFGDYIYG

[0237] SEQ ID NO: 165 (HCDR1 of rabbit-derived IL-19 Ab 17) GFSLTSYAMS

[0238] SEQ ID NO: 166 (HCDR2 of rabbit-derived IL-19 Ab 17) IIGSPGTTGYATWAKG

[0239] SEQ ID NO: 167 (HCDR3 of rabbit-derived IL-19 Ab 17) GWFYYGMAL SEQ ID NO: 168 (LCDR1 of rabbit-derived IL-19 Ab 18) QASESISSYLA

[0240] SEQ ID NO: 169 (LCDR2 of rabbit-derived IL-19 Ab 18) GASTLAS

[0241] SEQ ID NO: 170 (LCDR3 of rabbit-derived IL-19 Ab 18) QGYFGDYIYG

[0242] SEQ ID NO: 171 (HCDR1 of rabbit-derived IL-19 Ab 18) GFSLTSYAMS

[0243] SEQ ID NO: 172 (HCDR2 of rabbit-derived IL-19 Ab 18) IIGSPGTTGYATWAKG

[0244] SEQ ID NO: 173 (HCDR3 of rabbit-derived IL-19 Ab 18) GWFYYGMAL

[0245] SEQ ID NO: 174 (LCDR1 of rabbit-derived IL-19 Ab 19) QASESISSYLA

[0246] SEQ ID NO: 175 (LCDR2 of rabbit-derived IL-19 Ab 19) GASTLAS

[0247] SEQ ID NO: 176 (LCDR3 of rabbit-derived IL-19 Ab 19) QGYFGDYIYG

[0248] SEQ ID NO: 177 (HCDR1 of rabbit-derived IL-19 Ab 19) GFSLTSYAMS

[0249] SEQ ID NO: 178 (HCDR2 of rabbit-derived IL-19 Ab 19) IIGSPGTTGYATWAKG

[0250] SEQ ID NO: 179 (HCDR3 of rabbit-derived IL-19 Ab 19) GWFYYGMAL

[0251] SEQ ID NO: 180 (LCDR1 of rabbit-derived IL-19 Ab 20) QASESISSYLA

[0252] SEQ ID NO: 181 (LCDR2 of rabbit-derived IL-19 Ab 20) GASTLAS

[0253] SEQ ID NO: 182 (LCDR3 of rabbit-derived IL-19 Ab 20) QGYFGDYIYG

[0254] SEQ ID NO: 183 (HCDR1 of rabbit-derived IL-19 Ab 20) GFSLTSYAMS

[0255] SEQ ID NO: 184 (HCDR2 of rabbit-derived IL-19 Ab 20) IIGSPGTTGYATWAKG

[0256] SEQ ID NO: 185 (HCDR3 of rabbit-derived IL-19 Ab 20) GWFYYGMAL

[0257] SEQ ID NO: 186 (LCDR1 of rabbit-derived IL-19 Ab 21) QASQSISNYLS

[0258] SEQ ID NO: 187 (LCDR2 of rabbit-derived IL-19 Ab 21) WASNLAS

[0259] SEQ ID NO: 188 (LCDR3 of rabbit-derived IL-19 Ab 21) LGEFSCSSADCFA

[0260] SEQ ID NO: 189 (HCDR1 of rabbit-derived IL-19 Ab 21) GFDLSNYAMT

[0261] SEQ ID NO: 190 (HCDR2 of rabbit-derived IL-19 Ab 21) AIHGSGVTDCASWTRG

[0262] SEQ ID NO: 191 (HCDR3 of rabbit-derived IL-19 Ab 21) ESAGINTDYDL

[0263] SEQ ID NO: 192 (LCDR1 of rabbit-derived IL-19 Ab 22) QASQSISNYLS

[0264] SEQ ID NO: 193 (LCDR2 of rabbit-derived IL-19 Ab 22) WASNLAS

[0265] SEQ ID NO: 194 (LCDR3 of rabbit-derived IL-19 Ab 22) LGEFSCSSADCFA

[0266] SEQ ID NO: 195 (HCDR1 of rabbit-derived IL-19 Ab 22) GFDLSNYAMT

[0267] SEQ ID NO: 196 (HCDR2 of rabbit-derived IL-19 Ab 22) AIHGSGVTDCASWTRG

[0268] SEQ ID NO: 197 (HCDR3 of rabbit-derived IL-19 Ab 22) ESAGINTDYDL

[0269] SEQ ID NO: 198 (LCDR1 of rabbit-derived IL-19 Ab 23) QASKSIGSYLS

[0270] SEQ ID NO: 199 (LCDR2 of rabbit-derived IL-19 Ab 23) RASTLAS

[0271] SEQ ID NO: 200 (LCDR3 of rabbit-derived IL-19 Ab 23) QAYYGDYIYD

[0272] SEQ ID NO: 201 (HCDR1 of rabbit-derived IL-19 Ab 23) GFSLSSYPMS

[0273] SEQ ID NO: 202 (HCDR2 of rabbit-derived IL-19 Ab 23) IIGSTGSTGYANWAKG

[0274] SEQ ID NO: 203 (HCDR3 of rabbit-derived IL-19 Ab 23) GWFYYGLDL

[0275] SEQ ID NO: 204 (LCDR1 of rabbit-derived IL-19 Ab 24) QASQSIGSYLS

[0276] SEQ ID NO: 205 (LCDR2 of rabbit-derived IL-19 Ab 24) RASTLAS

[0277] SEQ ID NO: 206 (LCDR3 of rabbit-derived IL-19 Ab 24) QAYYGDYIYD

[0278] SEQ ID NO: 207 (HCDR1 of rabbit-derived IL-19 Ab 24) GFSLSSYPMS

[0279] SEQ ID NO: 208 (HCDR2 of rabbit-derived IL-19 Ab 24) IIGSTGSTGYANWAKG

[0280] SEQ ID NO: 209 (HCDR3 of rabbit-derived IL-19 Ab 24) GWFYYGLDL

[0281] SEQ ID NO: 210 (LCDR1 of rabbit-derived IL-19 Ab 25) QASQSIGSYLA

[0282] SEQ ID NO: 211 (LCDR2 of rabbit-derived IL-19 Ab 25) DASDLAS

[0283] SEQ ID NO: 212 (LCDR3 of rabbit-derived IL-19 Ab 25) QSAVYDSSYVVT

[0284] SEQ ID NO: 213 (HCDR1 of rabbit-derived IL-19 Ab 25) GFSLSSYDMS

[0285] SEQ ID NO: 214 (HCDR2 of rabbit-derived IL-19 Ab 25) ISDSLGTTWYANWAKG

[0286] SEQ ID NO: 215 (HCDR3 of rabbit-derived IL-19 Ab 25) ESGDIRIDYDL

[0287] SEQ ID NO: 216 (LCDR1 of rabbit-derived IL-19 Ab 26) QASQSIGSYLA

[0288] SEQ ID NO: 217 (LCDR2 of rabbit-derived IL-19 Ab 26) DASDLAS

[0289] SEQ ID NO: 218 (LCDR3 of rabbit-derived IL-19 Ab 26) QSAVYDSSYVVT

[0290] SEQ ID NO: 219 (HCDR1 of rabbit-derived IL-19 Ab 26) GFSLSSYDMS

[0291] SEQ ID NO: 220 (HCDR2 of rabbit-derived IL-19 Ab 26) ISDSLGTTWYANWAKG

[0292] SEQ ID NO: 221 (HCDR3 of rabbit-derived IL-19 Ab 26) ESGDIRIDYDL

[0293] SEQ ID NO: 222 (LCDR1 of rabbit-derived IL-19 Ab 27) QASQSIGSYLA

[0294] SEQ ID NO: 223 (LCDR2 of rabbit-derived IL-19 Ab 27) DASDLAS

[0295] SEQ ID NO: 224 (LCDR3 of rabbit-derived IL-19 Ab 27) QSAVYDSSYVVT

[0296] SEQ ID NO: 225 (HCDR1 of rabbit-derived IL-19 Ab 27) GFSLSSYDMS

[0297] SEQ ID NO: 226 (HCDR2 of rabbit-derived IL-19 Ab 27) ISDSLGTTWYANWAKG

[0298] SEQ ID NO: 227 (HCDR3 of rabbit-derived IL-19 Ab 27) ESGDIRIDYDL

[0299] SEQ ID NO: 228 (LCDR1 of rabbit-derived IL-19 Ab 28) QASQSIGSYLA

[0300] SEQ ID NO: 229 (LCDR2 of rabbit-derived IL-19 Ab 28) DASDLAS

[0301] SEQ ID NO: 230 (LCDR3 of rabbit-derived IL-19 Ab 28) QSAVYDSSYVVT

[0302] SEQ ID NO: 231 (HCDR1 of rabbit-derived IL-19 Ab 28) GFSLSSYDMS

[0303] SEQ ID NO: 232 (HCDR2 of rabbit-derived IL-19 Ab 28) ISDSLGTTWYANWAKG

[0304] SEQ ID NO: 233 (HCDR3 of rabbit-derived IL-19 Ab 28) ESGDIRIDYDL

[0305] SEQ ID NO: 234 (LCDR1 of rabbit-derived IL-19 Ab 29) QASQSLNINYLS

[0306] SEQ ID NO: 235 (LCDR2 of rabbit-derived IL-19 Ab 29) SASTLAS

[0307] SEQ ID NO: 236 (LCDR3 of rabbit-derived IL-19 Ab 29) QQSVNYGRVDNI

[0308] SEQ ID NO: 237 (HCDR1 of rabbit-derived IL-19 Ab 29) GFTISNYHMS

[0309] SEQ ID NO: 238 (HCDR2 of rabbit-derived IL-19 Ab 29) RIVSYGGTYYANWAKG

[0310] SEQ ID NO: 239 (HCDR3 of rabbit-derived IL-19 Ab 29) DSSGSGFSFAL

[0311] SEQ ID NO: 240 (LCDR1 of rabbit-derived IL-19 Ab 30) QASQSITTSYLS

[0312] SEQ ID NO: 241 (LCDR2 of rabbit-derived IL-19 Ab 30) KASTLAS

[0313] SEQ ID NO: 242 (LCDR3 of rabbit-derived IL-19 Ab 30) QQSHNYGRVDNI

[0314] SEQ ID NO: 243 (HCDR1 of rabbit-derived IL-19 Ab 30) GFTISNYHMS

[0315] SEQ ID NO: 244 (HCDR2 of rabbit-derived IL-19 Ab 30) RIVSYGGTYYANWAKG

[0316] SEQ ID NO: 245 (HCDR3 of rabbit-derived IL-19 Ab 30) DSSGSGFSFAL

[0317] SEQ ID NO: 246 (LCDR1 of rabbit-derived IL-19 Ab 31) QASQSITTSYLS

[0318] SEQ ID NO: 247 (LCDR2 of rabbit-derived IL-19 Ab 31) KASTLAS

[0319] SEQ ID NO: 248 (LCDR3 of rabbit-derived IL-19 Ab 31) QQSHNYGRVDNI

[0320] SEQ ID NO: 249 (HCDR1 of rabbit-derived IL-19 Ab 31) GFTISNYHMS

[0321] SEQ ID NO: 250 (HCDR2 of rabbit-derived IL-19 Ab 31) RIVSYGGTYYANWAKG

[0322] SEQ ID NO: 251 (HCDR3 of rabbit-derived IL-19 Ab 31) DSSGSGFSFAL

[0323] SEQ ID NO: 252 (LCDR1 of rabbit-derived IL-19 Ab 32) QASQSITTSYLS

[0324] SEQ ID NO: 253 (LCDR2 of rabbit-derived IL-19 Ab 32) KASTLAS

[0325] SEQ ID NO: 254 (LCDR3 of rabbit-derived IL-19 Ab 32) QQSHNYGRVDNI

[0326] SEQ ID NO: 255 (HCDR1 of rabbit-derived IL-19 Ab 32) GFTISNYHMS

[0327] SEQ ID NO: 256 (HCDR2 of rabbit-derived IL-19 Ab 32) RIVSYGGTYYANWAKG

[0328] SEQ ID NO: 257 (HCDR3 of rabbit-derived IL-19 Ab 32) DSSGSGFSFAL

[0329] SEQ ID NO: 258 (LCDR1 of rabbit-derived IL-19 Ab 33) QASQSITTSYLS

[0330] SEQ ID NO: 259 (LCDR2 of rabbit-derived IL-19 Ab 33) KASTLAS

[0331] SEQ ID NO: 260 (LCDR3 of rabbit-derived IL-19 Ab 33) QQSHNYGRVDNI

[0332] SEQ ID NO: 261 (HCDR1 of rabbit-derived IL-19 Ab 33) GFTISNYHMS

[0333] SEQ ID NO: 262 (HCDR2 of rabbit-derived IL-19 Ab 33) RIVSYGGTYYANWAKG

[0334] SEQ ID NO: 263 (HCDR3 of rabbit-derived IL-19 Ab 33) DSSGSGFSFAL

[0335] SEQ ID NO: 264 (LCDR1 of rabbit-derived IL-19 Ab 34) QASQNIYSNLA

[0336] SEQ ID NO: 265 (LCDR2 of rabbit-derived IL-19 Ab 34) KASTLAS

[0337] SEQ ID NO: 266 (LCDR3 of rabbit-derived IL-19 Ab 34) QAYVGNYIYT

[0338] SEQ ID NO: 267 (HCDR1 of rabbit-derived IL-19 Ab 34) GFSLSSYPMS

[0339] SEQ ID NO: 268 (HCDR2 of rabbit-derived IL-19 Ab 34) IIGSSGSIGYASWAKG

[0340] SEQ ID NO: 269 (HCDR3 of rabbit-derived IL-19 Ab 34) GWFYYGMDL

[0341] SEQ ID NO: 270 (LCDR1 of rabbit-derived IL-19 Ab 35) QASQSIGSNLA

[0342] SEQ ID NO: 271 (LCDR2 of rabbit-derived IL-19 Ab 35) RASTLAS

[0343] SEQ ID NO: 272 (LCDR3 of rabbit-derived IL-19 Ab 35) QGYYGDGIYG

[0344] SEQ ID NO: 273 (HCDR1 of rabbit-derived IL-19 Ab 35) GFSLSSYPMS

[0345] SEQ ID NO: 274 (HCDR2 of rabbit-derived IL-19 Ab 35) LIGSSGTIYFATWAKG

[0346] SEQ ID NO: 275 (HCDR3 of rabbit-derived IL-19 Ab 35) GWFYYGMDL

[0347] SEQ ID NO: 276 (LCDR1 of rabbit-derived IL-19 Ab 36) QASQSISSWLS

[0348] SEQ ID NO: 277 (LCDR2 of rabbit-derived IL-19 Ab 36) GASTLAS

[0349] SEQ ID NO: 278 (LCDR3 of rabbit-derived IL-19 Ab 36) QSYYYISSSSYT

[0350] SEQ ID NO: 279 (HCDR1 of rabbit-derived IL-19 Ab 36) GFSLSSYPMS

[0351] SEQ ID NO: 280 (HCDR2 of rabbit-derived IL-19 Ab 36) LIGSSGTIYFATWAKG

[0352] SEQ ID NO: 281 (HCDR3 of rabbit-derived IL-19 Ab 36) GWFYYGMDL

[0353] SEQ ID NO: 282 (LCDR1 of rabbit-derived IL-19 Ab 37) QASQSISSYLA

[0354] SEQ ID NO: 283 (LCDR2 of rabbit-derived IL-19 Ab 37) SASTLAS

[0355] SEQ ID NO: 284 (LCDR3 of rabbit-derived IL-19 Ab 37) QCHYHGSSYWDNS

[0356] SEQ ID NO: 285 (HCDR1 of rabbit-derived IL-19 Ab 37) GFSFSSSYWIC

[0357] SEQ ID NO: 286 (HCDR2 of rabbit-derived IL-19 Ab 37) CIDTGVSGDTYYANWAEG

[0358] SEQ ID NO: 287 (HCDR3 of rabbit-derived IL-19 Ab 37) DIFGSAIDNSL

[0359] SEQ ID NO: 288 (LCDR1 of rabbit-derived IL-19 Ab 38) QASQNIYSNLA

[0360] SEQ ID NO: 289 (LCDR2 of rabbit-derived IL-19 Ab 38) GASNLES

[0361] SEQ ID NO: 290 (LCDR3 of rabbit-derived IL-19 Ab 38) QGGYSGGIYA

[0362] SEQ ID NO: 291 (HCDR1 of rabbit-derived IL-19 Ab 38) GFSLTRHAMS

[0363] SEQ ID NO: 292 (HCDR2 of rabbit-derived IL-19 Ab 38) AIHGSGVTDYASWAKG

[0364] SEQ ID NO: 293 (HCDR3 of rabbit-derived IL-19 Ab 38) GSGL

[0365] SEQ ID NO: 294 (LCVR of rabbit-derived IL-19 Ab 39 ("R_39")) DIVMTQTPASVEAAVGGTVTIKCQASQSIYRYLSWYQQKPGQRPKLLIYGASNLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQSYYYSSSSGYGNVFGGGTEVVVK

[0366] SEQ ID NO: 295 (LCDR1 of rabbit-derived IL-19 Ab 39) QASQSIYRYLS

[0367] SEQ ID NO: 296 (LCDR2 of rabbit-derived IL-19 Ab 39) GASNLAS

[0368] SEQ ID NO: 297 (LCDR3 of rabbit-derived IL-19 Ab 39) QSYYYSSSSGYGNV

[0369] SEQ ID NO:298 (HCVR of rabbit-derived IL-19 Ab 39 ("R_39")) QEQLKESGGGLVQPGGSLKLSCKASGFDLSSYGVSWVRQAPGKGLEWIGYIDPVFGSTYYANWVNGRFTISSDNAQNTLYLQLNSLTAADTATYFCARGSGYVYYGYTYDLWGPGTLVTVSS

[0370] SEQ ID NO: 299 (HCDR1 of rabbit-derived IL-19 Ab 39) GFDLSSYGVS

[0371] SEQ ID NO:300 (HCDR2 of rabbit-derived IL-19 Ab 39) YIDPVFGSTYYANWVNG

[0372] SEQ ID NO: 301 (HCDR3 of rabbit-derived IL-19 Ab 39) GSGYVYYGYTYDL

[0373] SEQ ID NO:302 (LCVR of mouse-derived IL-19 Ab 5 ("M_5")) DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLSSYNQKNYLAWYQRKPGQSPKLLVYFASQRATGVPDRFIGSGSGSDFTLTISSVQAEDLADYFCQQHTRLPITFGAGTKLELK

[0374] SEQ ID NO: 303 (LCDR1 of mouse-derived IL-19 Ab 5) KSSQSLLSSYNQKNYLA

[0375] SEQ ID NO: 304 (LCDR2 of mouse-derived IL-19 Ab 5) FASQRAT

[0376] SEQ ID NO: 305 (LCDR3 of mouse-derived IL-19 Ab 5) QQHTRLPIT

[0377] SEQ ID NO:306 (HCVR of mouse-derived IL-19 Ab 5 ("M_5")) EVQLQQSGPVLVKPGASVKMSCKASGYPFNDYFLGWVKQSHGKSLEWIGSINPDNDYTMSNQKFKGKATLTVDKSSSTAYMELNSLTSEDSAVYYCARYDYDWAWFAHWGQGTLVTVSA

[0378] SEQ ID NO: 307 (HCDR1 of mouse-derived IL-19 Ab 5) GYPFNDYFLG

[0379] SEQ ID NO: 308 (HCDR2 of mouse-derived IL-19 Ab 5) SINPDNDYTMSNQKFKG

[0380] SEQ ID NO: 309 (HCDR3 of mouse-derived IL-19 Ab 5) YDYDWAWFAH

[0381] SEQ ID NO:310 (LC of rabbit-derived IL-19 Ab 39 ("R_39")) DIVMTQTPASVEAAVGGTVTIKCQASQSIYRYLSWYQQKPGQRPKLLIYGASNLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQSYYYSSSSGYGNVFGGGTE VVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC

[0382] SEQ ID NO:311 (HC of rabbit-derived IL-19 Ab 39 ("R_39")) QEQLKESGGGLVQPGGSLKLSCKASGFDLSSYGVSWVRQAPGKGLEWIGYIDPVFGSTYYANWVNGRFTISSDNAQNTLYLQLNSLTAADTATYFCARGSGYVYYGYTYDL WGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTC SKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKT ISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK

[0383] SEQ ID NO:312 (LC of mouse-derived IL-19 Ab 5 ("M_5")) DIVMTQSPSSLAMSVGQKVTMSCKSSQSLLSSYNQKNYLAWYQRKPGQSPKLLVYFASQRATGVPDRFIGSGSGSDFTLTISSVQAEDLADYFCQQHTRLPITFGAGTKLELKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0384] Sequence number 313 (HC of mouse-derived IL-19 Ab 5 (「M_5」)) EVQLQQSGPVLVKPGASVKMSCKASGYPFNDYFLGWVKQSHGKSLEWIGSINPDNDYTMSNQKFKGKATLTVDKSSSTAYMELNSLTSEDSAVYYCARYDYDWAWFAHWGQGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK

Claims

1. 1. A monoclonal antibody that binds to human IL-19, comprising 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, and the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, wherein the amino acid sequence of the LCDR1 is SEQ ID NO:3, the amino acid sequence of the LCDR2 is SEQ ID NO:4, the amino acid sequence of the LCDR3 is SEQ ID NO:5, the amino acid sequence of the HCDR1 is SEQ ID NO:7, the amino acid sequence of the HCDR2 is SEQ ID NO:8, and the amino acid sequence of the HCDR3 is SEQ ID NO:

9.

2. A monoclonal antibody comprising a light chain (LC) and a heavy chain (HC), wherein the amino acid sequence of the LC is SEQ ID NO:2, and the amino acid sequence of the HC is SEQ ID NO:

6.

3. 1. A monoclonal antibody that binds to human IL-19, comprising 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, and the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, wherein the amino acid sequence of the LCDR1 is SEQ ID NO:11, the amino acid sequence of the LCDR2 is SEQ ID NO:12, the amino acid sequence of the LCDR3 is SEQ ID NO:13, the amino acid sequence of the HCDR1 is SEQ ID NO:15, the amino acid sequence of the HCDR2 is SEQ ID NO:16, and the amino acid sequence of the HCDR3 is SEQ ID NO:

17.

4. A monoclonal antibody comprising a light chain (LC) and a heavy chain (HC), wherein the amino acid sequence of the LC is SEQ ID NO: 10, and the amino acid sequence of the HC is SEQ ID NO: 14.

Images