RU2806304C1 - Pharmaceutical composition for prevention and/or treatment of atopic dermatitis including il-31 antagonist as an active ingredient - Google Patents

Abstract

FIELD: medicine; allergology; dermatology.

SUBSTANCE: group of inventions discloses a method of treatment of atopic dermatitis including the administration of an IL-31 antagonist several times in equal quantities at equal intervals between the doses to a subject suffering from atopic dermatitis or predisposed to its development, at a dose of 25 to 100 mg/body/4 weeks, where atopic dermatitis is moderate to severe atopic dermatitis and topical therapy is insufficiently effective or intolerable (options).

EFFECT: use of a group of inventions ensures an increase in the effectiveness of the treatment regimen, the results of which cannot be achieved using standard therapeutic methods of treating atopic dermatitis.

12 cl, 4 tbl, 11 dwg, 6 ex

Description

Field to which the invention relates

In a non-limiting embodiment, the present invention, for example, provides a pharmaceutical composition for the prevention and/or treatment of atopic dermatitis, which includes an IL-31 antagonist as an active ingredient.

Background of the present invention

Atopic dermatitis is known to flare easily in response to external stimuli such as sweating, scratching and rubbing, and suppression or reduction of itching is the most important therapeutic goal. Atopic dermatitis is a disease characterized by skin inflammation, rashes or the development of eczema, as well as a chronic skin disease accompanied by scabies (itching). Without being bound by any theory, it is believed that atopic dermatitis occurs when an individual predisposed to developing allergic reactions (atopic predisposition), predisposed to developing diseases such as bronchial asthma, allergic rhinitis and allergic dermatitis, is exposed to various irritants. Although the mechanism of development of atopic dermatitis is not yet fully understood, Th2-associated cytokines (such as IL-4, IL-13 and IL-5) and chemical mediators (such as histamine and serotonin) that are produced as a result are thought to play an important role. cross-linking of IgE by Fcε receptors present on activated T cells, basophils or mast cells, activating the development of dermatitis.

Known treatments for atopic dermatitis include medical treatments using steroids, antihistamines and other drugs, as well as PUVA therapy using UV-A radiation. However, these therapeutic methods involve taking the drug or applying the drug to the affected areas of the body several times a day, which poses the potential problem of missing a dose or application of the drug. In addition, treatment using ultraviolet light may require visiting the clinic once or twice a week, which poses the potential problem of additional stress on the patient's body when visiting the clinic.

Moreover, it has been reported in the literature that the development of scabies associated with a disease such as atopic dermatitis is not only due to the release of histamine and the like (see Non-Patent Document 1). In this regard, the development of a therapeutic agent for the treatment of atopic dermatitis based on a new mechanism of action is an urgent problem.

IL-31 (interleukin-31) is a T cell cytokine. It is known that dermatitis-like symptoms similar to pruritus or atopic dermatitis are observed in transgenic mice that overexpress IL-31 (see Non-Patent Document 2). It has also been found that the receptor to which IL-31 binds is a heterodimer of IL-31RA (interleukin-31 receptor A) and OSMR (Oncostatin M receptor) (see Patent Document 1), and IL-31 transmits signals to cells through the specified receptor. It has been reported in the literature that the expression of human IL-31RA is increased in the thickened epidermis of patients suffering from atopic dermatitis (see Non-Patent Document 3).

Attempts to improve or successfully improve the symptoms of atopic dermatitis or the intensity of pruritus associated with atopic dermatitis using an IL-31 antagonist have been previously reported. In addition, the use of IL-31 neutralizing antibodies and IL-31RA neutralizing antibodies as IL-31 antagonists has been reported (see Patent Documents 2-16). However, although there are reports that the expression level of IL-31 protein or RNA is increased in the serum of patients suffering from atopic dermatitis (see Non-Patent Documents 4 and 5), and it is also reported that there is no difference between the expression levels of IL-31 31 in the skin of patients suffering from atopic dermatitis, as well as in the skin of healthy adults (see Patent Document 8).

List of cited literature

Patent Literature:

Patent document 1: WO 2004/003140,

patent document 2: WO 2005/079566,

patent document 3: WO 2006/063864,

patent document 4: WO 2006/063865,

patent document 5: WO 2009/071696,

patent document 6: WO 2006/088855,

patent document 7: WO 2006/088955,

Patent Document 8: WO 2006/088956,

patent document 9: WO 2007/133816,

patent document 10: WO 2007/142325,

patent document 11: WO 2009/072598,

patent document 12: WO 2006/122079,

patent document 13: WO 2007/143231,

patent document 14: WO 2008/028192,

patent document 15: WO 2009/072604,

patent document 16: WO 2010/064697.

Non-patent literature:

Non-patent document 1: J. Dermatol. Sci., 25, 20-28 (2001),

Non-Patent Document 2: Nat. Immunol., 5, 752-760 (2004),

non-patent document 3: J. Allergy Clin. Immunol., 117, 418-425 (2006),

non-patent document 4: J. Allergy Clin. Immunol., 122, 421-423 (2008),

Non-Patent Document 5: Ann Dermatol., 23, 468-473, (2011).

Summary of the Present Invention

Technical problem

In a non-limiting embodiment, the purpose of the present invention is to develop, for example, a pharmaceutical composition for the prevention and/or treatment of atopic dermatitis using a more effective treatment regimen.

Solving a technical problem

In a non-limiting embodiment of the present invention, the applicants have previously developed pharmaceutical compositions intended for the prevention and/or treatment of atopic dermatitis based on a new mechanism of action, however, having received unsatisfactory results, the applicants have continued extensive research and improvement of treatment regimens for many years to develop a more effective treatment regimen , which can reduce, for example, the burden on the patient’s body from taking a medicine or visiting a clinic, as well as for an additional contribution to improving the patient’s quality of life (QOL indicator).

As a result, the inventors of the present invention have unexpectedly established a more effective treatment regimen, the results of which cannot be achieved using standard therapeutic methods for treating atopic dermatitis.

In a non-limiting embodiment, the present invention includes the following objects:

[1] a pharmaceutical composition intended for the prevention and/or treatment of atopic dermatitis, including an IL-31 antagonist as an active ingredient, where

IL-31 antagonist is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.1 mg to 1000 mg/body/2 weeks, 0.1 mg to 1000 mg/body/4 weeks or from 0.1 mg to 1000 mg/body/8 weeks.

[2] The pharmaceutical composition according to claim [1], where the IL-31 antagonist is administered at a dose of 25 mg to 100 mg/body/4 weeks.

[3] Pharmaceutical composition according to paragraph [1] or paragraph [2], where the IL-31 antagonist is administered at a dose of 50 mg to 100 mg/body/4 weeks.

[4] A pharmaceutical composition for the prevention and/or treatment of atopic dermatitis, including an IL-31 antagonist as an active ingredient, where

IL-31 antagonist is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.01 to 10 mg/kg/2 weeks, 0.01 mg to 10 mg/kg/4 weeks or from 0.01 mg to 10 mg/kg/8 weeks

[5] The pharmaceutical composition according to claim [4], where the IL-31 antagonist is administered at a dose of 0.2 mg to 2 mg/kg/4 weeks.

[6] Pharmaceutical composition according to paragraph [4] or paragraph [5], where the IL-31 antagonist is administered at a dose of 0.5 mg/kg/4 weeks.

[7] The pharmaceutical composition according to any one of items [1] to [6] for use in the prevention and/or treatment of itching caused by atopic dermatitis.

[8] The pharmaceutical composition according to claim [7] for use in improving the symptoms of sleep disturbance caused by itching.

[9] The pharmaceutical composition according to claim [8], where the improvement of symptoms of sleep disturbance consists in increasing the time from falling asleep to waking up, and/or to reduce the delay in sleep onset (the period from the moment the patient goes to bed until falling asleep).

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling.

[11] The pharmaceutical composition according to claim [10], wherein the antibody contains an amino acid variant sequence of the conserved H chain region of IgG2, and the amino acid variant includes glutamic acid at position 419 (according to EU numbering) of the conserved H chain region sequence (SEQ ID NO: 15 ), found in natural IgG2, where

the antibody has an increased plasma half-life compared to a reference antibody comprising a conserved H chain region sequence found in naturally occurring IgG2, characterized by the same amino acid sequence except for an amino acid substitution at position 419.

[12] The pharmaceutical composition according to claim [11], where the antibody is characterized by an increased half-life in blood plasma due to a decrease in the isoelectric point (IEP) as a result of replacing the amino acid at position 419 with glutamic acid.

[13] The pharmaceutical composition according to paragraph [11] or paragraph [12] to provide an increased half-life in blood plasma compared to a pharmaceutical composition containing a reference antibody containing a sequence identical to the sequence of the conserved region of the H chain of natural IgG2, with the exception of the amino acid replacements in position 419.

[14] The pharmaceutical composition according to any one of claims [10]-[13], wherein the antibody does not cross-react with IL-31RA of any animal (mouse, rat and rabbit).

[15] The pharmaceutical composition according to any one of [10] to [14], wherein the antibody is an IL-31 neutralizing antibody or an IL-31RA neutralizing antibody.

[16] The pharmaceutical composition according to claim [15], wherein the anti-IL-31RA neutralizing antibody is any antibody selected from the following antibodies:

(1) anti-IL-31RA antibodies containing an H chain variable region containing CDR1 as set forth in SEQ ID NO: 1, CDR2 as set forth in SEQ ID NO: 2, and CDR3 as set forth in SEQ ID NO: 3 , and an L chain variable region containing CDR1 as set forth in SEQ ID NO: 4, CDR2 as set forth in SEQ ID NO: 5, and CDR3 as set forth in SEQ ID NO: 6,

(2) anti-IL-31RA antibodies comprising an H chain variable region as set forth in SEQ ID NO: 7 and an L chain variable region as set forth in SEQ ID NO: 8, and

(3) anti-IL-31RA antibodies containing an H chain as defined in SEQ ID NO: 9, and an L chain as defined in SEQ ID NO: 10.

[17] The pharmaceutical composition according to any one of paragraphs [1]-[16] for use in suppressing at least one symptom caused by atopic dermatitis selected from the group consisting of: redness, induration, papules, edema, excoriation and lichenification.

[18] The pharmaceutical composition as claimed in any one of [1] to [17], wherein the atopic dermatitis is moderate or severe atopic dermatitis where topical therapy is not sufficiently effective or is not tolerated.

[19] The pharmaceutical composition according to claim [18], wherein the topical therapy is a therapy using a topical steroid or a topical calcineurin inhibitor.

[20] The pharmaceutical composition according to any one of [1] to [19], wherein the IL-31 antagonist is administered subcutaneously.

[21] The pharmaceutical composition according to any one of [1] to [20], wherein the atopic dermatitis is atopic dermatitis caused by IL-31 signaling.

[22] The pharmaceutical composition according to any one of [1] to [21] for use in combination with a topical steroid or a topical calcineurin inhibitor, wherein the IL-31 antagonist is administered before, simultaneously with, or after administration of the steroid for for external use or a calcineurin inhibitor for external use.

[23] The pharmaceutical composition according to claim [22], wherein the IL-31 antagonist and a topical steroid or topical calcineurin inhibitor are administered sequentially or simultaneously.

[24] The pharmaceutical composition according to claim [22] or claim [23], wherein the administration of a topical steroid or a topical calcineurin inhibitor in combination with an IL-31 antagonist can reduce the dosage (amount applied) of the topical steroid or inhibitor topical calcineurin when used in combination, compared with a dosage of a topical steroid or a topical calcineurin inhibitor when administered continuously as a single agent.

[25] A combination of a pharmaceutical composition according to any one of [1] to [21] and a topical steroid or a topical calcineurin inhibitor.

[26] A method for preventing and/or treating atopic dermatitis, comprising administering an IL-31 antagonist to a subject suffering from or susceptible to developing atopic dermatitis, wherein

IL-31 antagonist is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.1 to 1000 mg/body/2 weeks, 0.1 to 1000 mg /body/4 weeks or from 0.1 to 1000 mg/body/8 weeks.

[27] A method of preventing and/or treating atopic dermatitis, comprising administering an IL-31 antagonist to a subject suffering from or predisposed to developing atopic dermatitis, wherein

IL-31 antagonist is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.01 to 10 mg/kg/2 weeks, 0.01 to 10 mg /kg/4 weeks or from 0.01 to 10 mg/kg/8 weeks.

[28] The use of an IL-31 antagonist for the production of a medicinal product intended for the prevention and/or treatment of atopic dermatitis, where

IL-31 antagonist is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.1 to 1000 mg/body/2 weeks, 0.1 to 1000 mg /body/4 weeks or from 0.1 to 1000 mg/body/8 weeks.

[29] The use of an IL-31 antagonist for the production of a medicinal product intended for the prevention and/or treatment of atopic dermatitis, where

IL-31 antagonist is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.01 to 10 mg/kg/2 weeks, 0.01 to 10 mg /kg/4 weeks or from 0.01 to 10 mg/kg/8 weeks.

[30] A product containing (i) a container, (ii) a pharmaceutical composition containing an IL-31 antagonist as an active ingredient in the container, and (iii) a document indicating that the IL-31 antagonist should be administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.1 to 1000 mg/body/2 weeks, 0.1 to 1000 mg/body/4 weeks, or 0.1 to 1000 mg/body/8 weeks.

[31] A product containing (i) a container, (ii) a pharmaceutical composition containing an IL-31 antagonist as an active ingredient in the container, and (iii) a document indicating that the IL-31 antagonist is to be administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.01 to 10 mg/kg/2 weeks, 0.01 to 10 mg/kg/4 weeks, or 0.01 to 10 mg/kg/8 weeks.

[32] A pharmaceutical composition for use in the prevention and/or treatment of atopic dermatitis, containing an IL-31 antagonist as an active ingredient, which is also intended for use in improving the symptoms of sleep disturbance caused by atopic dermatitis.

[33] The pharmaceutical composition according to claim [32], wherein sleep disturbance is caused by itching due to atopic dermatitis.

[34] The pharmaceutical composition according to paragraph [32] or paragraph [33], where the improvement of symptoms of sleep disturbance consists in increasing the time from falling asleep to waking up, and/or to reduce the delay in sleep onset (the period from the moment the patient goes to bed , before falling asleep).

[35] An IL-31 antagonist, for use in the prevention and/or treatment of atopic dermatitis, which should be administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0. 1 to 1000 mg/body/for 1 day to 12 weeks, preferably 0.1 to 1000 mg/body/2 weeks, 0.1 to 1000 mg/body/4 weeks or 0.1 to 1000 mg /body/8 weeks.

[36] An IL-31 antagonist used for the prevention and/or treatment of atopic dermatitis, which is administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.01 to 10 mg/kg/for 1 day to 12 weeks, preferably 0.01 to 10 mg/kg/2 weeks, 0.01 to 10 mg/kg/4 weeks or 0.01 to 10 mg/kg /8 weeks.

Any combinations of some or all of one or more of the elements (components) presented in any of paragraphs [1]-[36] above are also included in the present description, unless they are technically incompatible in terms of the prior art and contrary to the context of this inventions.

Therefore, one skilled in the art will naturally be able to directly and unambiguously state various embodiments of the present invention, such as, for example, “an IL-31 antagonist for use in the prevention and/or treatment of atopic dermatitis, which is administered several times in equal amounts through the same intervals between dosing to a subject suffering from or predisposed to developing atopic dermatitis at a dosage of 25 to 100 mg/body/4 weeks or 0.2 to 2 mg/kg/4 weeks, where atopic dermatitis is atopic dermatitis in moderate or severe form, while local therapy is insufficiently effective or intolerable."

Brief description of the figures

In fig. 1 is a graph showing the effect of pruritus suppression as measured by VAS following administration of single subcutaneous doses of CIM331 or placebo to preselected patients suffering from atopic dermatitis (AD).

In fig. 2 is a graph showing the effect of improvement in dermatitis according to EASI after administration of single subcutaneous doses of CIM331 or placebo to pre-selected patients suffering from atopic dermatitis.

In fig. 3 is a graph showing the presence or absence of improvement in QOL using sleep efficiency as an index after administration of single subcutaneous doses of CIM331 or placebo to preselected patients suffering from atopic dermatitis.

In fig. 4 is a graph showing the amount of topical steroid (Locoid) used after administration of single subcutaneous doses of CIM331 or placebo to preselected patients suffering from atopic dermatitis.

In fig. 5 is a graph showing the change in serum concentration of CIM331 after administration of single subcutaneous doses of CIM331 to preselected patients suffering from atopic dermatitis.

In fig. 6 is a graph showing the frequency of IL-31-induced itch-related behavior following administration of a single subcutaneous dose of 0.2 mg/kg CIM331 to cynomolgus monkeys.

In fig. 7 is a graph showing the frequency of IL-31-induced itch-related behavior following administration of a single subcutaneous dose of 1 mg/kg CIM331 to cynomolgus monkeys.

In fig. 8 shows a nonlinear analytical model using the Michaelis-Menten equation, where the symbols have the following meanings: X _sc means the amount of drug at the subcutaneous injection site, X ₁ means the amount of drug in the central chamber, X ₂ means the amount of drug in the peripheral chamber, F means bioavailability, k ₁₂ means the rate constant of drug transfer from the central chamber to the peripheral chamber, k ₂₁ means the rate constant of drug transfer from the peripheral chamber to the central chamber, k _a means the absorption constant, k _e1 means the unsaturated elimination rate constant, V _l means volumetric distribution of the central chamber, V _max means the clearance rate of the antibody when the antibody binds to all receptors, K _m means the concentration of the antibody to bind to 50% of the total amount of antigen, and C _p means the concentration of the antibody.

In fig. Figure 9 shows the predicted changes in CIM331 concentration in human serum.

In fig. 10 presents graphs, each of which illustrates the relationship between body weight and exposure at the optimal stimulation dose of CIM331 using a single-compartment model.

In fig. Figure 11 shows the estimated pruritus VAS parameter one year after CIM331 administration using an indirect inverse model.

Description of Embodiments of the Present Invention

The following are preferred non-limiting embodiments of the present invention.

All embodiments presented in the Examples section below are described with the understanding that they are, of course, equivalently described in the Description of Embodiments section of the present invention and are not limited by any practice, convention or law under which the contents of the Examples may be interpreted in a limiting manner in a country , where protection is sought for this patent application.

IL-31 (interleukin-31) is a T cell cytokine. IL-31 is known to be involved in the development of itch, and transgenic mice that overexpress IL-31 exhibit dermatitis-like symptoms similar to atopic dermatitis, with persistent scratching behavior observed.

The nucleotide and amino acid sequences of human IL-31 are also known: accession numbers RefSeq NM_001014336 and RefSeq NP_001014358, respectively.

The IL-31 receptor is formed by a heterodimer of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) (see Nat. Immunol., 5, 752-760 (2004)). It is known that IL-31RA, another name for NR10, produces many splice variants (see application WO 00/075314). Known splice variants include NR10.1 (652 amino acid residues), NR10.2 (252 amino acid residues), NR10.3 (662 amino acid residues, otherwise known as IL-31RAv4) and IL-31RAv3 (764 amino acid residues), and examples of preferred IL-31RAs include NR10.3 (IL-31RAv4) and IL-31RAv3. The nucleotide and amino acid sequences of human IL-31RA (IL-31RAv4) are also known: RefSeq accession number NM_001242638 and RefSeq NP_001229567, respectively. The nucleotide and amino acid sequences of human IL-31RA (IL-31RAv3) are also known: RefSeq accession number NM_139017 and RefSeq NP_620586, respectively. The nucleotide and amino acid sequences of human OSMR are also known: accession numbers RefSeq NM_003999 and RefSeq NP_003990, respectively.

As indicated herein, the IL-31 antagonist of the present invention, in one embodiment of the present invention, is a compound that inhibits or blocks intracellular signaling induced by IL-31. This compound can also be described as a compound that inhibits IL-31 signaling. The compound may be a naturally occurring compound or an artificially synthesized compound. Moreover, said compound may be a low molecular weight or high molecular weight compound such as a protein.

It is known that IL-31 present outside cells initiates signal transmission into the cell through the IL-31 receptor (a heterodimer of IL-31RA and OSMR) present on the cell surface (see article Nat. Immunol., 5, 752-760 (2004)) . The extracellular domain of the IL-31 receptor includes an IL-31-binding domain, and the binding of IL-31 to this domain causes a change in the conformation of the IL-31 receptor. As a result, intracellular signal transduction is initiated by the intracellular domain of the IL-31 receptor.

In one method, the ability of a particular compound to inhibit IL-31 signaling can be confirmed by assessing the ability of the compound to inhibit the binding of IL-31 to the IL-31 receptor. Examples of methods for assessing this ability include analysis using solid-phase ELISA or flow cytometry, as well as analysis using surface plasmon resonance. Using solid-phase ELISA, for example, it is possible to evaluate the ability of a compound to inhibit the binding of IL-31 to the IL-31 receptor, while the IL-31 receptor (or IL-31RA) is immobilized on the surface of the plate, obtaining a system for determining the amount of IL-31 bound to it using secondary antibodies, such as enzyme-labeled anti-IL-31 antibodies, and determine the ability of the added compound to reduce or not reduce the amount of detectable IL-31.

In an alternative method, the ability of a particular compound to inhibit IL-31 signaling can be confirmed by assessing the ability of the compound to inhibit IL-31-induced biological activity on cells. The term "biological activity" is not particularly limited and refers to an activity that can be quantitatively or qualitatively determined by any method, and examples of said biological activity include cell proliferative activity, protein phosphorylation activity, and gene/protein expression inducing activity. For example, the ability of a compound to inhibit IL-31 signaling can be assessed by obtaining cells expressing the IL-31 receptor on the surface and whose proliferative activity is induced in response to stimulation by external IL-31, and determining the ability of the added compound to reduce or not reduce IL-31. 31-induced proliferative activity of cells. Such cells may be naturally occurring IL-31 receptor expressing cells, or artificially produced recombinant IL-31 receptor expressing cells may be used. An example of suitable recombinant cells includes Ba/F3 cells expressing the IL-31 receptor. As an additional alternative method, you can use the method described in the article by Dillon et al. Nat. Immunol., 5, 752-760 (2004).

According to the present invention, the degree of inhibition of IL-31 signaling resulting from the action of an IL-31 antagonist may be, but is not limited to, at least 10% or more, preferably 20% or more, 30% or more, 40% or more more than, 50% or more, 60% or more, 70% or more and 80% or more, and especially preferably 90% or more, 95% or more, and 98% or more.

According to the present invention, in a preferred embodiment of the present invention, the compound that inhibits IL-31 signaling includes a protein that inhibits IL-31 signaling. A protein, as described herein, is not particularly limited as long as it has the property of specifically binding to IL-31 or the IL-31 receptor. Examples of preferred proteins include antibodies and antibody-like compounds (see Curr. Opin. Biotechnol., 17, 653-658 (2006), Curr. Opin. Struct. Biol. 7, 463-469 (1997) and Protein Sci. 15, 14-27 (2006)). Antibodies include any antibodies, such as monoclonal antibodies (eg, IgG, IgM, IgE, IgA and IgD), polyclonal antibodies, engineered antibodies (eg, chimeric antibodies, humanized antibodies, and glycosylated (genetically engineered) antibodies (see WO 99 applications /54342 and WO 00/61739)), antibody fragments (for example, Fab, F(ab')2, Fv, as well as CDR), multispecific antibodies (for example, bispecific antibodies), as well as conjugated antibodies (for example, conjugates of antibodies and polyethylene glycol (PEG), conjugates with radioactive isotopes or drugs). On the other hand, examples of antibody-like compounds include DARPin (see application WO 2002/020565), Affibody (antibody mimetic protein) (see application WO 1995/001937), avimer (see application WO 2004/044011), and also adnectin (see application WO 2002/032925). More preferred is an antibody that inhibits IL-31 signaling. Examples of other preferred proteins that inhibit IL-31 signaling include a protein containing the extracellular domain of IL-31RA and a protein containing both extracellular domains of the IL-31 receptor (heterodimer of IL-31RA and OSMR).

According to the present invention, preferred embodiments of antibodies that inhibit IL-31 signaling include antibodies that inhibit IL-31 signaling by binding to IL-31 (anti-IL-31 neutralizing antibodies), as well as antibodies that inhibit IL-31 signaling -31 due to binding to the IL-31 receptor (anti-IL-31 receptor-neutralizing antibodies). Anti-IL-31 receptor neutralizing antibodies include antibodies that inhibit IL-31 signaling by binding to IL-31RA (anti-IL-31RA neutralizing antibodies), antibodies that inhibit IL-31 signaling by binding to OSMR (anti-OSMR-neutralizing antibodies), as well as antibodies that inhibit IL-31 signaling by binding to the IL-31RA and OSMR heterodimer (anti-heterodimer-IL-31RA/OSMR-neutralizing antibodies). Among these anti-IL-31 receptor neutralizing antibodies, anti-IL-31RA neutralizing antibodies or anti-heterodimer-IL-31RA/OSMR neutralizing antibodies are preferred, and anti-IL-31RA neutralizing antibodies are more preferred.

Antibodies that inhibit IL-31 signaling as described herein, in a further embodiment or other embodiment of the present invention preferably comprise an amino acid variant sequence of the conserved IgG2 H chain region, wherein the amino acid variant includes glutamic acid at position 419 (as per EU numbering ) sequence of the conserved H chain region (SEQ ID NO: 15) found in natural IgG2. The advantage of this engineered antibody is an increased plasma half-life compared to a reference antibody comprising a conserved H chain region sequence found in naturally occurring IgG2, characterized by the same amino acid sequence except for an amino acid substitution at position 419. The increased half-life is believed to be in blood plasma is caused by a decrease in isoelectric point (IEP) as a result of replacing the amino acid at position 419 with glutamic acid (example 2).

Thus, an advantage of a pharmaceutical composition as described herein, in one embodiment of the present invention, is that the pharmaceutical composition provides an increase in the half-life of antibodies in blood plasma compared to a reference pharmaceutical composition containing a reference antibody comprising a conserved H region sequence chain found in natural IgG2 and characterized by the same amino acid sequence, with the exception of an amino acid substitution at position 419.

In this case, antibodies that inhibit IL-31 signaling as described herein are, in a preferred embodiment of the present invention, any of the following anti-IL-31RA neutralizing antibodies:

(1) anti-IL-31RA antibodies containing an H chain variable region containing CDR1 as set forth in SEQ ID NO: 1, CDR2 as set forth in SEQ ID NO: 2, and CDR3 as set forth in SEQ ID NO: 3, and an L chain variable region containing CDR1 as set forth in SEQ ID NO: 4, CDR2 as set forth in SEQ ID NO: 5, and CDR3 as set forth in SEQ ID NO: 6,

(2) anti-IL-31RA antibodies comprising an H chain variable region as set forth in SEQ ID NO: 7 and an L chain variable region as set forth in SEQ ID NO: 8, and

(3) anti-IL-31RA antibodies containing an H chain as defined in SEQ ID NO: 9, and an L chain as defined in SEQ ID NO: 10.

It should be understood that the term isoelectric point (IEP), also abbreviated "IEP" in the context, may refer to a theoretical and calculated isoelectric point or an experimentally measured isoelectric point unless otherwise indicated and the context requires.

For example, the IET value can be determined by an isoelectric focusing method known to one skilled in the art. The theoretical isoelectric point value can be calculated using nucleotide and amino acid sequence analysis software (eg Genetyx). Alternatively, the theoretical isoelectric point may be determined by conducting a pharmacokinetic study of the antibodies using, for example, plasma from mice, rats, rabbits, dogs, monkeys, humans, and the like. in combination with a method known to one skilled in the art, such as BIACORE, cell proliferation assay, solid phase ELISA, heterogeneous ELISA, RIA (radioimmunoassay) or immunofluorescence assay.

To compare the half-life of antibodies in blood plasma before and after the introduction of an amino acid change, a pharmacokinetic study of antibodies can be performed using a method known to one skilled in the art, using, for example, blood plasma from mice, rats, rabbits, dogs, monkeys, humans and etc.

Antibodies that inhibit IL-31 signaling as described herein, in yet another further embodiment or another embodiment of the present invention, preferably exhibit substantially no cross-reactivity with the IL-31RA of any animal (mouse, rat and rabbit), wherein they are characterized by cross-reactivity with human and cynomolgus monkey IL-31RA.

Methods for producing antibodies are well known to one skilled in the art, for example, antibodies can be produced using hybridoma technology (Nature, 256, 495 (1975)) or phage antibody library techniques (Nature, 352, 624-628 (1991) ), J. Mol. Biol., 222, 581-597 (1991)). When using IL-31 or IL-31 receptor as an antigen, a variety of anti-IL-31 antibodies or anti-IL-31 receptor antibodies can be produced by these methods. In addition, screening these antibodies using any of the methods described above to detect a compound that inhibits IL-31 signaling provides anti-IL-31 neutralizing antibodies or anti-IL-31 receptor neutralizing antibodies. A protein such as IL-31 or IL-31 receptor can also be produced using genetic engineering technology known to one skilled in the art. More specifically, the protein can be obtained by inserting a gene that encodes the desired protein into an expression vector, introducing the vector into an appropriate host cell, and then purifying the target protein expressed in the host cell or in the supernatant of a host cell culture.

Examples of preferred anti-IL-31 neutralizing antibodies include the anti-IL-31 antibodies described in WO 2006/122079, WO 2008/028192, and WO 2009/071696.

Examples of preferred anti-IL-31RA neutralizing antibodies include, but are not limited to, anti-IL-31RA antibodies (NR10) described in WO 2007/142325, anti-IL-31RA antibodies (NR10) described in WO application 2009/072604, as well as anti-IL-31RA antibodies (NR10) described in WO 2010/064697.

Moreover, examples of other preferred anti-IL-31RA neutralizing antibodies include human anti-IL-31RA neutralizing antibodies, more specifically include anti-IL-31RA neutralizing antibodies that recognize domain 1 and/or domain 2 of human IL-31RA . According to the present invention, the term “human IL-31RA domain 1” refers to a fragment of the amino acid sequence 53-152, as indicated in SEQ ID NO: 11 (LPAKP to LENIA). The term "domain 2" refers to a fragment of the amino acid sequence 153-259, as indicated in SEQ ID NO: 11 (KTEPP to EEAP).

Without any limitation, the more preferred anti-IL-31RA neutralizing antibodies are the anti-IL-31RA antibodies described in WO 2010/064697 containing an H chain (heavy chain) variable region including CDR1 as set forth in SEQ ID NO : 1, CDR2 as set forth in SEQ ID NO: 2, and CDR3 as set forth in SEQ ID NO: 3, and the L chain variable region including CDR1 as set forth in SEQ ID NO: 4, CDR2 as set forth in SEQ ID NO: 5, as well as CDR3, as set forth in SEQ ID NO: 6. More preferred are anti-IL-31RA antibodies containing the H chain variable region, as set forth in SEQ ID NO: 7, and the L chain variable region ( light chain) as defined in SEQ ID NO: 8. Most preferred are anti-IL-31RA antibodies containing an H chain, as defined in SEQ ID NO: 9, and an L chain, as defined in SEQ ID NO: 10.

Known methods for determining CDR include the method described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. (1991), Bethesda, MD, the method described in Chothia et al., Science, 233, 755-758 (1986), as well as a method based on the determination of antigen-antibody contact regions (see J. Mol. Biol ., 262, 732-745 (1996)). More specifically, in each of the methods, the CDR is determined as follows:

An example of preferred anti-IL-31RA neutralizing antibodies of the present invention includes anti-IL-31RA antibodies containing CDR1, CDR2, as well as CDR3 contained in the H chain variable region as indicated in SEQ ID NO: 7, and CDR1, CDR2 , as well as CDR3 contained in the L chain variable region as specified in SEQ ID NO: 8, designated as CDR1, CDR2 and CDR3 H chains, and CDR1, CDR2 and CDR3 L chains, respectively. CDRs in the composition of these antibodies can be determined by any specified method, i.e. the method described in the article by Kabat et al., the method described in the article by Chothia et al., as well as the method based on the determination of antigen-antibody contact areas, or using a combination of these methods.

In addition, preferred anti-IL-31RA neutralizing antibodies are anti-IL-31RA antibodies that bind to the same epitope as the anti-IL-31RA antibodies containing (characterized by) the H chain and L chain CDR sequences described above, H chain and L chain variable region sequences, and full-length H chain and L chain sequences. The term epitope refers to a specific structural unit of an antigen that is recognized by an antibody and to which it binds. If the antigen is a polypeptide, the epitope typically contains approximately 6 to 10 amino acids. Epitope identification can be accomplished using a method known to one skilled in the art, for example, a method that involves the production of peptides by fragmentation of the antigen, a method that involves site-directed mutagenesis of the antigen (for example, arginine/glutamic acid-scanning mutagenesis, J Biol. Chem., 270, 21619-21625 (1995), J. Biol. Chem., 281, 20464-20473 (2006)), as well as a method involving crystallization of the antigen-antibody complex (Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York (1999)). According to the present invention, the term “binds to the same epitope” means that the epitopes to which two antibodies bind are at least partially overlapping with each other. The degree of overlap is, but is not limited to, at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, and 80% or more, preferably 90% or more, and more preferably 100%.

In addition, preferred anti-IL-31RA neutralizing antibodies are anti-IL-31RA antibodies that compete for binding to IL-31RA with anti-IL-31RA antibodies containing the above-described H chain and L chain CDR sequences, variable region sequences H chain and L chain, as well as full-length H chain and L chain sequences. The ability of two antibodies to compete with each other can be assessed using, for example, a competitive ELISA method. Detailed description of the method: one of the two antibodies is pre-introduced with a label, for example, a fluorescent label. A system is prepared for detecting the binding of antibodies (labeled antibodies) to an antigen. A comparison is made between the option when other antibodies that do not contain the label (test antibodies) are present in the analyzed system, and the option when the antibodies under study are not present in the system. If the level of binding of labeled antibodies to an antigen decreases in the presence of the test antibodies, then it can be concluded that the test antibodies and the labeled antibodies compete with each other. According to the present invention, the degree of competition is, but is not limited to, at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, and 80% or more, and most preferably 90% or more, 95% or more, and 98% or more (ie, the level of binding of other antibodies is reduced).

The nucleotide sequence or amino acid sequence encoding antibodies that inhibit IL-31 signaling (eg, anti-IL-31 neutralizing antibodies or anti-IL-31RA neutralizing antibodies) of the present invention can be determined using a method known to one skilled in the art. field of technology. The amino acids contained in the amino acid sequence of the antibodies of the present invention can be subjected to post-translational modification (eg, modification that converts N-terminal glutamine to pyroglutamate using pyroglutamylation is well known to one skilled in the art). Even if the amino acids are post-translationally modified, the resulting amino acid sequence is naturally included in the amino acid sequences of the present invention.

The term "atopic dermatitis" as used herein preferably refers to, but is not limited to, IL-31 signaling-mediated or IL-31-inducible atopic dermatitis, or atopic dermatitis that is responsive to prophylaxis and/or treatment with using an IL-31 antagonist.

The term "itch" as used herein includes, but is not limited to, itch caused by the development of atopic dermatitis, and preferably itch caused by atopic dermatitis caused by IL-31 signaling or induced by IL-31. In addition, the term "pruritus" refers to pruritus associated with atopic dermatitis that is responsive to prophylaxis and/or treatment with an IL-31 antagonist.

Atopic dermatitis may be, for example, moderate or severe atopic dermatitis for which treatment with topical medications is insufficiently effective or intolerable, or standard medications are insufficiently effective or intolerable, or the use of topical medications is contraindicated (presence of contraindications) . More preferably, the atopic dermatitis is moderate to severe atopic dermatitis for which treatment with topical drugs is ineffective or intolerable.

For example, topical steroids (eg, glucocorticoids or their derivatives such as prednisolone and hydrocortisone) and topical calcineurin inhibitors, otherwise known as immunosuppressants (eg, tacrolimus and tacrolimus) are known for topical drug treatment.

In addition to topical steroids and topical calcineurin inhibitors, other compounds are known to be used as therapeutic agents for the treatment of atopic dermatitis, such as cyclosporine, methotrexate (MTX) or azathioprine (AZA) or antihistamines (various drugs known as antihistamines , which are classified as first-generation antihistamines and second-generation antihistamines).

More specifically, without any limitation, the following methods for treating atopic dermatitis are known: Furue et al., “Therapeutic Guidelines for Atopic Dermatitis,” the Japanese journal of dermatology, 119 (8), cc. 1515-1534 (2009), Sidbury R. et al., "Guidelines of care for the management of atopic dermatitis: Chapter 3. Management and treatment with phototherapy and systemic agents", J. Am. Acad Dermatol., cc. 327-337 (2014), and Saeki H. et al., J. Dermatol., 36, pp. 563-577 (2009).

(1) Cyclosporine-based drug (trade name Neoral)

Typically, a cyclosporine-based drug is administered orally to adult patients, with the dose in terms of cyclosporine being 3 mg/kg/day, in two doses divided throughout the day. Although the dose can be adjusted depending on symptoms, it should not exceed 5 mg/kg/day.

(2) Oral steroid preparation (trade name: Prednisolone tablets)

Typically, a steroid drug is administered orally to adult patients at a dose of 5 to 60 mg per day in terms of prednisolone (in the case of tablets - from 1 to 12 tablets, in the case of powder - from 0.5 to 6 g), divided into 1-4 doses. The dose may be adjusted depending on the patient's age or symptoms.

(3) Ultraviolet light therapy

Typically, the patient is advised to visit the clinic once or twice a week, although there are no generally accepted guidelines or recommendations.

(4) Antihistamine (trade name - Allegra)

Typically, the antihistamine is administered orally to adult patients as a single dose of 60 mg in terms of fexofenadine hydrochloride twice a day. Typically, for a child aged 7 years or older but younger than 12 years, the antihistamine is administered orally as a single dose of 30 mg in terms of fexofenadine hydrochloride twice daily; for a child aged 12 years or older, the drug is administered orally as a single dose of 60 mg per day. converted to fexofenadine hydrochloride twice a day. The dose can be adjusted depending on the symptoms.

(5) Steroid preparation for external use (trade name - Fulmeta)

Typically, an appropriate amount of a topical steroid preparation is applied to the affected area one to several times a day. The amount can be changed depending on the symptoms.

(6) Steroid-based preparation for external use (trade name - Locoid)

Typically, an appropriate amount of a topical steroid preparation is applied one to several times a day. The amount can be changed depending on the symptoms.

(7) Tacrolimus-based drug (trade name - Protopic)

Typically, for an adult patient, an appropriate amount of tacrolimus-based medication is applied to the affected area once or twice daily. The applied amount should be up to 5 g per 1 application procedure.

(8) Pimecrolimus-based drug (trade name - Elidel)

Typically, an appropriate amount of pimecrolimus is applied twice daily. The amount can be changed depending on the symptoms.

In one embodiment of the present invention, an IL-31 antagonist (e.g., anti-IL-31 neutralizing antibodies or anti-IL-31RA neutralizing antibodies), as described herein, can be administered in combination with a therapeutic drug or therapeutic agent described above. method. The IL-31 antagonist of the invention may be administered in combination with, for example, a topical steroid or a topical calcineurin inhibitor, and the IL-31 antagonist may be administered to a subject before, simultaneously with, or after administration of the topical steroid or topical calcineurin inhibitor. external use. As detailed below in section (4-5) "Effect of Combination Administration of CIM331 and a Topical Steroid or Similar Compounds", when patients in Phase II Phase II trials did not experience repeated dosing in response to CIM331 sufficient improvement in dermatitis symptoms, although a sufficient effect in reducing the intensity of itching was observed, when a topical steroid or similar compounds were administered in combination with CIM331 for a short period of time or for the required period of time after the onset of stage B, unexpectedly a persistent and significant improvement in symptoms was observed dermatitis effect.

When an IL-31 antagonist is administered in combination with a topical steroid or a topical calcineurin inhibitor, the order of administration, duration of administration, and frequency of administration of each agent are not particularly limited. The IL-31 antagonist of the invention can be administered in equal fixed doses (which will be described below) at equal intervals between fixed doses (inter-dose intervals). In a non-limiting preferred embodiment of the present invention, administration of an IL-31 antagonist as described herein in combination with a topical steroid or topical calcineurin inhibitor may provide a reduction in the dose (amount applied) of the topical steroid or topical calcineurin inhibitor compared to a dose of a topical steroid or a topical calcineurin inhibitor when administered chronically as a single agent (see FIG. 4). The dose of topical steroid or topical calcineurin inhibitor can be reduced by, but not limited to, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 60%, 70%, 80%, 90%, 95%, 98%, or 100%, compared to the continuous single agent dose.

The term "topical steroid" includes, but is not limited to, hydrocortisone, desonide, or prednisolone. The term "topical calcineurin inhibitor" includes, but is not limited to, pimecrolimus or tacrolimus.

The severity (eg, mild, moderate, or severe) of atopic dermatitis can be determined in accordance with classification systems known to one skilled in the art used to assess the severity of a rash or scabies experienced by a subject, using, for example, the Shiratori severity rating criteria , the visual analogue scale (VAS) described below, the verbal rating scale (VRS) for assessing the intensity of itching, the international scoring system for atopic dermatitis (SCORAD score) developed by the European working group on atopic dermatitis, the rash prevalence and severity index (EASI), developed in the USA, or the static investigator overall assessment (sIGA).

For example, the VAS consists of a 100 mm long straight line on which the subject (patient) indicates the intensity of scabies during the measurement by drawing a line from 0 to 100 mm long, where 0 mm means no scabies and 100 mm means the worst degree of scabies possible imagine. For example, if a patient gives a VAS intensity score of 40 mm or more, then the patient may be considered to be suffering from moderate to severe atopic dermatitis, and in one embodiment of the invention the VAS score may be 45 mm or more, or 50 mm or more. Similarly, if a subject rates their condition on the VRS as, for example, “moderate scabies” or more, then the subject may be considered to have moderate to severe atopic dermatitis (see Reich et al. (2012)). . Alternatively, if a subject is assessed, for example, by an EASI of 10 or more, an sIGA of 3 or more, or a total score of 4 or more when assessing the severity of scabies during the day or night using the Shiratori severity rating criterion, then he may be considered a subject suffering from moderate to severe atopic dermatitis. In another embodiment, if the subject's body surface area affected by a rash with signs of intense inflammation is, for example, 5% or more, then the subject may be considered to be suffering from moderate to severe atopic dermatitis. In another embodiment, if the subject's condition corresponds to the value of one or a combination of multiple indices, as described herein, then the subject may be considered to be suffering from moderate to severe atopic dermatitis.

The term "subject" as used herein preferably means, but is not limited to, an animal, more preferably a mammal (which may be a mouse, rat, rabbit, dog, monkey (e.g., cynomolgus), human, or similar mammals, and most preferably human). The term “person” can mean an adult (ie, 18 years of age or more) or a child (ie, 0 to 18 years of age, eg, 6 months to 18 years of age).

In one embodiment, the present invention provides a pharmaceutical composition for the prevention and/or treatment of atopic dermatitis (the term "prophylactic agent and/or therapeutic agent" may also be used synonymously with the term "pharmaceutical composition for prevention and/or treatment" containing an IL antagonist -31 as active ingredient.

In this case, the IL-31 antagonist is intended to be administered multiple times in equal amounts at regular dosing intervals, administered at predetermined intervals, and at predetermined dosages (doses), detailed below.

In one embodiment of the present invention, a pharmaceutical composition, as described in this context, can be used for the prevention and/or treatment of itching mediated by atopic dermatitis.

In yet another embodiment or other embodiment, a pharmaceutical composition as described herein can be used to improve the symptoms of sleep disturbance caused by atopic dermatitis, where the sleep disturbance may be caused by itching associated with atopic dermatitis. Improvements in sleep disorder symptoms may be characterized by, for example, an increase in the time from falling asleep to waking up, and/or a decrease in sleep onset delay (the period from the time the patient goes to bed until falling asleep).

In yet another additional embodiment or other embodiment, a pharmaceutical composition as described herein can be used to suppress at least one symptom caused by atopic dermatitis selected from the group consisting of: redness, induration, papules, swelling, excoriation, and lichenification .

In one embodiment of the present invention, prevention and/or treatment of atopic dermatitis may refer to, for example, but not limited to, administering a drug or the like to a subject who has been diagnosed with atopic dermatitis or exhibits various symptoms caused by atopic dermatitis (eg, itching , redness, induration, papules, edema, excoriation, lichenification, decreased quality of life (QOL), and sleep deprivation) to suppress one or more of these symptoms and/or, for example, administering a drug or the like to a subject who has previously developed atopic dermatitis or various symptoms caused by atopic dermatitis to exclude the development or reduce the incidence of one or more of these symptoms. Prophylaxis and/or treatment of atopic dermatitis may be prescribed or determined to be suitable for prophylaxis and/or treatment provided that they improve the symptoms of any of the various symptoms caused by atopic dermatitis, even if they cannot prevent and/or cure atopic dermatitis per se .

The term “subject predisposed to developing atopic dermatitis” may refer to, but is not limited to, a subject who has suffered from atopic dermatitis in the past and is at risk for varying development of symptoms of the disease, or may refer to a subject suspected of developing atopic dermatitis before before the treating physician or other clinician diagnoses or identifies the subject as developing atopic dermatitis.

In one embodiment, in some cases, prevention and treatment of atopic dermatitis can be considered synonymous.

In a trial of single doses of an IL-31 antagonist administered subcutaneously to patients suffering from atopic dermatitis, as described in the Examples section, improvements in sleep efficiency were observed in the group of patients treated with the IL-31 antagonist.

Although atopic dermatitis is not necessarily a serious, life-threatening disease, the symptoms associated with the disease significantly affect the subject's daily functioning. For example, itching, which is the most characteristic symptom, is an unpleasant sensation that significantly reduces the patient's quality of life (QOL), and according to the literature, it is a cause of sleep disturbance (see article Zuberbier T., Orlow S.J., Paller A.S., Taieb A. , Allen R., Hernanz-Hermosa J.M., Ocampo-Candiani J., Cox M., Langeraar J., Simon J.C., Patient perspective on the management of atopic dermatitis, J. Allergy Clin. Immunol., 118, 226-232 ( 2006)). In addition, in the case when the patient is a child, not only the child suffering from the disease, but also his parents experience a significant burden, and according to the literature, the parents of a child suffering from moderate or severe atopic dermatitis spend 3 hours every day on therapeutic and health care for the child, and their daily sleep time is reduced from 1 to 2 hours per day (see article Su J.S., Kemp A.S., Varigos G.A., Nolan T.M., Atopic eczema: its impact on the family and financial cost , Arch. Dis. Chil., 76, 159-162 (1997)).

Therefore, in another embodiment, the present invention provides a pharmaceutical composition for the prevention and/or treatment of atopic dermatitis, containing an IL-31 antagonist as an active ingredient, which provides further improvement in the symptoms of sleep disturbance caused by atopic dermatitis. In a further embodiment or another embodiment of the present invention, a pharmaceutical composition is provided for reducing QOL that is caused by atopic dermatitis. Improvement in symptoms of sleep disturbance can be characterized, for example, by an increase in the time from falling asleep to awakening, and/or a decrease in sleep onset delay (the period from the time the patient goes to bed until falling asleep).

The term "multiple times of administration in equal amounts at equal dosing intervals" as used herein, in one embodiment of the present invention may mean that the dose (initial dose) at which the IL-31 antagonist of the invention is initially administered to a subject is a constant dose at which the IL-31 antagonist is subsequently administered (namely, the dose that must be continuously administered after administration of the initial dose), and the IL-31 antagonist is administered at equal intervals between dosing (interdose interval). More specifically, the language presented above, for example, may mean that the interval between the administration of the initial dose and the administration of the first constant dose, or each interval between the administration of n times (n is an integer - 1 or more) of the constant dose and (n+1) administration the constant doses are equal, and the administered doses are equal. In another embodiment, in a further embodiment of the present invention, the term "multiple administrations in equal amounts at equal dosing intervals" as used in this context may mean that although the initial dose is different from the constant dose, each constant dose is equal and the antagonist IL-31 is administered at regular intervals between constant doses (dosing interval).

The dose (dosage), expressed in mg/kg or mg/body of the IL-31 antagonist of the invention, may refer to both the initial dose and continuous doses when the initial dose and continuous doses are equal, and may refer to continuous doses when the initial dose and constant doses vary unless otherwise indicated and unless inconsistent with the context.

One skilled in the art will understand that for certain dosing intervals (eg, every 4 weeks when the dosing interval is every 4 weeks), each interval includes a "tolerable range" and one skilled in the art technicians can determine the acceptable range if necessary.

In one embodiment of the present invention, the term "multiple administration times" may mean that, for example, the number of constant doses after the initial dose is administered is from 1 to 10,000 or more, for example, and more specifically, but not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, … 15, … 20, … 25, … 35, … 40, … 50, … 60, … 70, … 80, … 90, … 100 , … 500, … 1000, … 10000, ….

In one embodiment of the present invention, the interval between dosing of a pharmaceutical composition of the invention or an IL-31 antagonist of the invention is intended to be a minimum period of 1 day or more and a maximum period of 12 weeks or less, and more specifically may be , for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks , 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months or 3 months. The interval between dosing may be specified in various ways, and may be more specifically specified, for example, once daily or once every 12 weeks, or may be specified as every 24 hours or every 12 weeks.

According to the present invention, the dosage(s) may be expressed in units other than mg/kg, for example, a fixed dose (mg/body) corresponds to a dose calculated as the amount of drug per body weight of the subject, or a dose calculated as the amount of drug funds per unit surface area of the subject's body (mg/m ² ).

For example, when it is contemplated that an IL-31 antagonist, as described herein, is to be administered at a fixed dose (mg/body) to a subject suffering from or predisposed to developing atopic dermatitis, the doses of the IL-31 antagonist expressed in mg/body kg, as described herein, can be converted into doses expressed in mg/body, and the corresponding doses (mg/body) can be selected and administered to the subject. In this case, although the algorithm for converting mg/kg to mg/body is not limited, if necessary, the dosage in mg/body can be determined using an algorithm known to one skilled in the art. One possible example of such an algorithm is as follows.

Assuming that there is a minimum effective serum concentration and a maximum tolerable (empirical) serum concentration of the IL-31 antagonist of the invention, changing the mg/kg dosage to a mg/body dosage can be made given that the concentration of the IL-31 antagonist in serum is within the specified concentration range, regardless of body weight. The subject's body weight, for example, may be less than 100 kg or less than 120 kg. The dosage in mg/body for a subject with a large body weight (eg, body weight is more than 100 kg or more than 120 kg) can be increased if necessary, but not limited to. Moreover, if the mg/body dosage for a low body weight child significantly increases plasma drug levels, then the mg/kg dosage may be used.

In a non-limiting embodiment of the present invention, for a subject predisposed to developing atopic dermatitis, such as an adult or a child, the single dose of the IL-31 antagonist of the invention may be selected from the range of 0.1 mg to 1000 mg/body, for example, 0.2 mg to 360 mg/body, and preferably, for example, 10 mg to 100 mg/body, 10 mg to 75 mg/body, 10 mg to 50 mg/body, 10 mg to 40 mg/body, 10 mg to 39.5 mg/body, from 10 mg to 39 mg/body, from 10 mg to 38.5 mg/body, from 10 mg to 38 mg/body, from 10 mg to 37.5 mg/body, from 15 mg to 100 mg/body, from 15 mg to 75 mg/body, from 15 mg to 50 mg/body, from 15 mg to 40 mg/body, from 15 mg to 39.5 mg/body, from 15 mg to 39 mg/body, from 15 mg to 38.5 mg/body, from 15 mg to 38 mg/body, from 15 mg to 37.5 mg/body, from 17.5 mg to 100 mg/body, from 17, 5 mg to 75 mg/body, from 17.5 mg to 50 mg/body, from 17.5 mg to 40 mg/body, from 17.5 mg to 39.5 mg/body, from 17.5 mg to 39 mg/body, from 17.5 mg to 38.5 mg/body, from 17.5 mg to 38 mg/body, from 17.5 mg to 37.5 mg/body, from 20 mg to 100 mg/body, from 20 mg to 75 mg/body, from 20 mg to 50 mg/body, from 20 mg to 40 mg/body, from 20 mg to 39.5 mg/body, from 20 mg to 39 mg/body, from 20 mg up to 38.5 mg/body, from 20 mg to 38 mg/body, from 20 mg to 37.5 mg/body, from 22.5 mg to 100 mg/body, from 22.5 mg to 75 mg/body, from 22.5 mg to 50 mg/body, from 22.5 mg to 40 mg/body, from 22.5 mg to 39.5 mg/body, from 22.5 mg to 39 mg/body, from 22.5 mg to 38.5 mg/body, from 22.5 mg to 38 mg/body, from 22.5 mg to 37.5 mg/body, from 25 mg to 500 mg/body, from 25 mg to 200 mg/body , from 25 mg to 120 mg/body, from 25 mg to 110 mg/body, from 25 mg to 100 mg/body, from 25 mg to 90 mg/body, from 25 mg to 80 mg/body, from 25 mg to 79 mg/body, from 25 mg to 78 mg/body, from 25 mg to 77 mg/body, from 25 mg to 76 mg/body, from 25 mg to 75 mg/body, from 25 mg to 74 mg/body, from 25 mg to 73 mg/body, from 25 mg to 72 mg/body, from 25 mg to 71 mg/body, from 25 mg to 70 mg/body, from 25 mg to 50 mg/body, from 30 mg to 50 mg/body, from 30 mg to 75 mg/body, from 30 mg to 100 mg/body, from 30 mg to 150 mg/body, from 30 mg to 200 mg/body, from 30 mg to 250 mg/body, from 30 mg to 300 mg/body, from 40 mg to 70 mg/body, from 40 mg to 71 mg/body, from 40 mg to 72 mg/body, from 40 mg to 73 mg/body, from 40 mg to 74 mg /body, from 40 mg to 75 mg/body, from 40 mg to 76 mg/body, from 40 mg to 77 mg/body, from 40 mg to 78 mg/body, from 40 mg to 79 mg/body, from 40 mg to 80 mg/body, from 40 mg to 90 mg/body, from 40 mg to 100 mg/body, from 40 mg to 110 mg/body, from 40 mg to 120 mg/body, from 42.5 mg to 70 mg/body, from 42.5 mg to 71 mg/body, from 42.5 mg to 72 mg/body, from 42.5 mg to 73 mg/body, from 42.5 mg to 74 mg/body, from 42 .5 mg to 75 mg/body, from 42.5 mg to 76 mg/body, from 42.5 mg to 77 mg/body, from 42.5 mg to 78 mg/body, from 42.5 mg to 79 mg /body, from 42.5 mg to 80 mg/body, from 42.5 mg to 90 mg/body, from 42.5 mg to 100 mg/body, from 42.5 mg to 110 mg/body, from 42, 5 mg to 120 mg/body, from 45 mg to 70 mg/body, from 45 mg to 71 mg/body, from 45 mg to 72 mg/body, from 45 mg to 73 mg/body, from 45 mg to 74 mg /body, from 45 mg to 75 mg/body, from 45 mg to 76 mg/body, from 45 mg to 77 mg/body, from 45 mg to 78 mg/body, from 45 mg to 79 mg/body, from 45 mg to 80 mg/body, from 45 mg to 90 mg/body, from 45 mg to 100 mg/body, from 45 mg to 110 mg/body, from 45 mg to 120 mg/body, from 47.5 mg to 70 mg/body, from 47.5 mg to 71 mg/body, from 47.5 mg to 72 mg/body, from 47.5 mg to 73 mg/body, from 47.5 mg to 74 mg/body, from 47 .5 mg to 75 mg/body, from 47.5 mg to 76 mg/body, from 47.5 mg to 77 mg/body, from 47.5 mg to 78 mg/body, from 47.5 mg to 79 mg /body, from 47.5 mg to 80 mg/body, from 47.5 mg to 90 mg/body, from 47.5 mg to 100 mg/body, from 47.5 mg to 110 mg/body, from 47, 5 mg to 120 mg/body, from 50 mg to 70 mg/body, from 50 mg to 71 mg/body, from 50 mg to 72 mg/body, from 50 mg to 73 mg/body, from 50 mg to 74 mg /organism, from 50 mg to 75 mg/organism, from 50 mg to 76 mg/organism, from 50 mg to 77 mg/organism, from 50 mg to 78 mg/organism, from 50 mg to 79 mg/organism, from 50 mg to 80 mg/body, from 50 mg to 90 mg/body, from 50 mg to 100 mg/body, from 50 mg to 110 mg/body, from 50 mg to 120 mg/body, from 50 mg to 150 mg/ body, from 50 mg to 200 mg/body, from 50 mg to 250 mg/body, from 50 mg to 300 mg/body, from 52.5 mg to 70 mg/body, from 52.5 mg to 71 mg/body , from 52.5 mg to 72 mg/body, from 52.5 mg to 73 mg/body, from 52.5 mg to 74 mg/body, from 52.5 mg to 75 mg/body, from 52.5 mg up to 76 mg/body, from 52.5 mg to 77 mg/body, from 52.5 mg to 78 mg/body, from 52.5 mg to 79 mg/body, from 52.5 mg to 80 mg/body, from 52.5 mg to 90 mg/body, from 52.5 mg to 100 mg/body, from 52.5 mg to PO mg/body, from 52.5 mg to 120 mg/body, from 75 mg to 100 mg /body, from 75 mg to 150 mg/body, from 75 mg to 200 mg/body, from 75 mg to 250 mg/body, from 75 mg to 300 mg/body, from 100 mg to 150 mg/body, from 100 mg to 200 mg/body, from 100 mg to 250 mg/body, from 100 mg to 300 mg/body, from 150 mg to 200 mg/body, from 150 mg to 250 mg/body, from 150 mg to 300 mg/ body, from 200 mg to 250 mg/body and from 200 to 300 mg/body, and these doses can be administered several times at the intervals described above, in equal amounts at equal intervals. To avoid any misunderstanding, it is precisely stated that, for example, the interval "from 0.1 to 1000 mg/body" means that all dosages included in the interval between 0.1 and 1000 mg/body are specifically and individually listed in this description in increments 0.1 mg/body, e.g. 0.1 mg/body, 0.2 mg/body, 0.3 mg/body, 0.4 mg/body, ... 49.9 mg/body, 50 mg/body, 50.1 mg/body, 50.2 mg/body, … 99.8 mg/body, 99.9 mg/body, 100 mg/body, 100.1 mg/body, 100.2 mg/body, … 199 .9 mg/organism, 200 mg/organism, 200.1 mg/organism, ... 359.8 mg/organism, 359.9 mg/organism, 360 mg/organism, 360.1 mg/organism, ... 999.8 mg /body, 999.9 mg/body and 1000 mg/body. Thus, for example, it would be apparent to one skilled in the art that the range "50 to 200 mg/body" includes values listed specifically and individually, such as 50 mg/body, 50.5 mg/body, 51 mg/body, 51.5 mg/body, 52 mg/body, 52.5 mg/body, 53 mg/body, 53.5 mg/body, 54 mg/body, 54.5 mg/body, 55 mg/ body, 55.5 mg/body, 56 mg/body, 56.5 mg/body, 57 mg/body, 57.5 mg/body, 58 mg/body, 58.5 mg/body, 59 mg/body, 59.5 mg/body, 60 mg/body, 60.5 mg/body, 61 mg/body, 61.5 mg/body, 62 mg/body, 62.5 mg/body, 63 mg/body, 63, 5 mg/body, 64 mg/body, 64.5 mg/body, 65 mg/body, 65.5 mg/body, 66 mg/body, 66.5 mg/body, 67 mg/body, 67.5 mg /organism, 68 mg/organism, 68.5 mg/organism, 69 mg/organism, 69.5 mg/organism, 70 mg/organism, 70.5 mg/organism, 71 mg/organism, 71.5 mg/organism , 72 mg/body, 72.5 mg/body, 73 mg/body, 73.5 mg/body, 74 mg/body, 74.5 mg/body, 75 mg/body, 75.5 mg/body, 76 mg/body, 76.5 mg/body, 77 mg/body, 77.5 mg/body, 78 mg/body, 78.5 mg/body, 79 mg/body, 79.5 mg/body, 80 mg/ body, 80.5 mg/body, 81 mg/body, 81.5 mg/body, 82 mg/body, 82.5 mg/body, 83 mg/body, 83.5 mg/body, 84 mg/body, 84.5 mg/body, 85 mg/body, 85.5 mg/body, 86 mg/body, 86.5 mg/body, 87 mg/body, 87.5 mg/body, 88 mg/body, 88, 5 mg/body, 89 mg/body, 89.5 mg/body, 90 mg/body, 90.5 mg/body, 91 mg/body, 91.5 mg/body, 92 mg/body, 92.5 mg /organism, 93 mg/organism, 93.5 mg/organism, 94 mg/organism, 94.5 mg/organism, 95 mg/organism, 95.5 mg/organism, 96 mg/organism, 96.5 mg/organism , 97 mg/body, 97.5 mg/body, 98 mg/body, 98.5 mg/body, 99 mg/body, 99.5 mg/body, 100 mg/body, 100.5 mg/body, 101 mg/body, 101.5 mg/body, 102 mg/body, 102.5 mg/body, 103 mg/body, 103.5 mg/body, 104 mg/body, 104.5 mg/body, 105 mg/ body, 105.5 mg/body, 106 mg/body, 106.5 mg/body, 107 mg/body, 107.5 mg/body, 108 mg/body, 108.5 mg/body, 109 mg/body, 109.5 mg/body, 110 mg/body, 110.5 mg/body, 111 mg/body, 111.5 mg/body, 112 mg/body, 112.5 mg/body, 113 mg/body, 113, 5 mg/body, 114 mg/body, 114.5 mg/body, 115 mg/body, 115.5 mg/body, 116 mg/body, 116.5 mg/body, 117 mg/body, 117.5 mg /organism, 118 mg/organism, 118.5 mg/organism, 119 mg/organism, 119.5 mg/organism, 120 mg/organism, 120.5 mg/organism, 121 mg/organism, 121.5 mg/organism , 122 mg/body, 122.5 mg/body, 123 mg/body, 123.5 mg/body, 124 mg/body, 124.5 mg/body, 125 mg/body, 125.5 mg/body, 126 mg/body, 126.5 mg/body, 127 mg/body, 127.5 mg/body, 128 mg/body, 128.5 mg/body, 129 mg/body, 129.5 mg/body, 130 mg/ body, 130.5 mg/body, 131 mg/body, 131.5 mg/body, 132 mg/body, 132.5 mg/body, 133 mg/body, 133.5 mg/body, 134 mg/body, 134.5 mg/body, 135 mg/body, 135.5 mg/body, 136 mg/body, 136.5 mg/body, 137 mg/body, 137.5 mg/body, 138 mg/body, 138, 5 mg/body, 139 mg/body, 139.5 mg/body, 140 mg/body, 140.5 mg/body, 141 mg/body, 141.5 mg/body, 142 mg/body, 142.5 mg /organism, 143 mg/organism, 143.5 mg/organism, 144 mg/organism, 144.5 mg/organism, 145 mg/organism, 145.5 mg/organism, 146 mg/organism, 146.5 mg/organism , 147 mg/body, 147.5 mg/body, 148 mg/body, 148.5 mg/body, 149 mg/body, 149.5 mg/body, 150 mg/body, 150.5 mg/body, 151 mg/body, 151.5 mg/body, 152 mg/body, 152.5 mg/body, 153 mg/body, 153.5 mg/body, 154 mg/body, 154.5 mg/body, 155 mg/ body, 155.5 mg/body, 156 mg/body, 156.5 mg/body, 157 mg/body, 157.5 mg/body, 158 mg/body, 158.5 mg/body, 159 mg/body, 159.5 mg/body, 160 mg/body, 160.5 mg/body, 161 mg/body, 161.5 mg/body, 162 mg/body, 162.5 mg/body, 163 mg/body, 163, 5 mg/body, 164 mg/body, 164.5 mg/body, 165 mg/body, 165.5 mg/body, 166 mg/body, 166.5 mg/body, 167 mg/body, 167.5 mg /organism, 168 mg/organism, 168.5 mg/organism, 169 mg/organism, 169.5 mg/organism, 170 mg/organism, 170.5 mg/organism, 171 mg/organism, 171.5 mg/organism , 172 mg/body, 172.5 mg/body, 173 mg/body, 173.5 mg/body, 174 mg/body, 174.5 mg/body, 175 mg/body, 175.5 mg/body, 176 mg/body, 176.5 mg/body, 177 mg/body, 177.5 mg/body, 178 mg/body, 178.5 mg/body, 179 mg/body, 179.5 mg/body, 180 mg/ body, 180.5 mg/body, 181 mg/body, 181.5 mg/body, 182 mg/body, 182.5 mg/body, 183 mg/body, 183.5 mg/body, 184 mg/body, 184.5 mg/body, 185 mg/body, 185.5 mg/body, 186 mg/body, 186.5 mg/body, 187 mg/body, 187.5 mg/body, 188 mg/body, 188, 5 mg/body, 189 mg/body, 189.5 mg/body, 190 mg/body, 190.5 mg/body, 191 mg/body, 191.5 mg/body, 192 mg/body, 192.5 mg /organism, 193 mg/organism, 193.5 mg/organism, 194 mg/organism, 194.5 mg/organism, 195 mg/organism, 195.5 mg/organism, 196 mg/organism, 196.5 mg/organism , 197 mg/body, 197.5 mg/body, 198 mg/body, 198.5 mg/body, 199 mg/body, 199.5 mg/body, and 200 mg/body.

In another non-limiting embodiment of the present invention, for a subject suffering from or predisposed to developing atopic dermatitis, for example a child, the single dose may be selected from the range of 0.01 to 10 mg/kg, for example 0.05 to 7.5 mg/kg, 0.075 to 5 mg/kg or 0.1 to 3 mg/kg, and preferably, for example, 0.1 mg to 0.25 mg/kg, 0.1 mg to 0.3 mg /kg, from 0.1 mg to 0.5 mg/kg, from 0.1 mg to 0.75 mg/kg, from 0.1 mg to 1 mg/kg, from 0.1 mg to 1.5 mg /kg, from 0.1 mg to 2 mg/kg, from 0.1 mg to 3 mg/kg, from 0.125 mg to 0.25 mg/kg, from 0.125 mg to 0.3 mg/kg, from 0.125 mg up to 0.5 mg/kg, from 0.125 mg to 0.75 mg/kg, from 0.125 mg to 1 mg/kg, from 0.125 mg to 1.5 mg/kg, from 0.125 mg to 2 mg/kg, from 0.125 mg to 3 mg/kg, from 0.2 mg to 0.3 mg/kg, from 0.2 mg to 0.5 mg/kg, from 0.2 mg to 0.75 mg/kg, from 0.2 mg to 1 mg/kg, from 0.2 mg to 1.5 mg/kg, from 0.2 mg to 2 mg/kg, from 0.2 mg to 3 mg/kg, from 0.25 mg to 0, 3 mg/kg, from 0.25 mg to 0.5 mg/kg, from 0.25 mg to 0.75 mg/kg, from 0.25 mg to 1 mg/kg, from 0.25 mg to 1, 5 mg/kg, from 0.25 mg to 2 mg/kg, from 0.25 mg to 3 mg/kg, from 0.3 mg to 0.5 mg/kg, from 0.3 mg to 0.75 mg /kg, from 0.3 mg to 1 mg/kg, from 0.3 mg to 1.5 mg/kg, from 0.3 mg to 2 mg/kg, from 0.3 mg to 3 mg/kg, from 0.5 mg to 0.75 mg/kg, from 0.5 mg to 1 mg/kg, from 0.5 mg to 1.5 mg/kg, from 0.5 mg to 2 mg/kg, from 0. 5 mg to 3 mg/kg, from 0.75 mg to 1 mg/kg, from 0.75 mg to 1.5 mg/kg, from 0.75 mg to 2 mg/kg, from 0.75 mg to 3 mg/kg, from 1 mg to 1.5 mg/kg, from 1 mg to 2 mg/kg, from 1 mg to 3 mg/kg, from 1.5 mg to 2 mg/kg, from 1.5 mg to 3 mg/kg, from 2 mg to 3 mg/kg, from 0.15 mg to 2.9 mg/kg, from 0.2 mg to 2.8 mg/kg, from 0.25 mg to 2.7 mg /kg, from 0.3 mg to 2.6 mg/kg, from 0.35 mg to 2.5 mg/kg, from 0.4 mg to 2.4 mg/kg, from 0.425 mg to 2.3 mg /kg, from 0.45 mg to 2.2 mg/kg, from 0.475 to 2.1 mg/kg or from 0.5 to 2 mg/kg, or more preferably from 0.5 to 1.5 mg/kg , for example, as a dosage of the IL-31 antagonist of the invention, and these doses can be administered several times at the intervals described above between dosing in equal amounts at equal intervals. To avoid any misunderstanding, it is precisely stated that, for example, the interval "from 0.01 to 10 mg/kg" includes all doses included in the range from 0.01 to 10 mg/kg, listed specifically and individually in this description in increments of 0.005 mg/body, e.g. 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.03 mg/kg, 0.035 mg/kg, 0.04 mg/kg, … 0.125 mg/kg, ... 0.49 mg/kg, 0.495 mg/kg, 0.5 mg/kg, 0.505 mg/kg, 0.51 mg/kg, ... 0.98 mg/kg, 0.985 mg/kg, 0.99 mg/kg, 0.995 mg/kg, 1 mg/kg, 1.005 mg/kg, 1.01 mg/kg, ..., 1.49 mg/kg, 1.495 mg/kg, 1.5 mg/kg, 1.505 mg/kg, 1.51 mg/kg, ... 1.98 mg/kg, 1.985 mg/kg, 1.99 mg/kg, 1.995 mg/kg, 2 mg/kg, 2.005 mg/kg, 2.01 mg/kg, ... 2.99 mg/kg, 2.995 mg/kg, 3 mg/kg, 3.005 mg/kg, 3.01 mg/kg, ... 9.98 mg/kg, 9.985 mg/kg, 9.99 mg/kg, 9.995 mg/kg and 10 mg/kg. Thus, for example, it would be apparent to one skilled in the art that the range "0.1 to 3 mg/kg" would naturally include values listed specifically and individually, such as, for example, 0.1 mg/kg, 0. 11 mg/kg, 0.12 mg/kg, 0.125 mg/kg, 0.13 mg/kg, 0.14 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/ kg, 0.18 mg/kg, 0.19 mg/kg, 0.2 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.23 mg/kg, 0.24 mg/kg , 0.25 mg/kg, 0.26 mg/kg, 0.27 mg/kg, 0.28 mg/kg, 0.29 mg/kg, 0.3 mg/kg, 0.31 mg/kg, 0.32 mg/kg, 0.33 mg/kg, 0.34 mg/kg, 0.35 mg/kg, 0.36 mg/kg, 0.37 mg/kg, 0.38 mg/kg, 0 .39 mg/kg, 0.4 mg/kg, 0.41 mg/kg, 0.42 mg/kg, 0.43 mg/kg, 0.44 mg/kg, 0.45 mg/kg, 0, 46 mg/kg, 0.47 mg/kg, 0.48 mg/kg, 0.49 mg/kg, 0.5 mg/kg, 0.51 mg/kg, 0.52 mg/kg, 0.53 mg/kg, 0.54 mg/kg, 0.55 mg/kg, 0.56 mg/kg, 0.57 mg/kg, 0.58 mg/kg, 0.59 mg/kg, 0.6 mg /kg, 0.61 mg/kg, 0.62 mg/kg, 0.63 mg/kg, 0.64 mg/kg, 0.65 mg/kg, 0.66 mg/kg, 0.67 mg/ kg, 0.68 mg/kg, 0.69 mg/kg, 0.7 mg/kg, 0.71 mg/kg, 0.72 mg/kg, 0.73 mg/kg, 0.74 mg/kg , 0.75 mg/kg, 0.76 mg/kg, 0.77 mg/kg, 0.78 mg/kg, 0.79 mg/kg, 0.8 mg/kg, 0.81 mg/kg, 0.82 mg/kg, 0.83 mg/kg, 0.84 mg/kg, 0.85 mg/kg, 0.86 mg/kg, 0.87 mg/kg, 0.88 mg/kg, 0 .89 mg/kg, 0.9 mg/kg, 0.91 mg/kg, 0.92 mg/kg, 0.93 mg/kg, 0.94 mg/kg, 0.95 mg/kg, 0, 96 mg/kg, 0.97 mg/kg, 0.98 mg/kg, 0.99 mg/kg, 1 mg/kg, 1.01 mg/kg, 1.02 mg/kg, 1.03 mg/ kg, 1.04 mg/kg, 1.05 mg/kg, 1.06 mg/kg, 1.07 mg/kg, 1.08 mg/kg, 1.09 mg/kg, 1.1 mg/kg , 1.11 mg/kg, 1.12 mg/kg, 1.13 mg/kg, 1.14 mg/kg, 1.15 mg/kg, 1.16 mg/kg, 1.17 mg/kg, 1.18 mg/kg, 1.19 mg/kg, 1.2 mg/kg, 1.21 mg/kg, 1.22 mg/kg, 1.23 mg/kg, 1.24 mg/kg, 1 .25 mg/kg, 1.26 mg/kg, 1.27 mg/kg, 1.28 mg/kg, 1.29 mg/kg, 1.3 mg/kg, 1.31 mg/kg, 1, 32 mg/kg, 1.33 mg/kg, 1.34 mg/kg, 1.35 mg/kg, 1.36 mg/kg, 1.37 mg/kg, 1.38 mg/kg, 1.39 mg/kg, 1.4 mg/kg, 1.41 mg/kg, 1.42 mg/kg, 1.43 mg/kg, 1.44 mg/kg, 1.45 mg/kg, 1.46 mg /kg, 1.47 mg/kg, 1.48 mg/kg, 1.49 mg/kg, 1.5 mg/kg, 1.51 mg/kg, 1.52 mg/kg, 1.53 mg/ kg, 1.54 mg/kg, 1.55 mg/kg, 1.56 mg/kg, 1.57 mg/kg, 1.58 mg/kg, 1.59 mg/kg, 1.6 mg/kg , 1.61 mg/kg, 1.62 mg/kg, 1.63 mg/kg, 1.64 mg/kg, 1.65 mg/kg, 1.66 mg/kg, 1.67 mg/kg, 1.68 mg/kg, 1.69 mg/kg, 1.7 mg/kg, 1.71 mg/kg, 1.72 mg/kg, 1.73 mg/kg, 1.74 mg/kg, 1 .75 mg/kg, 1.76 mg/kg, 1.77 mg/kg, 1.78 mg/kg, 1.79 mg/kg, 1.8 mg/kg, 1.81 mg/kg, 1, 82 mg/kg, 1.83 mg/kg, 1.84 mg/kg, 1.85 mg/kg, 1.86 mg/kg, 1.87 mg/kg, 1.88 mg/kg, 1.89 mg/kg, 1.9 mg/kg, 1.91 mg/kg, 1.92 mg/kg, 1.93 mg/kg, 1.94 mg/kg, 1.95 mg/kg, 1.96 mg /kg, 1.97 mg/kg, 1.98 mg/kg, 1.99 mg/kg, 2 mg/kg, 2.01 mg/kg, 2.02 mg/kg, 2.03 mg/kg, 2.04 mg/kg, 2.05 mg/kg, 2.06 mg/kg, 2.07 mg/kg, 2.08 mg/kg, 2.09 mg/kg, 2.1 mg/kg, 2 ,11 mg/kg, 2.12 mg/kg, 2.13 mg/kg, 2.14 mg/kg, 2.15 mg/kg, 2.16 mg/kg, 2.17 mg/kg, 2, 18 mg/kg, 2.19 mg/kg, 2.2 mg/kg, 2.21 mg/kg, 2.22 mg/kg, 2.23 mg/kg, 2.24 mg/kg, 2.25 mg/kg, 2.26 mg/kg, 2.27 mg/kg, 2.28 mg/kg, 2.29 mg/kg, 2.3 mg/kg, 2.31 mg/kg, 2.32 mg /kg, 2.33 mg/kg, 2.34 mg/kg, 2.35 mg/kg, 2.36 mg/kg, 2.37 mg/kg, 2.38 mg/kg, 2.39 mg/ kg, 2.4 mg/kg, 2.41 mg/kg, 2.42 mg/kg, 2.43 mg/kg, 2.44 mg/kg, 2.45 mg/kg, 2.46 mg/kg , 2.47 mg/kg, 2.48 mg/kg, 2.49 mg/kg, 2.5 mg/kg, 2.51 mg/kg, 2.52 mg/kg, 2.53 mg/kg, 2.54 mg/kg, 2.55 mg/kg, 2.56 mg/kg, 2.57 mg/kg, 2.58 mg/kg, 2.59 mg/kg, 2.6 mg/kg, 2 .61 mg/kg, 2.62 mg/kg, 2.63 mg/kg, 2.64 mg/kg, 2.65 mg/kg, 2.66 mg/kg, 2.67 mg/kg, 2, 68 mg/kg, 2.69 mg/kg, 2.7 mg/kg, 2.71 mg/kg, 2.72 mg/kg, 2.73 mg/kg, 2.74 mg/kg, 2.75 mg/kg, 2.76 mg/kg, 2.77 mg/kg, 2.78 mg/kg, 2.79 mg/kg, 2.8 mg/kg, 2.81 mg/kg, 2.82 mg /kg, 2.83 mg/kg, 2.84 mg/kg, 2.85 mg/kg, 2.86 mg/kg, 2.87 mg/kg, 2.88 mg/kg, 2.89 mg/ kg, 2.9 mg/kg, 2.91 mg/kg, 2.92 mg/kg, 2.93 mg/kg, 2.94 mg/kg, 2.95 mg/kg, 2.96 mg/kg , 2.97 mg/kg, 2.98 mg/kg, 2.99 mg/kg and 3 mg/kg.

In the above-described embodiment of the present invention, where the IL-31 antagonist of the invention is administered several times in equal amounts at equal dosing intervals, using a predetermined dosing interval and a predetermined dose (dosage), the IL-31 antagonist of the invention can administered in a dosage range of “from 0.1 to 1000 mg/body/for 1 day to 12 weeks.” The range of "0.1 to 1000 mg/body/for 1 day to 12 weeks" as used herein means, for example, that a single dose is selected from the range of 0.1 to 1000 mg as the dosage (e.g. 100 mg/body) of the IL-31 antagonist of the invention, and any dosing interval selected from 1 day to 12 weeks as the dosing interval (eg, 4 weeks) of the IL-31 antagonist of the invention, and the IL antagonist -31 is administered to the subject several times in equal amounts at equal dosing intervals. For example, a dose of "100 mg/body/4 weeks" means that a 100 mg/body dose of the IL-31 antagonist of the invention is administered multiple times to a subject every 4 weeks in equal amounts at equal dosing intervals. In one embodiment of the present invention, where the IL-31 antagonist of the invention is administered multiple times in equal amounts at equal dosing intervals using a predetermined dosing interval and a predetermined dose (dosage), the IL-31 antagonist of the invention is preferably administered at a dosage ranging from 0.1 to 1000 mg/body/for 2 weeks to 8 weeks, and may be administered, for example, but not limited to, at a dose ranging from 0.1 to 1000 mg/body/2 weeks, from 0.1 to 1000 mg/body/4 weeks, from 0.1 to 1000 mg/body/6 weeks or from 0.1 to 1000 mg/body/8 weeks. In another embodiment, the IL-31 antagonist of the invention is more preferably administered at a dose ranging from 0.2 to 360 mg/body/for 2 weeks to 8 weeks, and may be administered, for example, at a dose ranging from 0.2 up to 360 mg/body/2 weeks, from 0.2 to 360 mg/body/4 weeks, from 0.2 to 360 mg/body/6 weeks or from 0.2 to 360 mg/body/8 weeks. In yet another embodiment, for example, the IL-31 antagonist of the invention is even more preferably administered at a dose ranging from 10 to 200 mg/body/over a period of 2 weeks to 8 weeks, and may be administered, for example, at a dose ranging from 10 to 200 mg/body/2 weeks, 10 to 200 mg/body/4 weeks, 10 to 200 mg/body/6 weeks, or 10 to 200 mg/body/8 weeks. In another embodiment, for example, the IL-31 antagonist of the invention is even more preferably administered at a dose ranging from 10 to 100 mg/body/for 2 weeks to 8 weeks, and may be administered, for example, at a dose ranging from 10 up to 100 mg/body/2 weeks, from 10 to 100 mg/body/4 weeks, from 10 to 100 mg/body/6 weeks or from 10 to 100 mg/body/8 weeks. In another embodiment, for example, the IL-31 antagonist of the invention can be administered in the range of 25 to 100 mg/body/4 weeks, 25 to 80 mg/body/4 weeks, 25 to 75 mg/body/4 weeks, 50 to 100 mg/body/4 weeks, 50 to 80 mg/body/4 weeks, or 50 to 75 mg/body/4 weeks, or 10 to 50 mg/body/2 weeks, or 20 to 40 mg /body/2 weeks. In a non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 50 mg/body/4 weeks, 50.5 mg/body/4 weeks, 51 mg/body/4 weeks, 51.5 mg/body/4 weeks, 52 mg/body/4 weeks, 52.5 mg/body/4 weeks, 53 mg/body/4 weeks, 53.5 mg/body/4 weeks, 54 mg/body/4 weeks, 54.5 mg /body/4 weeks, 55 mg/body/4 weeks, 55.5 mg/body/4 weeks, 56 mg/body/4 weeks, 56.5 mg/body/4 weeks, 57 mg/body/4 weeks, 57.5 mg/body/4 weeks, 58 mg/body/4 weeks, 58.5 mg/body/4 weeks, 59 mg/body/4 weeks, 59.5 mg/body/4 weeks, 60 mg/body /4 weeks, 60.5 mg/body/4 weeks, 61 mg/body/4 weeks, 61.5 mg/body/4 weeks, 62 mg/body/4 weeks, 62.5 mg/body/4 weeks, 63 mg/body/4 weeks, 63.5 mg/body/4 weeks, 64 mg/body/4 weeks, 64.5 mg/body/4 weeks, 65 mg/body/4 weeks, 65.5 mg/body /4 weeks, 66 mg/body/4 weeks, 66.5 mg/body/4 weeks, 67 mg/body/4 weeks, 67.5 mg/body/4 weeks, 68 mg/body/4 weeks, 68, 5 mg/body/4 weeks, 69 mg/body/4 weeks, 69.5 mg/body/4 weeks, 70 mg/body/4 weeks, 70.5 mg/body/4 weeks, 71 mg/body/4 weeks, 71.5 mg/body/4 weeks, 72 mg/body/4 weeks, 72.5 mg/body/4 weeks, 73 mg/body/4 weeks, 73.5 mg/body/4 weeks, 74 mg /body/4 weeks, 74.5 mg/body/4 weeks, 75 mg/body/4 weeks, 75.5 mg/body/4 weeks, 76 mg/body/4 weeks, 76.5 mg/body/4 weeks, 77 mg/body/4 weeks, 77.5 mg/body/4 weeks, 78 mg/body/4 weeks, 78.5 mg/body/4 weeks, 79 mg/body/4 weeks, 79.5 mg /body/4 weeks, 80 mg/body/4 weeks, 80.5 mg/body/4 weeks, 81 mg/body/4 weeks, 81.5 mg/body/4 weeks, 82 mg/body/4 weeks, 82.5 mg/body/4 weeks, 83 mg/body/4 weeks, 83.5 mg/body/4 weeks, 84 mg/body/4 weeks, 84.5 mg/body/4 weeks, 85 mg/body /4 weeks, 85.5 mg/body/4 weeks, 86 mg/body/4 weeks, 86.5 mg/body/4 weeks, 87 mg/body/4 weeks, 87.5 mg/body/4 weeks, 88 mg/body/4 weeks, 88.5 mg/body/4 weeks, 89 mg/body/4 weeks, 89.5 mg/body/4 weeks, 90 mg/body/4 weeks, 90.5 mg/body /4 weeks, 91 mg/body/4 weeks, 91.5 mg/body/4 weeks, 92 mg/body/4 weeks, 92.5 mg/body/4 weeks, 93 mg/body/4 weeks, 93, 5 mg/body/4 weeks, 94 mg/body/4 weeks, 94.5 mg/body/4 weeks, 95 mg/body/4 weeks, 95.5 mg/body/4 weeks, 96 mg/body/4 weeks, 96.5 mg/body/4 weeks, 97 mg/body/4 weeks, 97.5 mg/body/4 weeks, 98 mg/body/4 weeks, 98.5 mg/body/4 weeks, 99 mg /body/4 weeks, 99.5 mg/body/4 weeks, 100 mg/body/4 weeks, 100.5 mg/body/4 weeks, 101 mg/body/4 weeks, 101.5 mg/body/4 weeks, 102 mg/body/4 weeks, 102.5 mg/body/4 weeks, 103 mg/body/4 weeks, 103.5 mg/body/4 weeks, 104 mg/body/4 weeks, 104.5 mg /body/4 weeks, 105 mg/body/4 weeks, 105.5 mg/body/4 weeks, 106 mg/body/4 weeks, 106.5 mg/body/4 weeks, 107 mg/body/4 weeks, 107.5 mg/body/4 weeks, 108 mg/body/4 weeks, 108.5 mg/body/4 weeks, 109 mg/body/4 weeks, 109.5 mg/body/4 weeks, PO mg/body /4 weeks, 110.5 mg/body/4 weeks, 111 mg/body/4 weeks, 111.5 mg/body/4 weeks, 112 mg/body/4 weeks, 112.5 mg/body/4 weeks, 113 mg/body/4 weeks, 113.5 mg/body/4 weeks, 114 mg/body/4 weeks, 114.5 mg/body/4 weeks, 115 mg/body/4 weeks, 115.5 mg/body /4 weeks, 116 mg/body/4 weeks, 116.5 mg/body/4 weeks, 117 mg/body/4 weeks, 117.5 mg/body/4 weeks, 118 mg/body/4 weeks, 118, 5 mg/body/4 weeks, 119 mg/body/4 weeks, 119.5 mg/body/4 weeks, 120 mg/body/4 weeks, 120.5 mg/body/4 weeks, 121 mg/body/4 weeks, 121.5 mg/body/4 weeks, 122 mg/body/4 weeks, 122.5 mg/body/4 weeks, 123 mg/body/4 weeks, 123.5 mg/body/4 weeks, 124 mg /body/4 weeks, 124.5 mg/body/4 weeks, 125 mg/body/4 weeks, 125.5 mg/body/4 weeks, 126 mg/body/4 weeks, 126.5 mg/body/4 weeks, 127 mg/body/4 weeks, 127.5 mg/body/4 weeks, 128 mg/body/4 weeks, 128.5 mg/body/4 weeks, 129 mg/body/4 weeks, 129.5 mg /body/4 weeks, 130 mg/body/4 weeks, 130.5 mg/body/4 weeks, 131 mg/body/4 weeks, 131.5 mg/body/4 weeks, 132 mg/body/4 weeks, 132.5 mg/body/4 weeks, 133 mg/body/4 weeks, 133.5 mg/body/4 weeks, 134 mg/body/4 weeks, 134.5 mg/body/4 weeks, 135 mg/body /4 weeks, 135.5 mg/body/4 weeks, 136 mg/body/4 weeks, 136.5 mg/body/4 weeks, 137 mg/body/4 weeks, 137.5 mg/body/4 weeks, 138 mg/body/4 weeks, 138.5 mg/body/4 weeks, 139 mg/body/4 weeks, 139.5 mg/body/4 weeks, 140 mg/body/4 weeks, 140.5 mg/body /4 weeks, 141 mg/body/4 weeks, 141.5 mg/body/4 weeks, 142 mg/body/4 weeks, 142.5 mg/body/4 weeks, 143 mg/body/4 weeks, 143, 5 mg/body/4 weeks, 144 mg/body/4 weeks, 144.5 mg/body/4 weeks, 145 mg/body/4 weeks, 145.5 mg/body/4 weeks, 146 mg/body/4 weeks, 146.5 mg/body/4 weeks, 147 mg/body/4 weeks, 147.5 mg/body/4 weeks, 148 mg/body/4 weeks, 148.5 mg/body/4 weeks, 149 mg /body/4 weeks, 149.5 mg/body/4 weeks, 150 mg/body/4 weeks, 150.5 mg/body/4 weeks, 151 mg/body/4 weeks, 151.5 mg/body/4 weeks, 152 mg/body/4 weeks, 152.5 mg/body/4 weeks, 153 mg/body/4 weeks, 153.5 mg/body/4 weeks, 154 mg/body/4 weeks, 154.5 mg /body/4 weeks, 155 mg/body/4 weeks, 155.5 mg/body/4 weeks, 156 mg/body/4 weeks, 156.5 mg/body/4 weeks, 157 mg/body/4 weeks, 157.5 mg/body/4 weeks, 158 mg/body/4 weeks, 158.5 mg/body/4 weeks, 159 mg/body/4 weeks, 159.5 mg/body/4 weeks, 160 mg/body /4 weeks, 160.5 mg/body/4 weeks, 161 mg/body/4 weeks, 161.5 mg/body/4 weeks, 162 mg/body/4 weeks, 162.5 mg/body/4 weeks, 163 mg/body/4 weeks, 163.5 mg/body/4 weeks, 164 mg/body/4 weeks, 164.5 mg/body/4 weeks, 165 mg/body/4 weeks, 165.5 mg/body /4 weeks, 166 mg/body/4 weeks, 166.5 mg/body/4 weeks, 167 mg/body/4 weeks, 167.5 mg/body/4 weeks, 168 mg/body/4 weeks, 168, 5 mg/body/4 weeks, 169 mg/body/4 weeks, 169.5 mg/body/4 weeks, 170 mg/body/4 weeks, 170.5 mg/body/4 weeks, 171 mg/body/4 weeks, 171.5 mg/body/4 weeks, 172 mg/body/4 weeks, 172.5 mg/body/4 weeks, 173 mg/body/4 weeks, 173.5 mg/body/4 weeks, 174 mg /body/4 weeks, 174.5 mg/body/4 weeks, 175 mg/body/4 weeks, 175.5 mg/body/4 weeks, 176 mg/body/4 weeks, 176.5 mg/body/4 weeks, 177 mg/body/4 weeks, 177.5 mg/body/4 weeks, 178 mg/body/4 weeks, 178.5 mg/body/4 weeks, 179 mg/body/4 weeks, 179.5 mg /body/4 weeks, 180 mg/body/4 weeks, 180.5 mg/body/4 weeks, 181 mg/body/4 weeks, 181.5 mg/body/4 weeks, 182 mg/body/4 weeks, 182.5 mg/body/4 weeks, 183 mg/body/4 weeks, 183.5 mg/body/4 weeks, 184 mg/body/4 weeks, 184.5 mg/body/4 weeks, 185 mg/body /4 weeks, 185.5 mg/body/4 weeks, 186 mg/body/4 weeks, 186.5 mg/body/4 weeks, 187 mg/body/4 weeks, 187.5 mg/body/4 weeks, 188 mg/body/4 weeks, 188.5 mg/body/4 weeks, 189 mg/body/4 weeks, 189.5 mg/body/4 weeks, 190 mg/body/4 weeks, 190.5 mg/body /4 weeks, 191 mg/body/4 weeks, 191.5 mg/body/4 weeks, 192 mg/body/4 weeks, 192.5 mg/body/4 weeks, 193 mg/body/4 weeks, 193, 5 mg/body/4 weeks, 194 mg/body/4 weeks, 194.5 mg/body/4 weeks, 195 mg/body/4 weeks, 195.5 mg/body/4 weeks, 196 mg/body/4 weeks, 196.5 mg/body/4 weeks, 197 mg/body/4 weeks, 197.5 mg/body/4 weeks, 198 mg/body/4 weeks, 198.5 mg/body/4 weeks, 199 mg /body/4 weeks, 199.5 mg/body/4 weeks or 200 mg/body/4 weeks. In another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 50 mg/body/6 weeks, 50.5 mg/body/6 weeks, 51 mg/body/6 weeks, 51.5 mg/body /6 weeks, 52 mg/body/6 weeks, 52.5 mg/body/6 weeks, 53 mg/body/6 weeks, 53.5 mg/body/6 weeks, 54 mg/body/6 weeks, 54, 5 mg/body/6 weeks, 55 mg/body/6 weeks, 55.5 mg/body/6 weeks, 56 mg/body/6 weeks, 56.5 mg/body/6 weeks, 57 mg/body/6 weeks, 57.5 mg/body/6 weeks, 58 mg/body/6 weeks, 58.5 mg/body/6 weeks, 59 mg/body/6 weeks, 59.5 mg/body/6 weeks, 60 mg /body/6 weeks, 60.5 mg/body/6 weeks, 61 mg/body/6 weeks, 61.5 mg/body/6 weeks, 62 mg/body/6 weeks, 62.5 mg/body/6 weeks, 63 mg/body/6 weeks, 63.5 mg/body/6 weeks, 64 mg/body/6 weeks, 64.5 mg/body/6 weeks, 65 mg/body/6 weeks, 65.5 mg /body/6 weeks, 66 mg/body/6 weeks, 66.5 mg/body/6 weeks, 67 mg/body/6 weeks, 67.5 mg/body/6 weeks, 68 mg/body/6 weeks, 68.5 mg/body/6 weeks, 69 mg/body/6 weeks, 69.5 mg/body/6 weeks, 70 mg/body/6 weeks, 70.5 mg/body/6 weeks, 71 mg/body /6 weeks, 71.5 mg/body/6 weeks, 72 mg/body/6 weeks, 72.5 mg/body/6 weeks, 73 mg/body/6 weeks, 73.5 mg/body/6 weeks, 74 mg/body/6 weeks, 74.5 mg/body/6 weeks, 75 mg/body/6 weeks, 75.5 mg/body/6 weeks, 76 mg/body/6 weeks, 76.5 mg/body /6 weeks, 77 mg/body/6 weeks, 77.5 mg/body/6 weeks, 78 mg/body/6 weeks, 78.5 mg/body/6 weeks, 79 mg/body/6 weeks, 79, 5 mg/body/6 weeks, 80 mg/body/6 weeks, 80.5 mg/body/6 weeks, 81 mg/body/6 weeks, 81.5 mg/body/6 weeks, 82 mg/body/6 weeks, 82.5 mg/body/6 weeks, 83 mg/body/6 weeks, 83.5 mg/body/6 weeks, 84 mg/body/6 weeks, 84.5 mg/body/6 weeks, 85 mg /body/6 weeks, 85.5 mg/body/6 weeks, 86 mg/body/6 weeks, 86.5 mg/body/6 weeks, 87 mg/body/6 weeks, 87.5 mg/body/6 weeks, 88 mg/body/6 weeks, 88.5 mg/body/6 weeks, 89 mg/body/6 weeks, 89.5 mg/body/6 weeks, 90 mg/body/6 weeks, 90.5 mg /body/6 weeks, 91 mg/body/6 weeks, 91.5 mg/body/6 weeks, 92 mg/body/6 weeks, 92.5 mg/body/6 weeks, 93 mg/body/6 weeks, 93.5 mg/body/6 weeks, 94 mg/body/6 weeks, 94.5 mg/body/6 weeks, 95 mg/body/6 weeks, 95.5 mg/body/6 weeks, 96 mg/body /6 weeks, 96.5 mg/body/6 weeks, 97 mg/body/6 weeks, 97.5 mg/body/6 weeks, 98 mg/body/6 weeks, 98.5 mg/body/6 weeks, 99 mg/body/6 weeks, 99.5 mg/body/6 weeks, 100 mg/body/6 weeks, 100.5 mg/body/6 weeks, 101 mg/body/6 weeks, 101.5 mg/body /6 weeks, 102 mg/body/6 weeks, 102.5 mg/body/6 weeks, 103 mg/body/6 weeks, 103.5 mg/body/6 weeks, 104 mg/body/6 weeks, 104, 5 mg/body/6 weeks, 105 mg/body/6 weeks, 105.5 mg/body/6 weeks, 106 mg/body/6 weeks, 106.5 mg/body/6 weeks, 107 mg/body/6 weeks, 107.5 mg/body/6 weeks, 108 mg/body/6 weeks, 108.5 mg/body/6 weeks, 109 mg/body/6 weeks, 109.5 mg/body/6 weeks, 110 mg /body/6 weeks, 110.5 mg/body/6 weeks, 111 mg/body/6 weeks, 111.5 mg/body/6 weeks, 112 mg/body/6 weeks, 112.5 mg/body/6 weeks, 113 mg/body/6 weeks, 113.5 mg/body/6 weeks, 114 mg/body/6 weeks, 114.5 mg/body/6 weeks, 115 mg/body/6 weeks, 115.5 mg /body/6 weeks, 116 mg/body/6 weeks, 116.5 mg/body/6 weeks, 117 mg/body/6 weeks, 117.5 mg/body/6 weeks, 118 mg/body/6 weeks, 118.5 mg/body/6 weeks, 119 mg/body/6 weeks, 119.5 mg/body/6 weeks, 120 mg/body/6 weeks, 120.5 mg/body/6 weeks, 121 mg/body /6 weeks, 121.5 mg/body/6 weeks, 122 mg/body/6 weeks, 122.5 mg/body/6 weeks, 123 mg/body/6 weeks, 123.5 mg/body/6 weeks, 124 mg/body/6 weeks, 124.5 mg/body/6 weeks, 125 mg/body/6 weeks, 125.5 mg/body/6 weeks, 126 mg/body/6 weeks, 126.5 mg/body /6 weeks, 127 mg/body/6 weeks, 127.5 mg/body/6 weeks, 128 mg/body/6 weeks, 128.5 mg/body/6 weeks, 129 mg/body/6 weeks, 129, 5 mg/body/6 weeks, 130 mg/body/6 weeks, 130.5 mg/body/6 weeks, 131 mg/body/6 weeks, 131.5 mg/body/6 weeks, 132 mg/body/6 weeks, 132.5 mg/body/6 weeks, 133 mg/body/6 weeks, 133.5 mg/body/6 weeks, 134 mg/body/6 weeks, 134.5 mg/body/6 weeks, 135 mg /body/6 weeks, 135.5 mg/body/6 weeks, 136 mg/body/6 weeks, 136.5 mg/body/6 weeks, 137 mg/body/6 weeks, 137.5 mg/body/6 weeks, 138 mg/body/6 weeks, 138.5 mg/body/6 weeks, 139 mg/body/6 weeks, 139.5 mg/body/6 weeks, 140 mg/body/6 weeks, 140.5 mg /body/6 weeks, 141 mg/body/6 weeks, 141.5 mg/body/6 weeks, 142 mg/body/6 weeks, 142.5 mg/body/6 weeks, 143 mg/body/6 weeks, 143.5 mg/body/6 weeks, 144 mg/body/6 weeks, 144.5 mg/body/6 weeks, 145 mg/body/6 weeks, 145.5 mg/body/6 weeks, 146 mg/body /6 weeks, 146.5 mg/body/6 weeks, 147 mg/body/6 weeks, 147.5 mg/body/6 weeks, 148 mg/body/6 weeks, 148.5 mg/body/6 weeks, 149 mg/body/6 weeks, 149.5 mg/body/6 weeks, 150 mg/body/6 weeks, 150.5 mg/body/6 weeks, 151 mg/body/6 weeks, 151.5 mg/body /6 weeks, 152 mg/body/6 weeks, 152.5 mg/body/6 weeks, 153 mg/body/6 weeks, 153.5 mg/body/6 weeks, 154 mg/body/6 weeks, 154, 5 mg/body/6 weeks, 155 mg/body/6 weeks, 155.5 mg/body/6 weeks, 156 mg/body/6 weeks, 156.5 mg/body/6 weeks, 157 mg/body/6 weeks, 157.5 mg/body/6 weeks, 158 mg/body/6 weeks, 158.5 mg/body/6 weeks, 159 mg/body/6 weeks, 159.5 mg/body/6 weeks, 160 mg /body/6 weeks, 160.5 mg/body/6 weeks, 161 mg/body/6 weeks, 161.5 mg/body/6 weeks, 162 mg/body/6 weeks, 162.5 mg/body/6 weeks, 163 mg/body/6 weeks, 163.5 mg/body/6 weeks, 164 mg/body/6 weeks, 164.5 mg/body/6 weeks, 165 mg/body/6 weeks, 165.5 mg /body/6 weeks, 166 mg/body/6 weeks, 166.5 mg/body/6 weeks, 167 mg/body/6 weeks, 167.5 mg/body/6 weeks, 168 mg/body/6 weeks, 168.5 mg/body/6 weeks, 169 mg/body/6 weeks, 169.5 mg/body/6 weeks, 170 mg/body/6 weeks, 170.5 mg/body/6 weeks, 171 mg/body /6 weeks, 171.5 mg/body/6 weeks, 172 mg/body/6 weeks, 172.5 mg/body/6 weeks, 173 mg/body/6 weeks, 173.5 mg/body/6 weeks, 174 mg/body/6 weeks, 174.5 mg/body/6 weeks, 175 mg/body/6 weeks, 175.5 mg/body/6 weeks, 176 mg/body/6 weeks, 176.5 mg/body /6 weeks, 177 mg/body/6 weeks, 177.5 mg/body/6 weeks, 178 mg/body/6 weeks, 178.5 mg/body/6 weeks, 179 mg/body/6 weeks, 179, 5 mg/body/6 weeks, 180 mg/body/6 weeks, 180.5 mg/body/6 weeks, 181 mg/body/6 weeks, 181.5 mg/body/6 weeks, 182 mg/body/6 weeks, 182.5 mg/body/6 weeks, 183 mg/body/6 weeks, 183.5 mg/body/6 weeks, 184 mg/body/6 weeks, 184.5 mg/body/6 weeks, 185 mg /body/6 weeks, 185.5 mg/body/6 weeks, 186 mg/body/6 weeks, 186.5 mg/body/6 weeks, 187 mg/body/6 weeks, 187.5 mg/body/6 weeks, 188 mg/body/6 weeks, 188.5 mg/body/6 weeks, 189 mg/body/6 weeks, 189.5 mg/body/6 weeks, 190 mg/body/6 weeks, 190.5 mg /body/6 weeks, 191 mg/body/6 weeks, 191.5 mg/body/6 weeks, 192 mg/body/6 weeks, 192.5 mg/body/6 weeks, 193 mg/body/6 weeks, 193.5 mg/body/6 weeks, 194 mg/body/6 weeks, 194.5 mg/body/6 weeks, 195 mg/body/6 weeks, 195.5 mg/body/6 weeks, 196 mg/body /6 weeks, 196.5 mg/body/6 weeks, 197 mg/body/6 weeks, 197.5 mg/body/6 weeks, 198 mg/body/6 weeks, 198.5 mg/body/6 weeks, 199 mg/body/6 weeks, 199.5 mg/body/6 weeks, or 200 mg/body/6 weeks. In another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 50 mg/body/8 weeks, 50.5 mg/body/8 weeks, 51 mg/body/8 weeks, 51.5 mg/body /8 weeks, 52 mg/body/8 weeks, 52.5 mg/body/8 weeks, 53 mg/body/8 weeks, 53.5 mg/body/8 weeks, 54 mg/body/8 weeks, 54, 5 mg/body/8 weeks, 55 mg/body/8 weeks, 55.5 mg/body/8 weeks, 56 mg/body/8 weeks, 56.5 mg/body/8 weeks, 57 mg/body/8 weeks, 57.5 mg/body/8 weeks, 58 mg/body/8 weeks, 58.5 mg/body/8 weeks, 59 mg/body/8 weeks, 59.5 mg/body/8 weeks, 60 mg /body/8 weeks, 60.5 mg/body/8 weeks, 61 mg/body/8 weeks, 61.5 mg/body/8 weeks, 62 mg/body/8 weeks, 62.5 mg/body/8 weeks, 63 mg/body/8 weeks, 63.5 mg/body/8 weeks, 64 mg/body/8 weeks, 64.5 mg/body/8 weeks, 65 mg/body/8 weeks, 65.5 mg /body/8 weeks, 66 mg/body/8 weeks, 66.5 mg/body/8 weeks, 67 mg/body/8 weeks, 67.5 mg/body/8 weeks, 68 mg/body/8 weeks, 68.5 mg/body/8 weeks, 69 mg/body/8 weeks, 69.5 mg/body/8 weeks, 70 mg/body/8 weeks, 70.5 mg/body/8 weeks, 71 mg/body /8 weeks, 71.5 mg/body/8 weeks, 72 mg/body/8 weeks, 72.5 mg/body/8 weeks, 73 mg/body/8 weeks, 73.5 mg/body/8 weeks, 74 mg/body/8 weeks, 74.5 mg/body/8 weeks, 75 mg/body/8 weeks, 75.5 mg/body/8 weeks, 76 mg/body/8 weeks, 76.5 mg/body /8 weeks, 77 mg/body/8 weeks, 77.5 mg/body/8 weeks, 78 mg/body/8 weeks, 78.5 mg/body/8 weeks, 79 mg/body/8 weeks, 79, 5 mg/body/8 weeks, 80 mg/body/8 weeks, 80.5 mg/body/8 weeks, 81 mg/body/8 weeks, 81.5 mg/body/8 weeks, 82 mg/body/8 weeks, 82.5 mg/body/8 weeks, 83 mg/body/8 weeks, 83.5 mg/body/8 weeks, 84 mg/body/8 weeks, 84.5 mg/body/8 weeks, 85 mg /body/8 weeks, 85.5 mg/body/8 weeks, 86 mg/body/8 weeks, 86.5 mg/body/8 weeks, 87 mg/body/8 weeks, 87.5 mg/body/8 weeks, 88 mg/body/8 weeks, 88.5 mg/body/8 weeks, 89 mg/body/8 weeks, 89.5 mg/body/8 weeks, 90 mg/body/8 weeks, 90.5 mg /body/8 weeks, 91 mg/body/8 weeks, 91.5 mg/body/8 weeks, 92 mg/body/8 weeks, 92.5 mg/body/8 weeks, 93 mg/body/8 weeks, 93.5 mg/body/8 weeks, 94 mg/body/8 weeks, 94.5 mg/body/8 weeks, 95 mg/body/8 weeks, 95.5 mg/body/8 weeks, 96 mg/body /8 weeks, 96.5 mg/body/8 weeks, 97 mg/body/8 weeks, 97.5 mg/body/8 weeks, 98 mg/body/8 weeks, 98.5 mg/body/8 weeks, 99 mg/body/8 weeks, 99.5 mg/body/8 weeks, 100 mg/body/8 weeks, 100.5 mg/body/8 weeks, 101 mg/body/8 weeks, 101.5 mg/body /8 weeks, 102 mg/body/8 weeks, 102.5 mg/body/8 weeks, 103 mg/body/8 weeks, 103.5 mg/body/8 weeks, 104 mg/body/8 weeks, 104, 5 mg/body/8 weeks, 105 mg/body/8 weeks, 105.5 mg/body/8 weeks, 106 mg/body/8 weeks, 106.5 mg/body/8 weeks, 107 mg/body/8 weeks, 107.5 mg/body/8 weeks, 108 mg/body/8 weeks, 108.5 mg/body/8 weeks, 109 mg/body/8 weeks, 109.5 mg/body/8 weeks, 110 mg /body/8 weeks, 110.5 mg/body/8 weeks, 111 mg/body/8 weeks, 111.5 mg/body/8 weeks, 112 mg/body/8 weeks, 112.5 mg/body/8 weeks, 113 mg/body/8 weeks, 113.5 mg/body/8 weeks, 114 mg/body/8 weeks, 114.5 mg/body/8 weeks, 115 mg/body/8 weeks, 115.5 mg /body/8 weeks, 116 mg/body/8 weeks, 116.5 mg/body/8 weeks, 117 mg/body/8 weeks, 117.5 mg/body/8 weeks, 118 mg/body/8 weeks, 118.5 mg/body/8 weeks, 119 mg/body/8 weeks, 119.5 mg/body/8 weeks, 120 mg/body/8 weeks, 120.5 mg/body/8 weeks, 121 mg/body /8 weeks, 121.5 mg/body/8 weeks, 122 mg/body/8 weeks, 122.5 mg/body/8 weeks, 123 mg/body/8 weeks, 123.5 mg/body/8 weeks, 124 mg/body/8 weeks, 124.5 mg/body/8 weeks, 125 mg/body/8 weeks, 125.5 mg/body/8 weeks, 126 mg/body/8 weeks, 126.5 mg/body /8 weeks, 127 mg/body/8 weeks, 127.5 mg/body/8 weeks, 128 mg/body/8 weeks, 128.5 mg/body/8 weeks, 129 mg/body/8 weeks, 129, 5 mg/body/8 weeks, 130 mg/body/8 weeks, 130.5 mg/body/8 weeks, 131 mg/body/8 weeks, 131.5 mg/body/8 weeks, 132 mg/body/8 weeks, 132.5 mg/body/8 weeks, 133 mg/body/8 weeks, 133.5 mg/body/8 weeks, 134 mg/body/8 weeks, 134.5 mg/body/8 weeks, 135 mg /body/8 weeks, 135.5 mg/body/8 weeks, 136 mg/body/8 weeks, 136.5 mg/body/8 weeks, 137 mg/body/8 weeks, 137.5 mg/body/8 weeks, 138 mg/body/8 weeks, 138.5 mg/body/8 weeks, 139 mg/body/8 weeks, 139.5 mg/body/8 weeks, 140 mg/body/8 weeks, 140.5 mg /body/8 weeks, 141 mg/body/8 weeks, 141.5 mg/body/8 weeks, 142 mg/body/8 weeks, 142.5 mg/body/8 weeks, 143 mg/body/8 weeks, 143.5 mg/body/8 weeks, 144 mg/body/8 weeks, 144.5 mg/body/8 weeks, 145 mg/body/8 weeks, 145.5 mg/body/8 weeks, 146 mg/body /8 weeks, 146.5 mg/body/8 weeks, 147 mg/body/8 weeks, 147.5 mg/body/8 weeks, 148 mg/body/8 weeks, 148.5 mg/body/8 weeks, 149 mg/body/8 weeks, 149.5 mg/body/8 weeks, 150 mg/body/8 weeks, 150.5 mg/body/8 weeks, 151 mg/body/8 weeks, 151.5 mg/body /8 weeks, 152 mg/body/8 weeks, 152.5 mg/body/8 weeks, 153 mg/body/8 weeks, 153.5 mg/body/8 weeks, 154 mg/body/8 weeks, 154, 5 mg/body/8 weeks, 155 mg/body/8 weeks, 155.5 mg/body/8 weeks, 156 mg/body/8 weeks, 156.5 mg/body/8 weeks, 157 mg/body/8 weeks, 157.5 mg/body/8 weeks, 158 mg/body/8 weeks, 158.5 mg/body/8 weeks, 159 mg/body/8 weeks, 159.5 mg/body/8 weeks, 160 mg /body/8 weeks, 160.5 mg/body/8 weeks, 161 mg/body/8 weeks, 161.5 mg/body/8 weeks, 162 mg/body/8 weeks, 162.5 mg/body/8 weeks, 163 mg/body/8 weeks, 163.5 mg/body/8 weeks, 164 mg/body/8 weeks, 164.5 mg/body/8 weeks, 165 mg/body/8 weeks, 165.5 mg /body/8 weeks, 166 mg/body/8 weeks, 166.5 mg/body/8 weeks, 167 mg/body/8 weeks, 167.5 mg/body/8 weeks, 168 mg/body/8 weeks, 168.5 mg/body/8 weeks, 169 mg/body/8 weeks, 169.5 mg/body/8 weeks, 170 mg/body/8 weeks, 170.5 mg/body/8 weeks, 171 mg/body /8 weeks, 171.5 mg/body/8 weeks, 172 mg/body/8 weeks, 172.5 mg/body/8 weeks, 173 mg/body/8 weeks, 173.5 mg/body/8 weeks, 174 mg/body/8 weeks, 174.5 mg/body/8 weeks, 175 mg/body/8 weeks, 175.5 mg/body/8 weeks, 176 mg/body/8 weeks, 176.5 mg/body /8 weeks, 177 mg/body/8 weeks, 177.5 mg/body/8 weeks, 178 mg/body/8 weeks, 178.5 mg/body/8 weeks, 179 mg/body/8 weeks, 179, 5 mg/body/8 weeks, 180 mg/body/8 weeks, 180.5 mg/body/8 weeks, 181 mg/body/8 weeks, 181.5 mg/body/8 weeks, 182 mg/body/8 weeks, 182.5 mg/body/8 weeks, 183 mg/body/8 weeks, 183.5 mg/body/8 weeks, 184 mg/body/8 weeks, 184.5 mg/body/8 weeks, 185 mg /body/8 weeks, 185.5 mg/body/8 weeks, 186 mg/body/8 weeks, 186.5 mg/body/8 weeks, 187 mg/body/8 weeks, 187.5 mg/body/8 weeks, 188 mg/body/8 weeks, 188.5 mg/body/8 weeks, 189 mg/body/8 weeks, 189.5 mg/body/8 weeks, 190 mg/body/8 weeks, 190.5 mg /body/8 weeks, 191 mg/body/8 weeks, 191.5 mg/body/8 weeks, 192 mg/body/8 weeks, 192.5 mg/body/8 weeks, 193 mg/body/8 weeks, 193.5 mg/body/8 weeks, 194 mg/body/8 weeks, 194.5 mg/body/8 weeks, 195 mg/body/8 weeks, 195.5 mg/body/8 weeks, 196 mg/body /8 weeks, 196.5 mg/body/8 weeks, 197 mg/body/8 weeks, 197.5 mg/body/8 weeks, 198 mg/body/8 weeks, 198.5 mg/body/8 weeks, 199 mg/body/8 weeks, 199.5 mg/body/8 weeks, or 200 mg/body/8 weeks. In yet another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 50 mg/body/10 weeks, 50.5 mg/body/10 weeks, 51 mg/body/10 weeks, 51.5 mg/ body/10 weeks, 52 mg/body/10 weeks, 52.5 mg/body/10 weeks, 53 mg/body/10 weeks, 53.5 mg/body/10 weeks, 54 mg/body/10 weeks, 54 .5 mg/body/10 weeks, 55 mg/body/10 weeks, 55.5 mg/body/10 weeks, 56 mg/body/10 weeks, 56.5 mg/body/10 weeks, 57 mg/body/ 10 weeks, 57.5 mg/body/10 weeks, 58 mg/body/10 weeks, 58.5 mg/body/10 weeks, 59 mg/body/10 weeks, 59.5 mg/body/10 weeks, 60 mg/body/10 weeks, 60.5 mg/body/10 weeks, 61 mg/body/10 weeks, 61.5 mg/body/10 weeks, 62 mg/body/10 weeks, 62.5 mg/body/ 10 weeks, 63 mg/body/10 weeks, 63.5 mg/body/10 weeks, 64 mg/body/10 weeks, 64.5 mg/body/10 weeks, 65 mg/body/10 weeks, 65.5 mg/body/10 weeks, 66 mg/body/10 weeks, 66.5 mg/body/10 weeks, 67 mg/body/10 weeks, 67.5 mg/body/10 weeks, 68 mg/body/10 weeks , 68.5 mg/body/10 weeks, 69 mg/body/10 weeks, 69.5 mg/body/10 weeks, 70 mg/body/10 weeks, 70.5 mg/body/10 weeks, 71 mg/ body/10 weeks, 71.5 mg/body/10 weeks, 72 mg/body/10 weeks, 72.5 mg/body/10 weeks, 73 mg/body/10 weeks, 73.5 mg/body/10 weeks , 74 mg/body/10 weeks, 74.5 mg/body/10 weeks, 75 mg/body/10 weeks, 75.5 mg/body/10 weeks, 76 mg/body/10 weeks, 76.5 mg/ body/10 weeks, 77 mg/body/10 weeks, 77.5 mg/body/10 weeks, 78 mg/body/10 weeks, 78.5 mg/body/10 weeks, 79 mg/body/10 weeks, 79 .5 mg/body/10 weeks, 80 mg/body/10 weeks, 80.5 mg/body/10 weeks, 81 mg/body/10 weeks, 81.5 mg/body/10 weeks, 82 mg/body/ 10 weeks, 82.5 mg/body/10 weeks, 83 mg/body/10 weeks, 83.5 mg/body/10 weeks, 84 mg/body/10 weeks, 84.5 mg/body/10 weeks, 85 mg/body/10 weeks, 85.5 mg/body/10 weeks, 86 mg/body/10 weeks, 86.5 mg/body/10 weeks, 87 mg/body/10 weeks, 87.5 mg/body/ 10 weeks, 88 mg/body/10 weeks, 88.5 mg/body/10 weeks, 89 mg/body/10 weeks, 89.5 mg/body/10 weeks, 90 mg/body/10 weeks, 90.5 mg/body/10 weeks, 91 mg/body/10 weeks, 91.5 mg/body/10 weeks, 92 mg/body/10 weeks, 92.5 mg/body/10 weeks, 93 mg/body/10 weeks , 93.5 mg/body/10 weeks, 94 mg/body/10 weeks, 94.5 mg/body/10 weeks, 95 mg/body/10 weeks, 95.5 mg/body/10 weeks, 96 mg/ body/10 weeks, 96.5 mg/body/10 weeks, 97 mg/body/10 weeks, 97.5 mg/body/10 weeks, 98 mg/body/10 weeks, 98.5 mg/body/10 weeks , 99 mg/body/10 weeks, 99.5 mg/body/10 weeks, 100 mg/body/10 weeks, 100.5 mg/body/10 weeks, 101 mg/body/10 weeks, 101.5 mg/ body/10 weeks, 102 mg/body/10 weeks, 102.5 mg/body/10 weeks, 103 mg/body/10 weeks, 103.5 mg/body/10 weeks, 104 mg/body/10 weeks, 104 .5 mg/body/10 weeks, 105 mg/body/10 weeks, 105.5 mg/body/10 weeks, 106 mg/body/10 weeks, 106.5 mg/body/10 weeks, 107 mg/body/ 10 weeks, 107.5 mg/body/10 weeks, 108 mg/body/10 weeks, 108.5 mg/body/10 weeks, 109 mg/body/10 weeks, 109.5 mg/body/10 weeks, 110 mg/body/10 weeks, 110.5 mg/body/10 weeks, 111 mg/body/10 weeks, 111.5 mg/body/10 weeks, 112 mg/body/10 weeks, 112.5 mg/body/ 10 weeks, 113 mg/body/10 weeks, 113.5 mg/body/10 weeks, 114 mg/body/10 weeks, 114.5 mg/body/10 weeks, 115 mg/body/10 weeks, 115.5 mg/body/10 weeks, 116 mg/body/10 weeks, 116.5 mg/body/10 weeks, 117 mg/body/10 weeks, 117.5 mg/body/10 weeks, 118 mg/body/10 weeks , 118.5 mg/body/10 weeks, 119 mg/body/10 weeks, 119.5 mg/body/10 weeks, 120 mg/body/10 weeks, 120.5 mg/body/10 weeks, 121 mg/ body/10 weeks, 121.5 mg/body/10 weeks, 122 mg/body/10 weeks, 122.5 mg/body/10 weeks, 123 mg/body/10 weeks, 123.5 mg/body/10 weeks , 124 mg/body/10 weeks, 124.5 mg/body/10 weeks, 125 mg/body/10 weeks, 125.5 mg/body/10 weeks, 126 mg/body/10 weeks, 126.5 mg/ body/10 weeks, 127 mg/body/10 weeks, 127.5 mg/body/10 weeks, 128 mg/body/10 weeks, 128.5 mg/body/10 weeks, 129 mg/body/10 weeks, 129 .5 mg/body/10 weeks, 130 mg/body/10 weeks, 130.5 mg/body/10 weeks, 131 mg/body/10 weeks, 131.5 mg/body/10 weeks, 132 mg/body/ 10 weeks, 132.5 mg/body/10 weeks, 133 mg/body/10 weeks, 133.5 mg/body/10 weeks, 134 mg/body/10 weeks, 134.5 mg/body/10 weeks, 135 mg/body/10 weeks, 135.5 mg/body/10 weeks, 136 mg/body/10 weeks, 136.5 mg/body/10 weeks, 137 mg/body/10 weeks, 137.5 mg/body/ 10 weeks, 138 mg/body/10 weeks, 138.5 mg/body/10 weeks, 139 mg/body/10 weeks, 139.5 mg/body/10 weeks, 140 mg/body/10 weeks, 140.5 mg/body/10 weeks, 141 mg/body/10 weeks, 141.5 mg/body/10 weeks, 142 mg/body/10 weeks, 142.5 mg/body/10 weeks, 143 mg/body/10 weeks , 143.5 mg/body/10 weeks, 144 mg/body/10 weeks, 144.5 mg/body/10 weeks, 145 mg/body/10 weeks, 145.5 mg/body/10 weeks, 146 mg/ body/10 weeks, 146.5 mg/body/10 weeks, 147 mg/body/10 weeks, 147.5 mg/body/10 weeks, 148 mg/body/10 weeks, 148.5 mg/body/10 weeks , 149 mg/body/10 weeks, 149.5 mg/body/10 weeks, 150 mg/body/10 weeks, 150.5 mg/body/10 weeks, 151 mg/body/10 weeks, 151.5 mg/ body/10 weeks, 152 mg/body/10 weeks, 152.5 mg/body/10 weeks, 153 mg/body/10 weeks, 153.5 mg/body/10 weeks, 154 mg/body/10 weeks, 154 .5 mg/body/10 weeks, 155 mg/body/10 weeks, 155.5 mg/body/10 weeks, 156 mg/body/10 weeks, 156.5 mg/body/10 weeks, 157 mg/body/ 10 weeks, 157.5 mg/body/10 weeks, 158 mg/body/10 weeks, 158.5 mg/body/10 weeks, 159 mg/body/10 weeks, 159.5 mg/body/10 weeks, 160 mg/body/10 weeks, 160.5 mg/body/10 weeks, 161 mg/body/10 weeks, 161.5 mg/body/10 weeks, 162 mg/body/10 weeks, 162.5 mg/body/ 10 weeks, 163 mg/body/10 weeks, 163.5 mg/body/10 weeks, 164 mg/body/10 weeks, 164.5 mg/body/10 weeks, 165 mg/body/10 weeks, 165.5 mg/body/10 weeks, 166 mg/body/10 weeks, 166.5 mg/body/10 weeks, 167 mg/body/10 weeks, 167.5 mg/body/10 weeks, 168 mg/body/10 weeks , 168.5 mg/body/10 weeks, 169 mg/body/10 weeks, 169.5 mg/body/10 weeks, 170 mg/body/10 weeks, 170.5 mg/body/10 weeks, 171 mg/ body/10 weeks, 171.5 mg/body/10 weeks, 172 mg/body/10 weeks, 172.5 mg/body/10 weeks, 173 mg/body/10 weeks, 173.5 mg/body/10 weeks , 174 mg/body/10 weeks, 174.5 mg/body/10 weeks, 175 mg/body/10 weeks, 175.5 mg/body/10 weeks, 176 mg/body/10 weeks, 176.5 mg/ body/10 weeks, 177 mg/body/10 weeks, 177.5 mg/body/10 weeks, 178 mg/body/10 weeks, 178.5 mg/body/10 weeks, 179 mg/body/10 weeks, 179 .5 mg/body/10 weeks, 180 mg/body/10 weeks, 180.5 mg/body/10 weeks, 181 mg/body/10 weeks, 181.5 mg/body/10 weeks, 182 mg/body/ 10 weeks, 182.5 mg/body/10 weeks, 183 mg/body/10 weeks, 183.5 mg/body/10 weeks, 184 mg/body/10 weeks, 184.5 mg/body/10 weeks, 185 mg/body/10 weeks, 185.5 mg/body/10 weeks, 186 mg/body/10 weeks, 186.5 mg/body/10 weeks, 187 mg/body/10 weeks, 187.5 mg/body/ 10 weeks, 188 mg/body/10 weeks, 188.5 mg/body/10 weeks, 189 mg/body/10 weeks, 189.5 mg/body/10 weeks, 190 mg/body/10 weeks, 190.5 mg/body/10 weeks, 191 mg/body/10 weeks, 191.5 mg/body/10 weeks, 192 mg/body/10 weeks, 192.5 mg/body/10 weeks, 193 mg/body/10 weeks , 193.5 mg/body/10 weeks, 194 mg/body/10 weeks, 194.5 mg/body/10 weeks, 195 mg/body/10 weeks, 195.5 mg/body/10 weeks, 196 mg/ body/10 weeks, 196.5 mg/body/10 weeks, 197 mg/body/10 weeks, 197.5 mg/body/10 weeks, 198 mg/body/10 weeks, 198.5 mg/body/10 weeks , 199 mg/body/10 weeks, 199.5 mg/body/10 weeks, or 200 mg/body/10 weeks. In yet another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 50 mg/body/12 weeks, 50.5 mg/body/12 weeks, 51 mg/body/12 weeks, 51.5 mg/ body/12 weeks, 52 mg/body/12 weeks, 52.5 mg/body/12 weeks, 53 mg/body/12 weeks, 53.5 mg/body/12 weeks, 54 mg/body/12 weeks, 54 .5 mg/body/12 weeks, 55 mg/body/12 weeks, 55.5 mg/body/12 weeks, 56 mg/body/12 weeks, 56.5 mg/body/12 weeks, 57 mg/body/ 12 weeks, 57.5 mg/body/12 weeks, 58 mg/body/12 weeks, 58.5 mg/body/12 weeks, 59 mg/body/12 weeks, 59.5 mg/body/12 weeks, 60 mg/body/12 weeks, 60.5 mg/body/12 weeks, 61 mg/body/12 weeks, 61.5 mg/body/12 weeks, 62 mg/body/12 weeks, 62.5 mg/body/ 12 weeks, 63 mg/body/12 weeks, 63.5 mg/body/12 weeks, 64 mg/body/12 weeks, 64.5 mg/body/12 weeks, 65 mg/body/12 weeks, 65.5 mg/body/12 weeks, 66 mg/body/12 weeks, 66.5 mg/body/12 weeks, 67 mg/body/12 weeks, 67.5 mg/body/12 weeks, 68 mg/body/12 weeks , 68.5 mg/body/12 weeks, 69 mg/body/12 weeks, 69.5 mg/body/12 weeks, 70 mg/body/12 weeks, 70.5 mg/body/12 weeks, 71 mg/ body/12 weeks, 71.5 mg/body/12 weeks, 72 mg/body/12 weeks, 72.5 mg/body/12 weeks, 73 mg/body/12 weeks, 73.5 mg/body/12 weeks , 74 mg/body/12 weeks, 74.5 mg/body/12 weeks, 75 mg/body/12 weeks, 75.5 mg/body/12 weeks, 76 mg/body/12 weeks, 76.5 mg/ body/12 weeks, 77 mg/body/12 weeks, 77.5 mg/body/12 weeks, 78 mg/body/12 weeks, 78.5 mg/body/12 weeks, 79 mg/body/12 weeks, 79 .5 mg/body/12 weeks, 80 mg/body/12 weeks, 80.5 mg/body/12 weeks, 81 mg/body/12 weeks, 81.5 mg/body/12 weeks, 82 mg/body/ 12 weeks, 82.5 mg/body/12 weeks, 83 mg/body/12 weeks, 83.5 mg/body/12 weeks, 84 mg/body/12 weeks, 84.5 mg/body/12 weeks, 85 mg/body/12 weeks, 85.5 mg/body/12 weeks, 86 mg/body/12 weeks, 86.5 mg/body/12 weeks, 87 mg/body/12 weeks, 87.5 mg/body/ 12 weeks, 88 mg/body/12 weeks, 88.5 mg/body/12 weeks, 89 mg/body/12 weeks, 89.5 mg/body/12 weeks, 90 mg/body/12 weeks, 90.5 mg/body/12 weeks, 91 mg/body/12 weeks, 91.5 mg/body/12 weeks, 92 mg/body/12 weeks, 92.5 mg/body/12 weeks, 93 mg/body/12 weeks , 93.5 mg/body/12 weeks, 94 mg/body/12 weeks, 94.5 mg/body/12 weeks, 95 mg/body/12 weeks, 95.5 mg/body/12 weeks, 96 mg/ body/12 weeks, 96.5 mg/body/12 weeks, 97 mg/body/12 weeks, 97.5 mg/body/12 weeks, 98 mg/body/12 weeks, 98.5 mg/body/12 weeks , 99 mg/body/12 weeks, 99.5 mg/body/12 weeks, 100 mg/body/12 weeks, 100.5 mg/body/12 weeks, 101 mg/body/12 weeks, 101.5 mg/ body/12 weeks, 102 mg/body/12 weeks, 102.5 mg/body/12 weeks, 103 mg/body/12 weeks, 103.5 mg/body/12 weeks, 104 mg/body/12 weeks, 104 .5 mg/body/12 weeks, 105 mg/body/12 weeks, 105.5 mg/body/12 weeks, 106 mg/body/12 weeks, 106.5 mg/body/12 weeks, 107 mg/body/ 12 weeks, 107.5 mg/body/12 weeks, 108 mg/body/12 weeks, 108.5 mg/body/12 weeks, 109 mg/body/12 weeks, 109.5 mg/body/12 weeks, 110 mg/body/12 weeks, 110.5 mg/body/12 weeks, 111 mg/body/12 weeks, 111.5 mg/body/12 weeks, 112 mg/body/12 weeks, 112.5 mg/body/ 12 weeks, 113 mg/body/12 weeks, 113.5 mg/body/12 weeks, 114 mg/body/12 weeks, 114.5 mg/body/12 weeks, 115 mg/body/12 weeks, 115.5 mg/body/12 weeks, 116 mg/body/12 weeks, 116.5 mg/body/12 weeks, 117 mg/body/12 weeks, 117.5 mg/body/12 weeks, 118 mg/body/12 weeks , 118.5 mg/body/12 weeks, 119 mg/body/12 weeks, 119.5 mg/body/12 weeks, 120 mg/body/12 weeks, 120.5 mg/body/12 weeks, 121 mg/ body/12 weeks, 121.5 mg/body/12 weeks, 122 mg/body/12 weeks, 122.5 mg/body/12 weeks, 123 mg/body/12 weeks, 123.5 mg/body/12 weeks , 124 mg/body/12 weeks, 124.5 mg/body/12 weeks, 125 mg/body/12 weeks, 125.5 mg/body/12 weeks, 126 mg/body/12 weeks, 126.5 mg/ body/12 weeks, 127 mg/body/12 weeks, 127.5 mg/body/12 weeks, 128 mg/body/12 weeks, 128.5 mg/body/12 weeks, 129 mg/body/12 weeks, 129 .5 mg/body/12 weeks, 130 mg/body/12 weeks, 130.5 mg/body/12 weeks, 131 mg/body/12 weeks, 131.5 mg/body/12 weeks, 132 mg/body/ 12 weeks, 132.5 mg/body/12 weeks, 133 mg/body/12 weeks, 133.5 mg/body/12 weeks, 134 mg/body/12 weeks, 134.5 mg/body/12 weeks, 135 mg/body/12 weeks, 135.5 mg/body/12 weeks, 136 mg/body/12 weeks, 136.5 mg/body/12 weeks, 137 mg/body/12 weeks, 137.5 mg/body/ 12 weeks, 138 mg/body/12 weeks, 138.5 mg/body/12 weeks, 139 mg/body/12 weeks, 139.5 mg/body/12 weeks, 140 mg/body/12 weeks, 140.5 mg/body/12 weeks, 141 mg/body/12 weeks, 141.5 mg/body/12 weeks, 142 mg/body/12 weeks, 142.5 mg/body/12 weeks, 143 mg/body/12 weeks , 143.5 mg/body/12 weeks, 144 mg/body/12 weeks, 144.5 mg/body/12 weeks, 145 mg/body/12 weeks, 145.5 mg/body/12 weeks, 146 mg/ body/12 weeks, 146.5 mg/body/12 weeks, 147 mg/body/12 weeks, 147.5 mg/body/12 weeks, 148 mg/body/12 weeks, 148.5 mg/body/12 weeks , 149 mg/body/12 weeks, 149.5 mg/body/12 weeks, 150 mg/body/12 weeks, 150.5 mg/body/12 weeks, 151 mg/body/12 weeks, 151.5 mg/ body/12 weeks, 152 mg/body/12 weeks, 152.5 mg/body/12 weeks, 153 mg/body/12 weeks, 153.5 mg/body/12 weeks, 154 mg/body/12 weeks, 154 .5 mg/body/12 weeks, 155 mg/body/12 weeks, 155.5 mg/body/12 weeks, 156 mg/body/12 weeks, 156.5 mg/body/12 weeks, 157 mg/body/ 12 weeks, 157.5 mg/body/12 weeks, 158 mg/body/12 weeks, 158.5 mg/body/12 weeks, 159 mg/body/12 weeks, 159.5 mg/body/12 weeks, 160 mg/body/12 weeks, 160.5 mg/body/12 weeks, 161 mg/body/12 weeks, 161.5 mg/body/12 weeks, 162 mg/body/12 weeks, 162.5 mg/body/ 12 weeks, 163 mg/body/12 weeks, 163.5 mg/body/12 weeks, 164 mg/body/12 weeks, 164.5 mg/body/12 weeks, 165 mg/body/12 weeks, 165.5 mg/body/12 weeks, 166 mg/body/12 weeks, 166.5 mg/body/12 weeks, 167 mg/body/12 weeks, 167.5 mg/body/12 weeks, 168 mg/body/12 weeks , 168.5 mg/body/12 weeks, 169 mg/body/12 weeks, 169.5 mg/body/12 weeks, 170 mg/body/12 weeks, 170.5 mg/body/12 weeks, 171 mg/ body/12 weeks, 171.5 mg/body/12 weeks, 172 mg/body/12 weeks, 172.5 mg/body/12 weeks, 173 mg/body/12 weeks, 173.5 mg/body/12 weeks , 174 mg/body/12 weeks, 174.5 mg/body/12 weeks, 175 mg/body/12 weeks, 175.5 mg/body/12 weeks, 176 mg/body/12 weeks, 176.5 mg/ body/12 weeks, 177 mg/body/12 weeks, 177.5 mg/body/12 weeks, 178 mg/body/12 weeks, 178.5 mg/body/12 weeks, 179 mg/body/12 weeks, 179 .5 mg/body/12 weeks, 180 mg/body/12 weeks, 180.5 mg/body/12 weeks, 181 mg/body/12 weeks, 181.5 mg/body/12 weeks, 182 mg/body/ 12 weeks, 182.5 mg/body/12 weeks, 183 mg/body/12 weeks, 183.5 mg/body/12 weeks, 184 mg/body/12 weeks, 184.5 mg/body/12 weeks, 185 mg/body/12 weeks, 185.5 mg/body/12 weeks, 186 mg/body/12 weeks, 186.5 mg/body/12 weeks, 187 mg/body/12 weeks, 187.5 mg/body/ 12 weeks, 188 mg/body/12 weeks, 188.5 mg/body/12 weeks, 189 mg/body/12 weeks, 189.5 mg/body/12 weeks, 190 mg/body/12 weeks, 190.5 mg/body/12 weeks, 191 mg/body/12 weeks, 191.5 mg/body/12 weeks, 192 mg/body/12 weeks, 192.5 mg/body/12 weeks, 193 mg/body/12 weeks , 193.5 mg/body/12 weeks, 194 mg/body/12 weeks, 194.5 mg/body/12 weeks, 195 mg/body/12 weeks, 195.5 mg/body/12 weeks, 196 mg/ body/12 weeks, 196.5 mg/body/12 weeks, 197 mg/body/12 weeks, 197.5 mg/body/12 weeks, 198 mg/body/12 weeks, 198.5 mg/body/12 weeks , 199 mg/body/12 weeks, 199.5 mg/body/12 weeks, or 200 mg/body/12 weeks.

In a non-limiting embodiment, the IL-31 antagonist of the invention is preferably administered in the range of 25 to 100 mg/body/4 weeks, 50 to 100 mg/body/4 weeks, or 50 to 75 mg/body/4 weeks. In another non-limiting embodiment, the IL-31 antagonist of the invention is preferably administered in the range of 10 to 50 mg/body/2 weeks or 20 to 40 mg/body/2 weeks.

In another embodiment of the present invention, where the IL-31 antagonist of the invention is administered several times in equal amounts at equal dosing intervals, using a predetermined dosing interval and a predetermined dose (dosage), the IL-31 antagonist of the invention can be administered in the range “from 0.01 to 10 mg/kg/for 1 day to 12 weeks.” A dose of "0.01 to 10 mg/kg/for 1 day to 12 weeks" as used herein means, for example, that a single dose is selected from the range of 0.01 to 10 mg as the IL-31 antagonist dose of the invention, and any dosing interval is selected from 1 day to 12 weeks as the dosing interval (e.g., 4 weeks) of the IL-31 antagonist of the invention, and the IL-31 antagonist is administered to the subject several times in equal amounts at equal intervals. intervals between dosing. In an embodiment of the present invention where the IL-31 antagonist of the invention is administered multiple times in equal amounts at equal dosing intervals using a predetermined dosing interval and a predetermined dose (dosage), the IL-31 antagonist of the invention is preferably administered at dose from 0.01 to 10 mg/kg/for 2 weeks to 8 weeks, and it can be administered, but not limited to these values, for example, in the range of 0.01 to 10 mg/kg/2 weeks, from 0.01 to 10 mg/kg/4 weeks, 0.01 to 10 mg/kg/6 weeks, or 0.01 to 10 mg/kg/8 weeks. In another embodiment, the IL-31 antagonist of the invention is more preferably administered in the range of 0.1 to 3 mg/body/for 2 weeks to 8 weeks, and can be administered, for example, at a dose of 0.1 to 3 mg/body. kg/2 weeks, 0.1 to 3 mg/kg/4 weeks, 0.1 to 3 mg/kg/6 weeks, or 0.1 to 3 mg/kg/8 weeks. In yet another embodiment, for example, the IL-31 antagonist of the invention is more preferably administered at a dose of 0.2 to 2 mg/body/for 2 weeks to 8 weeks, and may be administered, for example, 0.2 to 2 mg/kg/2 weeks, 0.2 to 2 mg/kg/4 weeks, 0.2 to 2 mg/kg/6 weeks, or 0.2 to 2 mg/kg/8 weeks. In another embodiment, the IL-31 antagonist of the invention is even more preferably administered at a dose of 0.5 to 1.5 mg/body/for 4 weeks to 8 weeks, and can be administered, for example, from 0.5 to 1. 5 mg/kg/4 weeks, 0.5 to 1.5 mg/kg/6 weeks, or 0.5 to 1.5 mg/kg/8 weeks. In a non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 0.1 mg/kg/4 weeks, 0.11 mg/kg/4 weeks, 0.12 mg/kg/4 weeks, 0.125 mg/ kg/4 weeks, 0.13 mg/kg/4 weeks, 0.14 mg/kg/4 weeks, 0.15 mg/kg/4 weeks, 0.16 mg/kg/4 weeks, 0.17 mg/ kg/4 weeks, 0.18 mg/kg/4 weeks, 0.19 mg/kg/4 weeks, 0.2 mg/kg/4 weeks, 0.21 mg/kg/4 weeks, 0.22 mg/ kg/4 weeks, 0.23 mg/kg/4 weeks, 0.24 mg/kg/4 weeks, 0.25 mg/kg/4 weeks, 0.26 mg/kg/4 weeks, 0.27 mg/ kg/4 weeks, 0.28 mg/kg/4 weeks, 0.29 mg/kg/4 weeks, 0.3 mg/kg/4 weeks, 0.31 mg/kg/4 weeks, 0.32 mg/ kg/4 weeks, 0.33 mg/kg/4 weeks, 0.34 mg/kg/4 weeks, 0.35 mg/kg/4 weeks, 0.36 mg/kg/4 weeks, 0.37 mg/ kg/4 weeks, 0.38 mg/kg/4 weeks, 0.39 mg/kg/4 weeks, 0.4 mg/kg/4 weeks, 0.41 mg/kg/4 weeks, 0.42 mg/ kg/4 weeks, 0.43 mg/kg/4 weeks, 0.44 mg/kg/4 weeks, 0.45 mg/kg/4 weeks, 0.46 mg/kg/4 weeks, 0.47 mg/ kg/4 weeks, 0.48 mg/kg/4 weeks, 0.49 mg/kg/4 weeks, 0.5 mg/kg/4 weeks, 0.51 mg/kg/4 weeks, 0.52 mg/ kg/4 weeks, 0.53 mg/kg/4 weeks, 0.54 mg/kg/4 weeks, 0.55 mg/kg/4 weeks, 0.56 mg/kg/4 weeks, 0.57 mg/ kg/4 weeks, 0.58 mg/kg/4 weeks, 0.59 mg/kg/4 weeks, 0.6 mg/kg/4 weeks, 0.61 mg/kg/4 weeks, 0.62 mg/ kg/4 weeks, 0.63 mg/kg/4 weeks, 0.64 mg/kg/4 weeks, 0.65 mg/kg/4 weeks, 0.66 mg/kg/4 weeks, 0.67 mg/ kg/4 weeks, 0.68 mg/kg/4 weeks, 0.69 mg/kg/4 weeks, 0.7 mg/kg/4 weeks, 0.71 mg/kg/4 weeks, 0.72 mg/ kg/4 weeks, 0.73 mg/kg/4 weeks, 0.74 mg/kg/4 weeks, 0.75 mg/kg/4 weeks, 0.76 mg/kg/4 weeks, 0.77 mg/ kg/4 weeks, 0.78 mg/kg/4 weeks, 0.79 mg/kg/4 weeks, 0.8 mg/kg/4 weeks, 0.81 mg/kg/4 weeks, 0.82 mg/ kg/4 weeks, 0.83 mg/kg/4 weeks, 0.84 mg/kg/4 weeks, 0.85 mg/kg/4 weeks, 0.86 mg/kg/4 weeks, 0.87 mg/ kg/4 weeks, 0.88 mg/kg/4 weeks, 0.89 mg/kg/4 weeks, 0.9 mg/kg/4 weeks, 0.91 mg/kg/4 weeks, 0.92 mg/ kg/4 weeks, 0.93 mg/kg/4 weeks, 0.94 mg/kg/4 weeks, 0.95 mg/kg/4 weeks, 0.96 mg/kg/4 weeks, 0.97 mg/ kg/4 weeks, 0.98 mg/kg/4 weeks, 0.99 mg/kg/4 weeks, 1 mg/kg/4 weeks, 1.01 mg/kg/4 weeks, 1.02 mg/kg/ 4 weeks, 1.03 mg/kg/4 weeks, 1.04 mg/kg/4 weeks, 1.05 mg/kg/4 weeks, 1.06 mg/kg/4 weeks, 1.07 mg/kg/ 4 weeks, 1.08 mg/kg/4 weeks, 1.09 mg/kg/4 weeks, 1.1 mg/kg/4 weeks, 1.11 mg/kg/4 weeks, 1.12 mg/kg/ 4 weeks, 1.13 mg/kg/4 weeks, 1.14 mg/kg/4 weeks, 1.15 mg/kg/4 weeks, 1.16 mg/kg/4 weeks, 1.17 mg/kg/ 4 weeks, 1.18 mg/kg/4 weeks, 1.19 mg/kg/4 weeks, 1.2 mg/kg/4 weeks, 1.21 mg/kg/4 weeks, 1.22 mg/kg/ 4 weeks, 1.23 mg/kg/4 weeks, 1.24 mg/kg/4 weeks, 1.25 mg/kg/4 weeks, 1.26 mg/kg/4 weeks, 1.27 mg/kg/ 4 weeks, 1.28 mg/kg/4 weeks, 1.29 mg/kg/4 weeks, 1.3 mg/kg/4 weeks, 1.31 mg/kg/4 weeks, 1.32 mg/kg/ 4 weeks, 1.33 mg/kg/4 weeks, 1.34 mg/kg/4 weeks, 1.35 mg/kg/4 weeks, 1.36 mg/kg/4 weeks, 1.37 mg/kg/ 4 weeks, 1.38 mg/kg/4 weeks, 1.39 mg/kg/4 weeks, 1.4 mg/kg/4 weeks, 1.41 mg/kg/4 weeks, 1.42 mg/kg/ 4 weeks, 1.43 mg/kg/4 weeks, 1.44 mg/kg/4 weeks, 1.45 mg/kg/4 weeks, 1.46 mg/kg/4 weeks, 1.47 mg/kg/ 4 weeks, 1.48 mg/kg/4 weeks, 1.49 mg/kg/4 weeks, 1.5 mg/kg/4 weeks, 1.51 mg/kg/4 weeks, 1.52 mg/kg/ 4 weeks, 1.53 mg/kg/4 weeks, 1.54 mg/kg/4 weeks, 1.55 mg/kg/4 weeks, 1.56 mg/kg/4 weeks, 1.57 mg/kg/ 4 weeks, 1.58 mg/kg/4 weeks, 1.59 mg/kg/4 weeks, 1.6 mg/kg/4 weeks, 1.61 mg/kg/4 weeks, 1.62 mg/kg/ 4 weeks, 1.63 mg/kg/4 weeks, 1.64 mg/kg/4 weeks, 1.65 mg/kg/4 weeks, 1.66 mg/kg/4 weeks, 1.67 mg/kg/ 4 weeks, 1.68 mg/kg/4 weeks, 1.69 mg/kg/4 weeks, 1.7 mg/kg/4 weeks, 1.71 mg/kg/4 weeks, 1.72 mg/kg/ 4 weeks, 1.73 mg/kg/4 weeks, 1.74 mg/kg/4 weeks, 1.75 mg/kg/4 weeks, 1.76 mg/kg/4 weeks, 1.77 mg/kg/ 4 weeks, 1.78 mg/kg/4 weeks, 1.79 mg/kg/4 weeks, 1.8 mg/kg/4 weeks, 1.81 mg/kg/4 weeks, 1.82 mg/kg/ 4 weeks, 1.83 mg/kg/4 weeks, 1.84 mg/kg/4 weeks, 1.85 mg/kg/4 weeks, 1.86 mg/kg/4 weeks, 1.87 mg/kg/ 4 weeks, 1.88 mg/kg/4 weeks, 1.89 mg/kg/4 weeks, 1.9 mg/kg/4 weeks, 1.91 mg/kg/4 weeks, 1.92 mg/kg/ 4 weeks, 1.93 mg/kg/4 weeks, 1.94 mg/kg/4 weeks, 1.95 mg/kg/4 weeks, 1.96 mg/kg/4 weeks, 1.97 mg/kg/ 4 weeks, 1.98 mg/kg/4 weeks, 1.99 mg/kg/4 weeks, 2 mg/kg/4 weeks, 2.01 mg/kg/4 weeks, 2.02 mg/kg/4 weeks , 2.03 mg/kg/4 weeks, 2.04 mg/kg/4 weeks, 2.05 mg/kg/4 weeks, 2.06 mg/kg/4 weeks, 2.07 mg/kg/4 weeks , 2.08 mg/kg/4 weeks, 2.09 mg/kg/4 weeks, 2.1 mg/kg/4 weeks, 2.11 mg/kg/4 weeks, 2.12 mg/kg/4 weeks , 2.13 mg/kg/4 weeks, 2.14 mg/kg/4 weeks, 2.15 mg/kg/4 weeks, 2.16 mg/kg/4 weeks, 2.17 mg/kg/4 weeks , 2.18 mg/kg/4 weeks, 2.19 mg/kg/4 weeks, 2.2 mg/kg/4 weeks, 2.21 mg/kg/4 weeks, 2.22 mg/kg/4 weeks , 2.23 mg/kg/4 weeks, 2.24 mg/kg/4 weeks, 2.25 mg/kg/4 weeks, 2.26 mg/kg/4 weeks, 2.27 mg/kg/4 weeks , 2.28 mg/kg/4 weeks, 2.29 mg/kg/4 weeks, 2.3 mg/kg/4 weeks, 2.31 mg/kg/4 weeks, 2.32 mg/kg/4 weeks , 2.33 mg/kg/4 weeks, 2.34 mg/kg/4 weeks, 2.35 mg/kg/4 weeks, 2.36 mg/kg/4 weeks, 2.37 mg/kg/4 weeks , 2.38 mg/kg/4 weeks, 2.39 mg/kg/4 weeks, 2.4 mg/kg/4 weeks, 2.41 mg/kg/4 weeks, 2.42 mg/kg/4 weeks , 2.43 mg/kg/4 weeks, 2.44 mg/kg/4 weeks, 2.45 mg/kg/4 weeks, 2.46 mg/kg/4 weeks, 2.47 mg/kg/4 weeks , 2.48 mg/kg/4 weeks, 2.49 mg/kg/4 weeks, 2.5 mg/kg/4 weeks, 2.51 mg/kg/4 weeks, 2.52 mg/kg/4 weeks , 2.53 mg/kg/4 weeks, 2.54 mg/kg/4 weeks, 2.55 mg/kg/4 weeks, 2.56 mg/kg/4 weeks, 2.57 mg/kg/4 weeks , 2.58 mg/kg/4 weeks, 2.59 mg/kg/4 weeks, 2.6 mg/kg/4 weeks, 2.61 mg/kg/4 weeks, 2.62 mg/kg/4 weeks , 2.63 mg/kg/4 weeks, 2.64 mg/kg/4 weeks, 2.65 mg/kg/4 weeks, 2.66 mg/kg/4 weeks, 2.67 mg/kg/4 weeks , 2.68 mg/kg/4 weeks, 2.69 mg/kg/4 weeks, 2.7 mg/kg/4 weeks, 2.71 mg/kg/4 weeks, 2.72 mg/kg/4 weeks , 2.73 mg/kg/4 weeks, 2.74 mg/kg/4 weeks, 2.75 mg/kg/4 weeks, 2.76 mg/kg/4 weeks, 2.77 mg/kg/4 weeks , 2.78 mg/kg/4 weeks, 2.79 mg/kg/4 weeks, 2.8 mg/kg/4 weeks, 2.81 mg/kg/4 weeks, 2.82 mg/kg/4 weeks , 2.83 mg/kg/4 weeks, 2.84 mg/kg/4 weeks, 2.85 mg/kg/4 weeks, 2.86 mg/kg/4 weeks, 2.87 mg/kg/4 weeks , 2.88 mg/kg/4 weeks, 2.89 mg/kg/4 weeks, 2.9 mg/kg/4 weeks, 2.91 mg/kg/4 weeks, 2.92 mg/kg/4 weeks , 2.93 mg/kg/4 weeks, 2.94 mg/kg/4 weeks, 2.95 mg/kg/4 weeks, 2.96 mg/kg/4 weeks, 2.97 mg/kg/4 weeks , 2.98 mg/kg/4 weeks, 2.99 mg/kg/4 weeks, or 3 mg/kg/4 weeks. In another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 0.1 mg/kg/6 weeks, 0.11 mg/kg/6 weeks, 0.12 mg/kg/6 weeks, 0.125 mg /kg/6 weeks, 0.13 mg/kg/6 weeks, 0.14 mg/kg/6 weeks, 0.15 mg/kg/6 weeks, 0.16 mg/kg/6 weeks, 0.17 mg /kg/6 weeks, 0.18 mg/kg/6 weeks, 0.19 mg/kg/6 weeks, 0.2 mg/kg/6 weeks, 0.21 mg/kg/6 weeks, 0.22 mg /kg/6 weeks, 0.23 mg/kg/6 weeks, 0.24 mg/kg/6 weeks, 0.25 mg/kg/6 weeks, 0.26 mg/kg/6 weeks, 0.27 mg /kg/6 weeks, 0.28 mg/kg/6 weeks, 0.29 mg/kg/6 weeks, 0.3 mg/kg/6 weeks, 0.31 mg/kg/6 weeks, 0.32 mg /kg/6 weeks, 0.33 mg/kg/6 weeks, 0.34 mg/kg/6 weeks, 0.35 mg/kg/6 weeks, 0.36 mg/kg/6 weeks, 0.37 mg /kg/6 weeks, 0.38 mg/kg/6 weeks, 0.39 mg/kg/6 weeks, 0.4 mg/kg/6 weeks, 0.41 mg/kg/6 weeks, 0.42 mg /kg/6 weeks, 0.43 mg/kg/6 weeks, 0.44 mg/kg/6 weeks, 0.45 mg/kg/6 weeks, 0.46 mg/kg/6 weeks, 0.47 mg /kg/6 weeks, 0.48 mg/kg/6 weeks, 0.49 mg/kg/6 weeks, 0.5 mg/kg/6 weeks, 0.51 mg/kg/6 weeks, 0.52 mg /kg/6 weeks, 0.53 mg/kg/6 weeks, 0.54 mg/kg/6 weeks, 0.55 mg/kg/6 weeks, 0.56 mg/kg/6 weeks, 0.57 mg /kg/6 weeks, 0.58 mg/kg/6 weeks, 0.59 mg/kg/6 weeks, 0.6 mg/kg/6 weeks, 0.61 mg/kg/6 weeks, 0.62 mg /kg/6 weeks, 0.63 mg/kg/6 weeks, 0.64 mg/kg/6 weeks, 0.65 mg/kg/6 weeks, 0.66 mg/kg/6 weeks, 0.67 mg /kg/6 weeks, 0.68 mg/kg/6 weeks, 0.69 mg/kg/6 weeks, 0.7 mg/kg/6 weeks, 0.71 mg/kg/6 weeks, 0.72 mg /kg/6 weeks, 0.73 mg/kg/6 weeks, 0.74 mg/kg/6 weeks, 0.75 mg/kg/6 weeks, 0.76 mg/kg/6 weeks, 0.77 mg /kg/6 weeks, 0.78 mg/kg/6 weeks, 0.79 mg/kg/6 weeks, 0.8 mg/kg/6 weeks, 0.81 mg/kg/6 weeks, 0.82 mg /kg/6 weeks, 0.83 mg/kg/6 weeks, 0.84 mg/kg/6 weeks, 0.85 mg/kg/6 weeks, 0.86 mg/kg/6 weeks, 0.87 mg /kg/6 weeks, 0.88 mg/kg/6 weeks, 0.89 mg/kg/6 weeks, 0.9 mg/kg/6 weeks, 0.91 mg/kg/6 weeks, 0.92 mg /kg/6 weeks, 0.93 mg/kg/6 weeks, 0.94 mg/kg/6 weeks, 0.95 mg/kg/6 weeks, 0.96 mg/kg/6 weeks, 0.97 mg /kg/6 weeks, 0.98 mg/kg/6 weeks, 0.99 mg/kg/6 weeks, 1 mg/kg/6 weeks, 1.01 mg/kg/6 weeks, 1.02 mg/kg /6 weeks, 1.03 mg/kg/6 weeks, 1.04 mg/kg/6 weeks, 1.05 mg/kg/6 weeks, 1.06 mg/kg/6 weeks, 1.07 mg/kg /6 weeks, 1.08 mg/kg/6 weeks, 1.09 mg/kg/6 weeks, 1.1 mg/kg/6 weeks, 1.11 mg/kg/6 weeks, 1.12 mg/kg /6 weeks, 1.13 mg/kg/6 weeks, 1.14 mg/kg/6 weeks, 1.15 mg/kg/6 weeks, 1.16 mg/kg/6 weeks, 1.17 mg/kg /6 weeks, 1.18 mg/kg/6 weeks, 1.19 mg/kg/6 weeks, 1.2 mg/kg/6 weeks, 1.21 mg/kg/6 weeks, 1.22 mg/kg /6 weeks, 1.23 mg/kg/6 weeks, 1.24 mg/kg/6 weeks, 1.25 mg/kg/6 weeks, 1.26 mg/kg/6 weeks, 1.27 mg/kg /6 weeks, 1.28 mg/kg/6 weeks, 1.29 mg/kg/6 weeks, 1.3 mg/kg/6 weeks, 1.31 mg/kg/6 weeks, 1.32 mg/kg /6 weeks, 1.33 mg/kg/6 weeks, 1.34 mg/kg/6 weeks, 1.35 mg/kg/6 weeks, 1.36 mg/kg/6 weeks, 1.37 mg/kg /6 weeks, 1.38 mg/kg/6 weeks, 1.39 mg/kg/6 weeks, 1.4 mg/kg/6 weeks, 1.41 mg/kg/6 weeks, 1.42 mg/kg /6 weeks, 1.43 mg/kg/6 weeks, 1.44 mg/kg/6 weeks, 1.45 mg/kg/6 weeks, 1.46 mg/kg/6 weeks, 1.47 mg/kg /6 weeks, 1.48 mg/kg/6 weeks, 1.49 mg/kg/6 weeks, 1.5 mg/kg/6 weeks, 1.51 mg/kg/6 weeks, 1.52 mg/kg /6 weeks, 1.53 mg/kg/6 weeks, 1.54 mg/kg/6 weeks, 1.55 mg/kg/6 weeks, 1.56 mg/kg/6 weeks, 1.57 mg/kg /6 weeks, 1.58 mg/kg/6 weeks, 1.59 mg/kg/6 weeks, 1.6 mg/kg/6 weeks, 1.61 mg/kg/6 weeks, 1.62 mg/kg /6 weeks, 1.63 mg/kg/6 weeks, 1.64 mg/kg/6 weeks, 1.65 mg/kg/6 weeks, 1.66 mg/kg/6 weeks, 1.67 mg/kg /6 weeks, 1.68 mg/kg/6 weeks, 1.69 mg/kg/6 weeks, 1.7 mg/kg/6 weeks, 1.71 mg/kg/6 weeks, 1.72 mg/kg /6 weeks, 1.73 mg/kg/6 weeks, 1.74 mg/kg/6 weeks, 1.75 mg/kg/6 weeks, 1.76 mg/kg/6 weeks, 1.77 mg/kg /6 weeks, 1.78 mg/kg/6 weeks, 1.79 mg/kg/6 weeks, 1.8 mg/kg/6 weeks, 1.81 mg/kg/6 weeks, 1.82 mg/kg /6 weeks, 1.83 mg/kg/6 weeks, 1.84 mg/kg/6 weeks, 1.85 mg/kg/6 weeks, 1.86 mg/kg/6 weeks, 1.87 mg/kg /6 weeks, 1.88 mg/kg/6 weeks, 1.89 mg/kg/6 weeks, 1.9 mg/kg/6 weeks, 1.91 mg/kg/6 weeks, 1.92 mg/kg /6 weeks, 1.93 mg/kg/6 weeks, 1.94 mg/kg/6 weeks, 1.95 mg/kg/6 weeks, 1.96 mg/kg/6 weeks, 1.97 mg/kg /6 weeks, 1.98 mg/kg/6 weeks, 1.99 mg/kg/6 weeks, 2 mg/kg/6 weeks, 2.01 mg/kg/6 weeks, 2.02 mg/kg/6 weeks, 2.03 mg/kg/6 weeks, 2.04 mg/kg/6 weeks, 2.05 mg/kg/6 weeks, 2.06 mg/kg/6 weeks, 2.07 mg/kg/6 weeks, 2.08 mg/kg/6 weeks, 2.09 mg/kg/6 weeks, 2.1 mg/kg/6 weeks, 2.11 mg/kg/6 weeks, 2.12 mg/kg/6 weeks, 2.13 mg/kg/6 weeks, 2.14 mg/kg/6 weeks, 2.15 mg/kg/6 weeks, 2.16 mg/kg/6 weeks, 2.17 mg/kg/6 weeks, 2.18 mg/kg/6 weeks, 2.19 mg/kg/6 weeks, 2.2 mg/kg/6 weeks, 2.21 mg/kg/6 weeks, 2.22 mg/kg/6 weeks, 2.23 mg/kg/6 weeks, 2.24 mg/kg/6 weeks, 2.25 mg/kg/6 weeks, 2.26 mg/kg/6 weeks, 2.27 mg/kg/6 weeks, 2.28 mg/kg/6 weeks, 2.29 mg/kg/6 weeks, 2.3 mg/kg/6 weeks, 2.31 mg/kg/6 weeks, 2.32 mg/kg/6 weeks, 2.33 mg/kg/6 weeks, 2.34 mg/kg/6 weeks, 2.35 mg/kg/6 weeks, 2.36 mg/kg/6 weeks, 2.37 mg/kg/6 weeks, 2.38 mg/kg/6 weeks, 2.39 mg/kg/6 weeks, 2.4 mg/kg/6 weeks, 2.41 mg/kg/6 weeks, 2.42 mg/kg/6 weeks, 2.43 mg/kg/6 weeks, 2.44 mg/kg/6 weeks, 2.45 mg/kg/6 weeks, 2.46 mg/kg/6 weeks, 2.47 mg/kg/6 weeks, 2.48 mg/kg/6 weeks, 2.49 mg/kg/6 weeks, 2.5 mg/kg/6 weeks, 2.51 mg/kg/6 weeks, 2.52 mg/kg/6 weeks, 2.53 mg/kg/6 weeks, 2.54 mg/kg/6 weeks, 2.55 mg/kg/6 weeks, 2.56 mg/kg/6 weeks, 2.57 mg/kg/6 weeks, 2.58 mg/kg/6 weeks, 2.59 mg/kg/6 weeks, 2.6 mg/kg/6 weeks, 2.61 mg/kg/6 weeks, 2.62 mg/kg/6 weeks, 2.63 mg/kg/6 weeks, 2.64 mg/kg/6 weeks, 2.65 mg/kg/6 weeks, 2.66 mg/kg/6 weeks, 2.67 mg/kg/6 weeks, 2.68 mg/kg/6 weeks, 2.69 mg/kg/6 weeks, 2.7 mg/kg/6 weeks, 2.71 mg/kg/6 weeks, 2.72 mg/kg/6 weeks, 2.73 mg/kg/6 weeks, 2.74 mg/kg/6 weeks, 2.75 mg/kg/6 weeks, 2.76 mg/kg/6 weeks, 2.77 mg/kg/6 weeks, 2.78 mg/kg/6 weeks, 2.79 mg/kg/6 weeks, 2.8 mg/kg/6 weeks, 2.81 mg/kg/6 weeks, 2.82 mg/kg/6 weeks, 2.83 mg/kg/6 weeks, 2.84 mg/kg/6 weeks, 2.85 mg/kg/6 weeks, 2.86 mg/kg/6 weeks, 2.87 mg/kg/6 weeks, 2.88 mg/kg/6 weeks, 2.89 mg/kg/6 weeks, 2.9 mg/kg/6 weeks, 2.91 mg/kg/6 weeks, 2.92 mg/kg/6 weeks, 2.93 mg/kg/6 weeks, 2.94 mg/kg/6 weeks, 2.95 mg/kg/6 weeks, 2.96 mg/kg/6 weeks, 2.97 mg/kg/6 weeks, 2.98 mg/kg/6 weeks, 2.99 mg/kg/6 weeks, or 3 mg/kg/6 weeks. In yet another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 0.1 mg/kg/8 weeks, 0.11 mg/kg/8 weeks, 0.12 mg/kg/8 weeks, 0.125 mg/kg/8 weeks, 0.13 mg/kg/8 weeks, 0.14 mg/kg/8 weeks, 0.15 mg/kg/8 weeks, 0.16 mg/kg/8 weeks, 0.17 mg/kg/8 weeks, 0.18 mg/kg/8 weeks, 0.19 mg/kg/8 weeks, 0.2 mg/kg/8 weeks, 0.21 mg/kg/8 weeks, 0.22 mg/kg/8 weeks, 0.23 mg/kg/8 weeks, 0.24 mg/kg/8 weeks, 0.25 mg/kg/8 weeks, 0.26 mg/kg/8 weeks, 0.27 mg/kg/8 weeks, 0.28 mg/kg/8 weeks, 0.29 mg/kg/8 weeks, 0.3 mg/kg/8 weeks, 0.31 mg/kg/8 weeks, 0.32 mg/kg/8 weeks, 0.33 mg/kg/8 weeks, 0.34 mg/kg/8 weeks, 0.35 mg/kg/8 weeks, 0.36 mg/kg/8 weeks, 0.37 mg/kg/8 weeks, 0.38 mg/kg/8 weeks, 0.39 mg/kg/8 weeks, 0.4 mg/kg/8 weeks, 0.41 mg/kg/8 weeks, 0.42 mg/kg/8 weeks, 0.43 mg/kg/8 weeks, 0.44 mg/kg/8 weeks, 0.45 mg/kg/8 weeks, 0.46 mg/kg/8 weeks, 0.47 mg/kg/8 weeks, 0.48 mg/kg/8 weeks, 0.49 mg/kg/8 weeks, 0.5 mg/kg/8 weeks, 0.51 mg/kg/8 weeks, 0.52 mg/kg/8 weeks, 0.53 mg/kg/8 weeks, 0.54 mg/kg/8 weeks, 0.55 mg/kg/8 weeks, 0.56 mg/kg/8 weeks, 0.57 mg/kg/8 weeks, 0.58 mg/kg/8 weeks, 0.59 mg/kg/8 weeks, 0.6 mg/kg/8 weeks, 0.61 mg/kg/8 weeks, 0.62 mg/kg/8 weeks, 0.63 mg/kg/8 weeks, 0.64 mg/kg/8 weeks, 0.65 mg/kg/8 weeks, 0.66 mg/kg/8 weeks, 0.67 mg/kg/8 weeks, 0.68 mg/kg/8 weeks, 0.69 mg/kg/8 weeks, 0.7 mg/kg/8 weeks, 0.71 mg/kg/8 weeks, 0.72 mg/kg/8 weeks, 0.73 mg/kg/8 weeks, 0.74 mg/kg/8 weeks, 0.75 mg/kg/8 weeks, 0.76 mg/kg/8 weeks, 0.77 mg/kg/8 weeks, 0.78 mg/kg/8 weeks, 0.79 mg/kg/8 weeks, 0.8 mg/kg/8 weeks, 0.81 mg/kg/8 weeks, 0.82 mg/kg/8 weeks, 0.83 mg/kg/8 weeks, 0.84 mg/kg/8 weeks, 0.85 mg/kg/8 weeks, 0.86 mg/kg/8 weeks, 0.87 mg/kg/8 weeks, 0.88 mg/kg/8 weeks, 0.89 mg/kg/8 weeks, 0.9 mg/kg/8 weeks, 0.91 mg/kg/8 weeks, 0.92 mg/kg/8 weeks, 0.93 mg/kg/8 weeks, 0.94 mg/kg/8 weeks, 0.95 mg/kg/8 weeks, 0.96 mg/kg/8 weeks, 0.97 mg/kg/8 weeks, 0.98 mg/kg/8 weeks, 0.99 mg/kg/8 weeks, 1 mg/kg/8 weeks, 1.01 mg/kg/8 weeks, 1.02 mg/ kg/8 weeks, 1.03 mg/kg/8 weeks, 1.04 mg/kg/8 weeks, 1.05 mg/kg/8 weeks, 1.06 mg/kg/8 weeks, 1.07 mg/ kg/8 weeks, 1.08 mg/kg/8 weeks, 1.09 mg/kg/8 weeks, 1.1 mg/kg/8 weeks, 1.11 mg/kg/8 weeks, 1.12 mg/ kg/8 weeks, 1.13 mg/kg/8 weeks, 1.14 mg/kg/8 weeks, 1.15 mg/kg/8 weeks, 1.16 mg/kg/8 weeks, 1.17 mg/ kg/8 weeks, 1.18 mg/kg/8 weeks, 1.19 mg/kg/8 weeks, 1.2 mg/kg/8 weeks, 1.21 mg/kg/8 weeks, 1.22 mg/ kg/8 weeks, 1.23 mg/kg/8 weeks, 1.24 mg/kg/8 weeks, 1.25 mg/kg/8 weeks, 1.26 mg/kg/8 weeks, 1.27 mg/ kg/8 weeks, 1.28 mg/kg/8 weeks, 1.29 mg/kg/8 weeks, 1.3 mg/kg/8 weeks, 1.31 mg/kg/8 weeks, 1.32 mg/ kg/8 weeks, 1.33 mg/kg/8 weeks, 1.34 mg/kg/8 weeks, 1.35 mg/kg/8 weeks, 1.36 mg/kg/8 weeks, 1.37 mg/ kg/8 weeks, 1.38 mg/kg/8 weeks, 1.39 mg/kg/8 weeks, 1.4 mg/kg/8 weeks, 1.41 mg/kg/8 weeks, 1.42 mg/ kg/8 weeks, 1.43 mg/kg/8 weeks, 1.44 mg/kg/8 weeks, 1.45 mg/kg/8 weeks, 1.46 mg/kg/8 weeks, 1.47 mg/ kg/8 weeks, 1.48 mg/kg/8 weeks, 1.49 mg/kg/8 weeks, 1.5 mg/kg/8 weeks, 1.51 mg/kg/8 weeks, 1.52 mg/ kg/8 weeks, 1.53 mg/kg/8 weeks, 1.54 mg/kg/8 weeks, 1.55 mg/kg/8 weeks, 1.56 mg/kg/8 weeks, 1.57 mg/ kg/8 weeks, 1.58 mg/kg/8 weeks, 1.59 mg/kg/8 weeks, 1.6 mg/kg/8 weeks, 1.61 mg/kg/8 weeks, 1.62 mg/ kg/8 weeks, 1.63 mg/kg/8 weeks, 1.64 mg/kg/8 weeks, 1.65 mg/kg/8 weeks, 1.66 mg/kg/8 weeks, 1.67 mg/ kg/8 weeks, 1.68 mg/kg/8 weeks, 1.69 mg/kg/8 weeks, 1.7 mg/kg/8 weeks, 1.71 mg/kg/8 weeks, 1.72 mg/ kg/8 weeks, 1.73 mg/kg/8 weeks, 1.74 mg/kg/8 weeks, 1.75 mg/kg/8 weeks, 1.76 mg/kg/8 weeks, 1.77 mg/ kg/8 weeks, 1.78 mg/kg/8 weeks, 1.79 mg/kg/8 weeks, 1.8 mg/kg/8 weeks, 1.81 mg/kg/8 weeks, 1.82 mg/ kg/8 weeks, 1.83 mg/kg/8 weeks, 1.84 mg/kg/8 weeks, 1.85 mg/kg/8 weeks, 1.86 mg/kg/8 weeks, 1.87 mg/ kg/8 weeks, 1.88 mg/kg/8 weeks, 1.89 mg/kg/8 weeks, 1.9 mg/kg/8 weeks, 1.91 mg/kg/8 weeks, 1.92 mg/ kg/8 weeks, 1.93 mg/kg/8 weeks, 1.94 mg/kg/8 weeks, 1.95 mg/kg/8 weeks, 1.96 mg/kg/8 weeks, 1.97 mg/ kg/8 weeks, 1.98 mg/kg/8 weeks, 1.99 mg/kg/8 weeks, 2 mg/kg/8 weeks, 2.01 mg/kg/8 weeks, 2.02 mg/kg/ 8 weeks, 2.03 mg/kg/8 weeks, 2.04 mg/kg/8 weeks, 2.05 mg/kg/8 weeks, 2.06 mg/kg/8 weeks, 2.07 mg/kg/ 8 weeks, 2.08 mg/kg/8 weeks, 2.09 mg/kg/8 weeks, 2.1 mg/kg/8 weeks, 2.11 mg/kg/8 weeks, 2.12 mg/kg/ 8 weeks, 2.13 mg/kg/8 weeks, 2.14 mg/kg/8 weeks, 2.15 mg/kg/8 weeks, 2.16 mg/kg/8 weeks, 2.17 mg/kg/ 8 weeks, 2.18 mg/kg/8 weeks, 2.19 mg/kg/8 weeks, 2.2 mg/kg/8 weeks, 2.21 mg/kg/8 weeks, 2.22 mg/kg/ 8 weeks, 2.23 mg/kg/8 weeks, 2.24 mg/kg/8 weeks, 2.25 mg/kg/8 weeks, 2.26 mg/kg/8 weeks, 2.27 mg/kg/ 8 weeks, 2.28 mg/kg/8 weeks, 2.29 mg/kg/8 weeks, 2.3 mg/kg/8 weeks, 2.31 mg/kg/8 weeks, 2.32 mg/kg/ 8 weeks, 2.33 mg/kg/8 weeks, 2.34 mg/kg/8 weeks, 2.35 mg/kg/8 weeks, 2.36 mg/kg/8 weeks, 2.37 mg/kg/ 8 weeks, 2.38 mg/kg/8 weeks, 2.39 mg/kg/8 weeks, 2.4 mg/kg/8 weeks, 2.41 mg/kg/8 weeks, 2.42 mg/kg/ 8 weeks, 2.43 mg/kg/8 weeks, 2.44 mg/kg/8 weeks, 2.45 mg/kg/8 weeks, 2.46 mg/kg/8 weeks, 2.47 mg/kg/ 8 weeks, 2.48 mg/kg/8 weeks, 2.49 mg/kg/8 weeks, 2.5 mg/kg/8 weeks, 2.51 mg/kg/8 weeks, 2.52 mg/kg/ 8 weeks, 2.53 mg/kg/8 weeks, 2.54 mg/kg/8 weeks, 2.55 mg/kg/8 weeks, 2.56 mg/kg/8 weeks, 2.57 mg/kg/ 8 weeks, 2.58 mg/kg/8 weeks, 2.59 mg/kg/8 weeks, 2.6 mg/kg/8 weeks, 2.61 mg/kg/8 weeks, 2.62 mg/kg/ 8 weeks, 2.63 mg/kg/8 weeks, 2.64 mg/kg/8 weeks, 2.65 mg/kg/8 weeks, 2.66 mg/kg/8 weeks, 2.67 mg/kg/ 8 weeks, 2.68 mg/kg/8 weeks, 2.69 mg/kg/8 weeks, 2.7 mg/kg/8 weeks, 2.71 mg/kg/8 weeks, 2.72 mg/kg/ 8 weeks, 2.73 mg/kg/8 weeks, 2.74 mg/kg/8 weeks, 2.75 mg/kg/8 weeks, 2.76 mg/kg/8 weeks, 2.77 mg/kg/ 8 weeks, 2.78 mg/kg/8 weeks, 2.79 mg/kg/8 weeks, 2.8 mg/kg/8 weeks, 2.81 mg/kg/8 weeks, 2.82 mg/kg/ 8 weeks, 2.83 mg/kg/8 weeks, 2.84 mg/kg/8 weeks, 2.85 mg/kg/8 weeks, 2.86 mg/kg/8 weeks, 2.87 mg/kg/ 8 weeks, 2.88 mg/kg/8 weeks, 2.89 mg/kg/8 weeks, 2.9 mg/kg/8 weeks, 2.91 mg/kg/8 weeks, 2.92 mg/kg/ 8 weeks, 2.93 mg/kg/8 weeks, 2.94 mg/kg/8 weeks, 2.95 mg/kg/8 weeks, 2.96 mg/kg/8 weeks, 2.97 mg/kg/ 8 weeks, 2.98 mg/kg/8 weeks, 2.99 mg/kg/8 weeks, or 3 mg/kg/8 weeks. In another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 0.1 mg/kg/10 weeks, 0.11 mg/kg/10 weeks, 0.12 mg/kg/10 weeks, 0.125 mg /kg/10 weeks, 0.13 mg/kg/10 weeks, 0.14 mg/kg/10 weeks, 0.15 mg/kg/10 weeks, 0.16 mg/kg/10 weeks, 0.17 mg /kg/10 weeks, 0.18 mg/kg/10 weeks, 0.19 mg/kg/10 weeks, 0.2 mg/kg/10 weeks, 0.21 mg/kg/10 weeks, 0.22 mg /kg/10 weeks, 0.23 mg/kg/10 weeks, 0.24 mg/kg/10 weeks, 0.25 mg/kg/10 weeks, 0.26 mg/kg/10 weeks, 0.27 mg /kg/10 weeks, 0.28 mg/kg/10 weeks, 0.29 mg/kg/10 weeks, 0.3 mg/kg/10 weeks, 0.31 mg/kg/10 weeks, 0.32 mg /kg/10 weeks, 0.33 mg/kg/10 weeks, 0.34 mg/kg/10 weeks, 0.35 mg/kg/10 weeks, 0.36 mg/kg/10 weeks, 0.37 mg /kg/10 weeks, 0.38 mg/kg/10 weeks, 0.39 mg/kg/10 weeks, 0.4 mg/kg/10 weeks, 0.41 mg/kg/10 weeks, 0.42 mg /kg/10 weeks, 0.43 mg/kg/10 weeks, 0.44 mg/kg/10 weeks, 0.45 mg/kg/10 weeks, 0.46 mg/kg/10 weeks, 0.47 mg /kg/10 weeks, 0.48 mg/kg/10 weeks, 0.49 mg/kg/10 weeks, 0.5 mg/kg/10 weeks, 0.51 mg/kg/10 weeks, 0.52 mg /kg/10 weeks, 0.53 mg/kg/10 weeks, 0.54 mg/kg/10 weeks, 0.55 mg/kg/10 weeks, 0.56 mg/kg/10 weeks, 0.57 mg /kg/10 weeks, 0.58 mg/kg/10 weeks, 0.59 mg/kg/10 weeks, 0.6 mg/kg/10 weeks, 0.61 mg/kg/10 weeks, 0.62 mg /kg/10 weeks, 0.63 mg/kg/10 weeks, 0.64 mg/kg/10 weeks, 0.65 mg/kg/10 weeks, 0.66 mg/kg/10 weeks, 0.67 mg /kg/10 weeks, 0.68 mg/kg/10 weeks, 0.69 mg/kg/10 weeks, 0.7 mg/kg/10 weeks, 0.71 mg/kg/10 weeks, 0.72 mg /kg/10 weeks, 0.73 mg/kg/10 weeks, 0.74 mg/kg/10 weeks, 0.75 mg/kg/10 weeks, 0.76 mg/kg/10 weeks, 0.77 mg /kg/10 weeks, 0.78 mg/kg/10 weeks, 0.79 mg/kg/10 weeks, 0.8 mg/kg/10 weeks, 0.81 mg/kg/10 weeks, 0.82 mg /kg/10 weeks, 0.83 mg/kg/10 weeks, 0.84 mg/kg/10 weeks, 0.85 mg/kg/10 weeks, 0.86 mg/kg/10 weeks, 0.87 mg /kg/10 weeks, 0.88 mg/kg/10 weeks, 0.89 mg/kg/10 weeks, 0.9 mg/kg/10 weeks, 0.91 mg/kg/10 weeks, 0.92 mg /kg/10 weeks, 0.93 mg/kg/10 weeks, 0.94 mg/kg/10 weeks, 0.95 mg/kg/10 weeks, 0.96 mg/kg/10 weeks, 0.97 mg /kg/10 weeks, 0.98 mg/kg/10 weeks, 0.99 mg/kg/10 weeks, 1 mg/kg/10 weeks, 1.01 mg/kg/10 weeks, 1.02 mg/kg /10 weeks, 1.03 mg/kg/10 weeks, 1.04 mg/kg/10 weeks, 1.05 mg/kg/10 weeks, 1.06 mg/kg/10 weeks, 1.07 mg/kg /10 weeks, 1.08 mg/kg/10 weeks, 1.09 mg/kg/10 weeks, 1.1 mg/kg/10 weeks, 1.11 mg/kg/10 weeks, 1.12 mg/kg /10 weeks, 1.13 mg/kg/10 weeks, 1.14 mg/kg/10 weeks, 1.15 mg/kg/10 weeks, 1.16 mg/kg/10 weeks, 1.17 mg/kg /10 weeks, 1.18 mg/kg/10 weeks, 1.19 mg/kg/10 weeks, 1.2 mg/kg/10 weeks, 1.21 mg/kg/10 weeks, 1.22 mg/kg /10 weeks, 1.23 mg/kg/10 weeks, 1.24 mg/kg/10 weeks, 1.25 mg/kg/10 weeks, 1.26 mg/kg/10 weeks, 1.27 mg/kg /10 weeks, 1.28 mg/kg/10 weeks, 1.29 mg/kg/10 weeks, 1.3 mg/kg/10 weeks, 1.31 mg/kg/10 weeks, 1.32 mg/kg /10 weeks, 1.33 mg/kg/10 weeks, 1.34 mg/kg/10 weeks, 1.35 mg/kg/10 weeks, 1.36 mg/kg/10 weeks, 1.37 mg/kg /10 weeks, 1.38 mg/kg/10 weeks, 1.39 mg/kg/10 weeks, 1.4 mg/kg/10 weeks, 1.41 mg/kg/10 weeks, 1.42 mg/kg /10 weeks, 1.43 mg/kg/10 weeks, 1.44 mg/kg/10 weeks, 1.45 mg/kg/10 weeks, 1.46 mg/kg/10 weeks, 1.47 mg/kg /10 weeks, 1.48 mg/kg/10 weeks, 1.49 mg/kg/10 weeks, 1.5 mg/kg/10 weeks, 1.51 mg/kg/10 weeks, 1.52 mg/kg /10 weeks, 1.53 mg/kg/10 weeks, 1.54 mg/kg/10 weeks, 1.55 mg/kg/10 weeks, 1.56 mg/kg/10 weeks, 1.57 mg/kg /10 weeks, 1.58 mg/kg/10 weeks, 1.59 mg/kg/10 weeks, 1.6 mg/kg/10 weeks, 1.61 mg/kg/10 weeks, 1.62 mg/kg /10 weeks, 1.63 mg/kg/10 weeks, 1.64 mg/kg/10 weeks, 1.65 mg/kg/10 weeks, 1.66 mg/kg/10 weeks, 1.67 mg/kg /10 weeks, 1.68 mg/kg/10 weeks, 1.69 mg/kg/10 weeks, 1.7 mg/kg/10 weeks, 1.71 mg/kg/10 weeks, 1.72 mg/kg /10 weeks, 1.73 mg/kg/10 weeks, 1.74 mg/kg/10 weeks, 1.75 mg/kg/10 weeks, 1.76 mg/kg/10 weeks, 1.77 mg/kg /10 weeks, 1.78 mg/kg/10 weeks, 1.79 mg/kg/10 weeks, 1.8 mg/kg/10 weeks, 1.81 mg/kg/10 weeks, 1.82 mg/kg /10 weeks, 1.83 mg/kg/10 weeks, 1.84 mg/kg/10 weeks, 1.85 mg/kg/10 weeks, 1.86 mg/kg/10 weeks, 1.87 mg/kg /10 weeks, 1.88 mg/kg/10 weeks, 1.89 mg/kg/10 weeks, 1.9 mg/kg/10 weeks, 1.91 mg/kg/10 weeks, 1.92 mg/kg /10 weeks, 1.93 mg/kg/10 weeks, 1.94 mg/kg/10 weeks, 1.95 mg/kg/10 weeks, 1.96 mg/kg/10 weeks, 1.97 mg/kg /10 weeks, 1.98 mg/kg/10 weeks, 1.99 mg/kg/10 weeks, 2 mg/kg/10 weeks, 2.01 mg/kg/10 weeks, 2.02 mg/kg/10 weeks, 2.03 mg/kg/10 weeks, 2.04 mg/kg/10 weeks, 2.05 mg/kg/10 weeks, 2.06 mg/kg/10 weeks, 2.07 mg/kg/10 weeks, 2.08 mg/kg/10 weeks, 2.09 mg/kg/10 weeks, 2.1 mg/kg/10 weeks, 2.11 mg/kg/10 weeks, 2.12 mg/kg/10 weeks, 2.13 mg/kg/10 weeks, 2.14 mg/kg/10 weeks, 2.15 mg/kg/10 weeks, 2.16 mg/kg/10 weeks, 2.17 mg/kg/10 weeks, 2.18 mg/kg/10 weeks, 2.19 mg/kg/10 weeks, 2.2 mg/kg/10 weeks, 2.21 mg/kg/10 weeks, 2.22 mg/kg/10 weeks, 2.23 mg/kg/10 weeks, 2.24 mg/kg/10 weeks, 2.25 mg/kg/10 weeks, 2.26 mg/kg/10 weeks, 2.27 mg/kg/10 weeks, 2.28 mg/kg/10 weeks, 2.29 mg/kg/10 weeks, 2.3 mg/kg/10 weeks, 2.31 mg/kg/10 weeks, 2.32 mg/kg/10 weeks, 2.33 mg/kg/10 weeks, 2.34 mg/kg/10 weeks, 2.35 mg/kg/10 weeks, 2.36 mg/kg/10 weeks, 2.37 mg/kg/10 weeks, 2.38 mg/kg/10 weeks, 2.39 mg/kg/10 weeks, 2.4 mg/kg/10 weeks, 2.41 mg/kg/10 weeks, 2.42 mg/kg/10 weeks, 2.43 mg/kg/10 weeks, 2.44 mg/kg/10 weeks, 2.45 mg/kg/10 weeks, 2.46 mg/kg/10 weeks, 2.47 mg/kg/10 weeks, 2.48 mg/kg/10 weeks, 2.49 mg/kg/10 weeks, 2.5 mg/kg/10 weeks, 2.51 mg/kg/10 weeks, 2.52 mg/kg/10 weeks, 2.53 mg/kg/10 weeks, 2.54 mg/kg/10 weeks, 2.55 mg/kg/10 weeks, 2.56 mg/kg/10 weeks, 2.57 mg/kg/10 weeks, 2.58 mg/kg/10 weeks, 2.59 mg/kg/10 weeks, 2.6 mg/kg/10 weeks, 2.61 mg/kg/10 weeks, 2.62 mg/kg/10 weeks, 2.63 mg/kg/10 weeks, 2.64 mg/kg/10 weeks, 2.65 mg/kg/10 weeks, 2.66 mg/kg/10 weeks, 2.67 mg/kg/10 weeks, 2.68 mg/kg/10 weeks, 2.69 mg/kg/10 weeks, 2.7 mg/kg/10 weeks, 2.71 mg/kg/10 weeks, 2.72 mg/kg/10 weeks, 2.73 mg/kg/10 weeks, 2.74 mg/kg/10 weeks, 2.75 mg/kg/10 weeks, 2.76 mg/kg/10 weeks, 2.77 mg/kg/10 weeks, 2.78 mg/kg/10 weeks, 2.79 mg/kg/10 weeks, 2.8 mg/kg/10 weeks, 2.81 mg/kg/10 weeks, 2.82 mg/kg/10 weeks, 2.83 mg/kg/10 weeks, 2.84 mg/kg/10 weeks, 2.85 mg/kg/10 weeks, 2.86 mg/kg/10 weeks, 2.87 mg/kg/10 weeks, 2.88 mg/kg/10 weeks, 2.89 mg/kg/10 weeks, 2.9 mg/kg/10 weeks, 2.91 mg/kg/10 weeks, 2.92 mg/kg/10 weeks, 2.93 mg/kg/10 weeks, 2.94 mg/kg/10 weeks, 2.95 mg/kg/10 weeks, 2.96 mg/kg/10 weeks, 2.97 mg/kg/10 weeks, 2.98 mg/kg/10 weeks, 2.99 mg/kg/10 weeks, or 3 mg/kg/10 weeks. In another non-limiting embodiment, the IL-31 antagonist of the invention can be administered, for example, at a dose of 0.1 mg/kg/12 weeks, 0.11 mg/kg/12 weeks, 0.12 mg/kg/12 weeks, 0.125 mg/ kg/12 weeks, 0.13 mg/kg/12 weeks, 0.14 mg/kg/12 weeks, 0.15 mg/kg/12 weeks, 0.16 mg/kg/12 weeks, 0.17 mg/ kg/12 weeks, 0.18 mg/kg/12 weeks, 0.19 mg/kg/12 weeks, 0.2 mg/kg/12 weeks, 0.21 mg/kg/12 weeks, 0.22 mg/ kg/12 weeks, 0.23 mg/kg/12 weeks, 0.24 mg/kg/12 weeks, 0.25 mg/kg/12 weeks, 0.26 mg/kg/12 weeks, 0.27 mg/ kg/12 weeks, 0.28 mg/kg/12 weeks, 0.29 mg/kg/12 weeks, 0.3 mg/kg/12 weeks, 0.31 mg/kg/12 weeks, 0.32 mg/ kg/12 weeks, 0.33 mg/kg/12 weeks, 0.34 mg/kg/12 weeks, 0.35 mg/kg/12 weeks, 0.36 mg/kg/12 weeks, 0.37 mg/ kg/12 weeks, 0.38 mg/kg/12 weeks, 0.39 mg/kg/12 weeks, 0.4 mg/kg/12 weeks, 0.41 mg/kg/12 weeks, 0.42 mg/ kg/12 weeks, 0.43 mg/kg/12 weeks, 0.44 mg/kg/12 weeks, 0.45 mg/kg/12 weeks, 0.46 mg/kg/12 weeks, 0.47 mg/ kg/12 weeks, 0.48 mg/kg/12 weeks, 0.49 mg/kg/12 weeks, 0.5 mg/kg/12 weeks, 0.51 mg/kg/12 weeks, 0.52 mg/ kg/12 weeks, 0.53 mg/kg/12 weeks, 0.54 mg/kg/12 weeks, 0.55 mg/kg/12 weeks, 0.56 mg/kg/12 weeks, 0.57 mg/ kg/12 weeks, 0.58 mg/kg/12 weeks, 0.59 mg/kg/12 weeks, 0.6 mg/kg/12 weeks, 0.61 mg/kg/12 weeks, 0.62 mg/ kg/12 weeks, 0.63 mg/kg/12 weeks, 0.64 mg/kg/12 weeks, 0.65 mg/kg/12 weeks, 0.66 mg/kg/12 weeks, 0.67 mg/ kg/12 weeks, 0.68 mg/kg/12 weeks, 0.69 mg/kg/12 weeks, 0.7 mg/kg/12 weeks, 0.71 mg/kg/12 weeks, 0.72 mg/ kg/12 weeks, 0.73 mg/kg/12 weeks, 0.74 mg/kg/12 weeks, 0.75 mg/kg/12 weeks, 0.76 mg/kg/12 weeks, 0.77 mg/ kg/12 weeks, 0.78 mg/kg/12 weeks, 0.79 mg/kg/12 weeks, 0.8 mg/kg/12 weeks, 0.81 mg/kg/12 weeks, 0.82 mg/ kg/12 weeks, 0.83 mg/kg/12 weeks, 0.84 mg/kg/12 weeks, 0.85 mg/kg/12 weeks, 0.86 mg/kg/12 weeks, 0.87 mg/ kg/12 weeks, 0.88 mg/kg/12 weeks, 0.89 mg/kg/12 weeks, 0.9 mg/kg/12 weeks, 0.91 mg/kg/12 weeks, 0.92 mg/ kg/12 weeks, 0.93 mg/kg/12 weeks, 0.94 mg/kg/12 weeks, 0.95 mg/kg/12 weeks, 0.96 mg/kg/12 weeks, 0.97 mg/ kg/12 weeks, 0.98 mg/kg/12 weeks, 0.99 mg/kg/12 weeks, 1 mg/kg/12 weeks, 1.01 mg/kg/12 weeks, 1.02 mg/kg/ 12 weeks, 1.03 mg/kg/12 weeks, 1.04 mg/kg/12 weeks, 1.05 mg/kg/12 weeks, 1.06 mg/kg/12 weeks, 1.07 mg/kg/ 12 weeks, 1.08 mg/kg/12 weeks, 1.09 mg/kg/12 weeks, 1.1 mg/kg/12 weeks, 1.11 mg/kg/12 weeks, 1.12 mg/kg/ 12 weeks, 1.13 mg/kg/12 weeks, 1.14 mg/kg/12 weeks, 1.15 mg/kg/12 weeks, 1.16 mg/kg/12 weeks, 1.17 mg/kg/ 12 weeks, 1.18 mg/kg/12 weeks, 1.19 mg/kg/12 weeks, 1.2 mg/kg/12 weeks, 1.21 mg/kg/12 weeks, 1.22 mg/kg/ 12 weeks, 1.23 mg/kg/12 weeks, 1.24 mg/kg/12 weeks, 1.25 mg/kg/12 weeks, 1.26 mg/kg/12 weeks, 1.27 mg/kg/ 12 weeks, 1.28 mg/kg/12 weeks, 1.29 mg/kg/12 weeks, 1.3 mg/kg/12 weeks, 1.31 mg/kg/12 weeks, 1.32 mg/kg/ 12 weeks, 1.33 mg/kg/12 weeks, 1.34 mg/kg/12 weeks, 1.35 mg/kg/12 weeks, 1.36 mg/kg/12 weeks, 1.37 mg/kg/ 12 weeks, 1.38 mg/kg/12 weeks, 1.39 mg/kg/12 weeks, 1.4 mg/kg/12 weeks, 1.41 mg/kg/12 weeks, 1.42 mg/kg/ 12 weeks, 1.43 mg/kg/12 weeks, 1.44 mg/kg/12 weeks, 1.45 mg/kg/12 weeks, 1.46 mg/kg/12 weeks, 1.47 mg/kg/ 12 weeks, 1.48 mg/kg/12 weeks, 1.49 mg/kg/12 weeks, 1.5 mg/kg/12 weeks, 1.51 mg/kg/12 weeks, 1.52 mg/kg/ 12 weeks, 1.53 mg/kg/12 weeks, 1.54 mg/kg/12 weeks, 1.55 mg/kg/12 weeks, 1.56 mg/kg/12 weeks, 1.57 mg/kg/ 12 weeks, 1.58 mg/kg/12 weeks, 1.59 mg/kg/12 weeks, 1.6 mg/kg/12 weeks, 1.61 mg/kg/12 weeks, 1.62 mg/kg/ 12 weeks, 1.63 mg/kg/12 weeks, 1.64 mg/kg/12 weeks, 1.65 mg/kg/12 weeks, 1.66 mg/kg/12 weeks, 1.67 mg/kg/ 12 weeks, 1.68 mg/kg/12 weeks, 1.69 mg/kg/12 weeks, 1.7 mg/kg/12 weeks, 1.71 mg/kg/12 weeks, 1.72 mg/kg/ 12 weeks, 1.73 mg/kg/12 weeks, 1.74 mg/kg/12 weeks, 1.75 mg/kg/12 weeks, 1.76 mg/kg/12 weeks, 1.77 mg/kg/ 12 weeks, 1.78 mg/kg/12 weeks, 1.79 mg/kg/12 weeks, 1.8 mg/kg/12 weeks, 1.81 mg/kg/12 weeks, 1.82 mg/kg/ 12 weeks, 1.83 mg/kg/12 weeks, 1.84 mg/kg/12 weeks, 1.85 mg/kg/12 weeks, 1.86 mg/kg/12 weeks, 1.87 mg/kg/ 12 weeks, 1.88 mg/kg/12 weeks, 1.89 mg/kg/12 weeks, 1.9 mg/kg/12 weeks, 1.91 mg/kg/12 weeks, 1.92 mg/kg/ 12 weeks, 1.93 mg/kg/12 weeks, 1.94 mg/kg/12 weeks, 1.95 mg/kg/12 weeks, 1.96 mg/kg/12 weeks, 1.97 mg/kg/ 12 weeks, 1.98 mg/kg/12 weeks, 1.99 mg/kg/12 weeks, 2 mg/kg/12 weeks, 2.01 mg/kg/12 weeks, 2.02 mg/kg/12 weeks , 2.03 mg/kg/12 weeks, 2.04 mg/kg/12 weeks, 2.05 mg/kg/12 weeks, 2.06 mg/kg/12 weeks, 2.07 mg/kg/12 weeks , 2.08 mg/kg/12 weeks, 2.09 mg/kg/12 weeks, 2.1 mg/kg/12 weeks, 2.11 mg/kg/12 weeks, 2.12 mg/kg/12 weeks , 2.13 mg/kg/12 weeks, 2.14 mg/kg/12 weeks, 2.15 mg/kg/12 weeks, 2.16 mg/kg/12 weeks, 2.17 mg/kg/12 weeks , 2.18 mg/kg/12 weeks, 2.19 mg/kg/12 weeks, 2.2 mg/kg/12 weeks, 2.21 mg/kg/12 weeks, 2.22 mg/kg/12 weeks , 2.23 mg/kg/12 weeks, 2.24 mg/kg/12 weeks, 2.25 mg/kg/12 weeks, 2.26 mg/kg/12 weeks, 2.27 mg/kg/12 weeks , 2.28 mg/kg/12 weeks, 2.29 mg/kg/12 weeks, 2.3 mg/kg/12 weeks, 2.31 mg/kg/12 weeks, 2.32 mg/kg/12 weeks , 2.33 mg/kg/12 weeks, 2.34 mg/kg/12 weeks, 2.35 mg/kg/12 weeks, 2.36 mg/kg/12 weeks, 2.37 mg/kg/12 weeks , 2.38 mg/kg/12 weeks, 2.39 mg/kg/12 weeks, 2.4 mg/kg/12 weeks, 2.41 mg/kg/12 weeks, 2.42 mg/kg/12 weeks , 2.43 mg/kg/12 weeks, 2.44 mg/kg/12 weeks, 2.45 mg/kg/12 weeks, 2.46 mg/kg/12 weeks, 2.47 mg/kg/12 weeks , 2.48 mg/kg/12 weeks, 2.49 mg/kg/12 weeks, 2.5 mg/kg/12 weeks, 2.51 mg/kg/12 weeks, 2.52 mg/kg/12 weeks , 2.53 mg/kg/12 weeks, 2.54 mg/kg/12 weeks, 2.55 mg/kg/12 weeks, 2.56 mg/kg/12 weeks, 2.57 mg/kg/12 weeks , 2.58 mg/kg/12 weeks, 2.59 mg/kg/12 weeks, 2.6 mg/kg/12 weeks, 2.61 mg/kg/12 weeks, 2.62 mg/kg/12 weeks , 2.63 mg/kg/12 weeks, 2.64 mg/kg/12 weeks, 2.65 mg/kg/12 weeks, 2.66 mg/kg/12 weeks, 2.67 mg/kg/12 weeks , 2.68 mg/kg/12 weeks, 2.69 mg/kg/12 weeks, 2.7 mg/kg/12 weeks, 2.71 mg/kg/12 weeks, 2.72 mg/kg/12 weeks , 2.73 mg/kg/12 weeks, 2.74 mg/kg/12 weeks, 2.75 mg/kg/12 weeks, 2.76 mg/kg/12 weeks, 2.77 mg/kg/12 weeks , 2.78 mg/kg/12 weeks, 2.79 mg/kg/12 weeks, 2.8 mg/kg/12 weeks, 2.81 mg/kg/12 weeks, 2.82 mg/kg/12 weeks , 2.83 mg/kg/12 weeks, 2.84 mg/kg/12 weeks, 2.85 mg/kg/12 weeks, 2.86 mg/kg/12 weeks, 2.87 mg/kg/12 weeks , 2.88 mg/kg/12 weeks, 2.89 mg/kg/12 weeks, 2.9 mg/kg/12 weeks, 2.91 mg/kg/12 weeks, 2.92 mg/kg/12 weeks , 2.93 mg/kg/12 weeks, 2.94 mg/kg/12 weeks, 2.95 mg/kg/12 weeks, 2.96 mg/kg/12 weeks, 2.97 mg/kg/12 weeks , 2.98 mg/kg/12 weeks, 2.99 mg/kg/12 weeks, or 3 mg/kg/12 weeks.

When the IL-31 antagonist of the invention is administered several times in equal amounts at equal dosing intervals to a subject suffering from or susceptible to developing atopic dermatitis, using the predetermined dosing interval and predetermined dosage described above, it may Sustainably suppress or improve the symptoms of atopic dermatitis and/or one or more of the various symptoms caused by atopic dermatitis (eg, itching, redness, induration, papules, swelling, excoriation, lichenification, decreased QOL, and sleep deprivation). The dose administered in equal amounts and at equal intervals between doses is determined, for example, taking into account the effect and safety.

In one embodiment of the present invention, the method of administering the pharmaceutical composition of the invention to a subject can be selected from oral or parenteral administration. Generally, if the active ingredient is a low molecular weight compound, oral or parenteral administration is preferred, and if the active ingredient is a high molecular weight compound, parenteral administration is preferred, but not limited to. Examples of parenteral administration include: injection, intranasal, intrapulmonary, and transdermal administration. Additionally, injections include intravenous, intramuscular, intraperitoneal and subcutaneous injections. Depending on which of these methods is used to administer the pharmaceutical composition of the invention, it can be administered systemically or locally. For example, transdermal administration using subcutaneous injections is preferred.

In one embodiment of the present invention, the pharmaceutical composition of the invention can be prepared as a combination of the IL-31 antagonist used as an active ingredient with pharmaceutically acceptable carriers using known methods. For example, if desired, the IL-31 antagonist may be combined with pharmaceutically acceptable carriers or vehicles, such as, for example, sterile water or saline, vegetable oils, emulsifiers, suspensions, surfactants, stabilizers, flavoring agents, excipients, fillers, preservatives and binding agents, and processed into a pharmaceutical product. Examples of carriers include anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, triglycerides containing medium chain fatty acid residues, hydrogenated polyoxyethylene-60 -castor oil, sucrose, carboxymethylcellulose, corn starch, and inorganic salts. If necessary, the amount of active ingredient in these drugs can be varied within the specified dosage ranges.

In another embodiment, the present invention provides a method for preventing and/or treating atopic dermatitis, comprising administering an IL-31 antagonist to a subject suffering from or susceptible to developing atopic dermatitis.

In this case, the IL-31 antagonist can be administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.1 to 1000 mg/body/over 1 day to 12 weeks, preferably 0.1 to 1000 mg/body/2 weeks, 0.1 to 1000 mg/body/4 weeks, or 0.1 to 1000 mg/body/8 weeks. In another embodiment, the IL-31 antagonist may be administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.01 to 10 mg/kg/for 1 day to 12 weeks, preferably 0.01 to 10 mg/kg/2 weeks, 0.01 to 10 mg/kg/4 weeks, or 0.01 to 10 mg/kg/8 weeks. Additionally, in said prophylactic or therapeutic method, the IL-31 antagonist may be administered before, simultaneously with, or after the administration of a topical steroid or topical calcineurin inhibitor.

In yet another embodiment, the present invention provides a product comprising at least (i) a container (e.g., single injection), (ii) a pharmaceutical composition containing an IL-31 antagonist as an active ingredient in the container, and (iii) document stating that an IL-31 antagonist should be administered several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 0.1 to 1000 mg/body/over from 1 day to 12 weeks or from 0.01 to 10 mg/kg/for from 1 day to 12 weeks. In addition, if necessary, the packaging of said product may further contain a label, a syringe, an injection needle, a pharmacologically acceptable medium, an alcohol-impregnated cotton cloth, a patch, and the like. The container, for example, may be a vial, a glass bottle, or a syringe, and may be formed from any of a variety of materials, such as glass or plastic. The container containing the pharmaceutical composition has an outlet that is sealed, for example, with a rubber stopper. The container is provided, for example, with a label indicating that the pharmaceutical composition is intended for use in the prevention or treatment of a selected pathological condition. In some cases, the label may contain a description of an embodiment of the present invention wherein the IL-31 antagonist is used in combination with a topical steroid or a topical calcineurin inhibitor.

All technical documents cited in this context are incorporated herein by reference in their entirety.

The term "and/or" as used herein, in combination with the terms specified before and after it, means that the term "and/or" includes all combinations in which "and" and "or" are combined as appropriate.

The terms used in this context are intended to illustrate specific embodiments of the present invention, and do not limit the scope or spirit of the invention. It should be understood that terms (including technical and scientific terms) used in this context have, unless otherwise indicated, the generally accepted meanings known to those skilled in the art to which this invention relates and should not be interpreted in any idealized manner. or in an overly formal sense.

The term "comprise", "contains" or "comprising" as used in this context is intended to indicate the presence of the claimed object(s) (e.g. member(s)), stage(s), element(s) and number(s) ), and does not preclude the presence of other entity(ies) (such as member(s)), stage(s), element(s), and number(s)) unless specifically stated in the context.

Schematic diagrams used in describing embodiments of the present invention may be presented in a simplified form to enhance clarity.

It should be understood that the numerical value used in this context may vary within a certain range, as is known to those skilled in the art, unless otherwise inconsistent with the context. For example, the term "1 mg" can be interpreted as "about 1 mg" and should be understood to include a certain range of variation as described herein and in the prior art. Moreover, the interval "from 1 to 5 times" used in this context can be interpreted as an enumeration of "1, 2, 3, 4 or 5 times", that is, each value is given specifically and individually, if this does not contradict the given context . In addition, the enumeration "20, ... 25 times", used in this context, for example, can be interpreted as the enumeration "20, 21, 22, 23, 24 or 25 times", that is, each value is given specifically and individually, if it does not conflict with the given context. Moreover, the range "from 1 to 5000 pg/ml", for example, used in this context, can be interpreted, for example, as listing "1 pg/ml, 2 pg/ml, 3 pg/ml, 4 pg/ml, 5 pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9 pg/ml, 10 pg/ml, … 15 pg/ml, … 20 pg/ml, … 25 pg/ml, … 30 pg /ml, ... 35 pg/ml, ... 40 pg/ml, ... 45 pg/ml, ... 50 pg/ml, ... 55 pg/ml, ... 60 pg/ml, ... 65 pg/ml, ... 70 pg/ml , ... 75 pg/ml, ... 80 pg/ml, ... 85 pg/ml, ... 90 pg/ml, ... 95 pg/ml, ... 100 pg/ml, ... 150 pg/ml, ... 200 pg/ml, ... 250 pg/ml, … 300 pg/ml, … 350 pg/ml, … 400 pg/ml, … 450 pg/ml, … 500 pg/ml, … 600 pg/ml, … 700 pg/ml, … 800 pg /ml, ... 900 pg/ml, ... 1000 pg/ml, ... 2000 pg/ml, ... 3000 pg/ml, ... 4000 pg/ml, ... 5000 pg/ml", but not limited to them, unless this contradicts this context. In addition, the interval "10 pg/ml, ... 15 pg/ml" used in this context, for example, can be interpreted as listing "10 pg/ml, 11 pg/ml, 12 pg/ml, 13 pg/ml, 14 pg/ml or 15 pg/ml", that is, each value is given specifically and individually, unless inconsistent with the given context. Thus, one skilled in the art will naturally understand directly and unambiguously that, for example, the range "1 to 5000 pg/ml" includes a specific and individual listing of, for example, values such as 100 pg/ml, 224 pg/ml , as well as 1500 pg/ml. The same interpretation is applied, as appropriate, to numerical values used in a given context, unless otherwise inconsistent with the given context, and one of ordinary skill in the art would naturally and clearly understand that each value is specifically and individually enumerated.

Examples

It should be understood that the examples described below are provided only to more specifically describe the present invention, and it is not limited to these examples.

Example 1

Preparation of antibodies against human IL-31RA

The drug CIM331 (H chain, SEQ ID NO: 9, L chain, SEQ ID NO: 10), which is an antibody against human IL-31RA, which is also described in the application WO 2010/064697, was prepared using a method known to the person skilled in the art. this field of technology, in accordance with the description presented in the above application. According to WO 2010/064697, CIM331 antibodies exhibit neutralizing activity against human IL-31RA and cynomolgus IL-31RA.

Example 2

Modification of amino acid residues in antibodies

Antibodies in which at least one amino acid residue that can be exposed on the surface of the antibody has been modified to reduce the isoelectric point (IEP) value of the antibody (designated as “reduced IEP antibodies”), which may reduce the intracellular uptake of the antibody or may slow down the clearance of antibodies from blood plasma, as described or proposed, for example, in the application WO 2009/041643. Anti-human IL-31RA antibodies, CIM331, were generated by substituting multiple amino acid residues in the CDR that may have an effect on altering IET, as described in WO 2009/041643 (eg, K62Q, K64Q and G65D in the H chain variable region, R24Q , N27aD and L54E in the variable region of the L chain (Kabat numbering)).

It was previously established that the IET value can also be changed as a result of replacing amino acid residues in the conserved regions of antibodies. This method is described, for example, in application WO 2014/145159.

To test the effect of substitution of amino acid residues in conserved regions on the IET value, anti-human IgE antibodies were prepared using the method described in Reference Example 1. More specifically, natural Ab1 antibodies were prepared containing Ab1H (SEQ ID NO: 12) as the heavy chain and Ab1L (SEQ ID NO: 13) as the light chain.

The value of the theoretical isoelectric point (IEP) of the antibodies obtained in this way was calculated according to a known method, using the GENETYX-SV/RC software version 9.1.0 (GENETYX CORPORATION) (see article Skoog V. and Wichman A., Calculation of the isoelectric points of polypeptides from the amino acid composition, trends in analytical chemistry, vol. 5, no. 4, 82-83 (1986)). It is assumed that all the side chains of cysteine residues in the antibody molecule form disulfide bonds, and the calculation was carried out excluding the contribution of the side chains of cysteine residues to the pKa value. The theoretical IET of Ab1 was 6.77.

The resulting Ab1s were antibodies containing natural human IgG1 as conserved regions. According to the present invention, Ab1H-P600 were created by modifying the Fc fragment of the Ab1H heavy chain of the Ab1 antibody by replacing proline at position 238 and serine at position 298 according to EU numbering, with aspartic acid and alanine, respectively. Moreover, the Fc variant was obtained (Ab1H-P850) according to the method described in reference example 1, with the introduction of the Q419K mutation (according to EU numbering), that is, the replacement of an uncharged amino acid with a positively charged amino acid was introduced in the Fc fragment of Ab1H-P600. Ab1L (SEQ ID NO: 13) was used as the light chain.

In the case of antibodies containing the resulting variant Fc fragment (Ab1H-P850), an experiment was carried out using a Biacore T200 installation (from GE Healthcare), and the binding of soluble human Fcγ R2b (otherwise known as “human Fcγ RIIb” or “hFcγ R2b”) was assessed. with an antigen-antibody complex. Soluble human Fcγ R2b was prepared in His-tag-containing form by a procedure known in the art. An appropriate amount of anti-His antibodies was immobilized onto the CM5 sensor chip (GE Healthcare) using the amine condensation method, then using a His capture kit (GE Healthcare), human Fcγ R2b was immobilized onto the specified chip. Then the antigen-antibody complex and working buffer solution (as a reference solution) were pumped into the device, where the complex was bound to human Fcγ R2b immobilized on the sensor chip. The working buffer solution was a 20 mM solution of N-(2-acetamide)-2-aminoethanesulfonic acid containing 150 mM NaCl, 1.2 mM CaCl ₂ and 0.05% (w/v) Tween 20, pH 7 ,4, and the said buffer solution was also used to dilute soluble human Fcγ RIIb. To regenerate the sensor chip, a solution of 10 mM glycine-HCl, pH 1.5, was used. All measurements were carried out at 25°C. The analysis was performed based on the binding level (RU, arbitrary units) calculated from the sensorgrams obtained during the experiment, and the result was expressed as a relative value, with the binding value obtained using P600 taken as 1.00. To calculate the parameters, Biacore T100 Evaluation Software (GE Healthcare) was used.

Comparison of the binding results of Ab1H-P600 and Ab1H-P850 showed that hFcγ R2b immobilized on the Biacore sensor chip binds to a greater extent to Ab1H-P850 (the binding level of Ab1H-P600 was taken as 1.00, the binding level of Ab1H-P850 was 2. 22). Results from the Biacore assay indicate that the affinity of Ab1H-P850 for hFcγ R2b (alone) is comparable to the affinity of Ab1H-P600 for hFcγ R2b (alone) (data not shown).

Without being based on any theory, this result can be explained as follows.

It is known that the Biacore sensor chip has a negative charge, and this charged state can be considered a property similar to the surface of a cell membrane. Therefore, it is proposed that the binding of hFcγ R2b immobilized on the negatively charged Biacore sensor chip to the antigen-antibody complex is similar to the binding of the antigen-antibody complex to hFcγ R2b present on the surface of the cell membrane, which is also negatively charged.

According to the present invention, in antibodies containing a variant of the Fc fragment (Ab1H-P850), obtained as a result of modification of the amino acid residue at position 419 of the Fc fragment, which increases the IET, the charge of the Fc fragment shifts to the positive region compared to the charge of the fragment before the introduction of the modification (antibody , containing Ab1H-P600). Therefore, it can be assumed that the Coulombic interaction between the Fc moiety (positive charge) and the sensor chip (negative charge) is enhanced as a result of amino acid modification, which increases the IET. In addition, it is expected that this effect will be similarly observed on the surface of the cell membrane, which is also negatively charged. Therefore, an intracellular uptake rate-enhancing effect is expected to be observed in vivo.

Conversely, if you use a variant of the Fc fragment obtained by introducing an amino acid that reduces the IET (for example, such as aspartic acid or glutamic acid) at position 419 of the Fc fragment, the charge of the Fc fragment will shift to a negative region compared to the charge of the fragment before introducing the modification . As a result, the Coulombic interaction between the Fc moiety (negative charge) and the cell membrane surface (negative charge) will be weakened by the amino acid modification, which reduces the IET. This is expected to slow the rate of intracellular uptake of antibodies in vivo and have the effect of increasing the plasma half-life of antibodies. Ab1 are antibodies containing natural human IgG1 as conserved regions, and the amino acid residue at position 419 (EC numbering) is glutamine (Q) in all natural human antibodies of the IgG1-IgG4 class. Thus, it is obvious to one skilled in the art that the above-described result can also be obtained regardless of the type of IgG.

The amino acid sequence of CIM331 contains an amino acid variant obtained by substitution Gln(Q)419Glu(E).

During preclinical testing prior to clinical trials of CIM331, the following important finding was noted. The interaction of the CIM331 antigen-antibody with IL-31RA of each animal (mouse, rat and rabbit) was assessed on a Biacore device (Biacore T100 (GE Healthcare)), according to methods known in the art. As a result, it was found that CIM331 does not show cross-reactivity with IL-31RA of any animal (mouse, rat and rabbit) (see internal report Sakurai T, Esaki K., Cross-reactivity of CH5427227 with NR10 (IL-31RA) from mice , rats and rabbits (Test No. TOX08-0198S), Chugai Pharmaceutical Co., Ltd. (2010)).

Thus, in order to test the effect described below related to the dose of CIM331 and the dosing interval, prior to administration of CIM331 to humans, it would be apparent even to one skilled in the art that CIM331 would first need to be administered to humanoid models (e.g., cynomolgus monkeys) that exhibit cross-reactivity. and then predict the effect by extrapolating the results to humans.

Example 3A

IL-31-induced itch-reducing effect in cynomolgus monkeys following subcutaneous administration of CIM331

The effect of subcutaneous administration of CIM331 on pruritus induced by intravenous administration of IL-31 to cynomolgus monkeys was examined. The frequency of itch-mediated movements was considered as an indicator of itch reactivity. The frequency of itch-mediated scratching behavior was measured visually by viewing 2-hour video recordings of each macaque's behavior, and moving a front or hind paw to scratch a body part was counted as one instance of itch-mediated scratching behavior. However, itch-mediated scratching behaviors that resulted in one or two scratching movements were not included in the calculation of movement frequency for itch-mediated scratching and were considered random events.

First, before administration of CIM331, the behavior of each animal (cynomolgus monkeys) that did not receive IL-31 cynomolgus monkeys was recorded with a video camera (2 h). The behavior of each animal was then assessed by viewing the resulting video recordings, and the frequency of itch-mediated scratching movements in non-IL-31 cynomolgus monkeys was measured as described above.

Cynomolgus monkeys were administered subcutaneously CIM331 as a single dose of 0.2 or 1 mg/kg, and to evaluate the effect of subcutaneous administration of CIM331 after IL-31 administration to cynomolgus monkeys, the frequency of itch-mediated scratching movements was determined as described below. Cynomolgus monkeys were administered subcutaneous CIM331 as a single dose of 0.2 mg/kg, cynomolgus IL-31 was administered intravenously at a dose of 1 μg/kg before subcutaneous administration of CIM331, and on days 3, 15, 28, 42, 56, and 93 after s.c. introduction of CIM331. After administration of IL-31 to cynomolgus macaques, the individual behavior of the animals was recorded using a video camera (2 h). In the same manner, cynomolgus monkeys were administered subcutaneous CIM331 as a single dose of 1 mg/kg, and cynomolgus IL-31 was administered intravenously at a dose of 1 μg/kg before subcutaneous administration of CIM331, and on days 28, 42, 56, 77, 79, 81 , 84 and 93 following subcutaneous administration of CIM331. After administration of IL-31 to cynomolgus macaques, the individual behavior of the animals was recorded using a video camera (2 h). The individual behavior of the animals was then analyzed by viewing the resulting video recordings, and the frequency of scratching movements mediated by itch after administration of IL-31 to cynomolgus monkeys was determined according to the method described above.

It was found that when IL-31 was administered to cynomolgus macaques prior to CIM331 administration, development of itch was observed, as evidenced by an increase in the frequency of itch-mediated scratching movements compared to the behavior of animals before administration of IL-31 to cynomolgus macaques. It was also found that administration of a single subcutaneous dose of CIM331 to cynomolgus monkeys reduced the frequency of itch-mediated scratching observed after IL-31 administration to cynomolgus monkeys.

Subcutaneous administration of CIM331 to cynomolgus monkeys as a single dose of 0.2 mg/kg was found to reduce the mean frequency of itch-mediated scratching observed after IL-31 administration to cynomolgus monkeys, as assessed on day 3 after CIM331 administration compared with behavior of animals prior to administration of CIM331, and such administration was also found to reduce the mean frequency of itch-mediated scratching observed following IL-31 administration to cynomolgus monkeys, even at day 42 post-CIM331 administration (see FIG. 6). Moreover, subcutaneous administration of CIM331 as a single dose of 1 mg/kg was found to reduce the mean frequency of itch-mediated scratching observed after IL-31 administration in cynomolgus monkeys, even at day 77 after CIM331 administration (see FIG. 7 ).

For human dosage determination, the effective plasma concentration of CIM331 was determined from an in vivo macaque model of cynomolgus IL-31-induced itch in which systemic itch in cynomolgus monkeys was induced by administration of cynomolgus IL-31. In this study, CIM331 was administered intravenously to the same cynomolgus macaque, and the dose was gradually increased from 3 to 100 μg/kg (3, 10, 40, 60, and 100 μg/kg) to increase plasma drug concentrations. The day after CIM331 administration, a blood sample was collected at each step to measure the plasma concentration of CIM331. In addition, itch-mediated scratching movements induced by intravenous administration of IL-31 to cynomolgus monkeys at a dose of 1 μg/kg were recorded using a video camera for 2 hours after administration, and the frequency of itch-mediated scratching movements was then determined. To determine the frequency of itch-mediated scratching behaviors, video recordings (2 h) of macaque behavior were reviewed, and moving a front or hind paw to scratch a part of the body was counted as one instance of itch-mediated scratching behavior. However, itch-mediated scratching behaviors that resulted in one or two scratching movements were not included in the calculation of movement frequency for itch-mediated scratching and were considered random events. When CIM331 was administered intravenously and the dose was gradually increased, the mean plasma concentration of CIM331 on the day after CIM331 administration gradually increased in a dose-dependent manner. CIM331 had a significant inhibitory effect on IL-31-induced itch in cynomolgus monkeys following administration of CIM331 at a dose of 40 μg/kg (mean plasma concentration the day after administration was 670 ng/mL).

The average plasma concentration of 670 ng/ml was considered as the predicted effective concentration of CIM331 in human plasma. The in vivo pharmacokinetics (PK) of antibodies in humans and cynomolgus monkeys have been reported to be similar (see Jennifer Q. Dong et al., Quantitative Prediction of Human Pharmacokinetics for Monoclonal Antibodies, Clin. Pharmacokinet, 50 (2), 131 -142 (2011), Jie Ling et al., Interspecies Scaling of Therapeutic Monoclonal Antibodies: Initial Look, J. Clin. Pharmacol., 49 (12), 1382-1402 (2009), Rong Deng et al., Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data, mAbs, 3 (1), 61-66 (2011)). Thus, the PK parameters obtained as a result of nonlinear analysis of data on changes in the concentration of CIM331 in the blood plasma of cynomolgus monkeys were used as predicted values of PK parameters for humans. For nonlinear analysis, a nonlinear analytical model constructed using the Michaelis-Menten equation was used, as presented in FIG. 8.

Following intravenous and subcutaneous administration of CIM331 to cynomolgus monkeys at doses of 0.04 mg/kg, 0.2 mg/kg, and 1.0 mg/kg, the mean changes in plasma CIM331 concentrations for the respective groups of animals were simultaneously analyzed using the model described above. and calculated the optimal parameters. Using the obtained parameters, it is possible to predict changes in serum concentrations after administration of CIM331 to humans. It was predicted that if CIM331 was administered to a human at a dose of 1 mg/kg, the concentration of CIM331 in the blood serum would be at least 670 ng/ml, that is, the calculated effective concentration of CIM331 in human serum would be maintained for 56 days (see Fig. . 9). The 1 mg/kg dose at which CIM331 is expected to sustain the IL-31 signaling inhibitory effect for 1 month or more was determined to be the expected clinically optimal dose.

Example 3B

Single dose subcutaneous administration to patients suffering from atopic dermatitis

In the phase I study drug groups, one dose of CIM331 was administered subcutaneously, i.e. 0.3 mg/kg, 1 mg/kg, and 3 mg/kg body weight, as well as placebo, were administered as a single dose to the abdomen of each of 36 patients suffering from atopic dermatitis who met the following criteria (each group included 9 patients).

Patients who were administered CIM331 were selected to be patients suffering from atopic dermatitis who met the criteria described below, although they had been treated with a topical steroid for 12 weeks or more.

- The Rash Extension and Severity Index is 10 or more, and the rash with significant inflammation affects 5% or more of the body surface area.

- The overall score for assessing the severity of scabies during the day and at night based on the Shiratori classification of the severity of the disease is 4 or more.

- The average VAS itching intensity is ≥50 mm.

For use as an investigational drug, the drug was prepared by filling a vial with 1 ml of a solution that contains CIM331 antibodies at a concentration of 100 mg/ml, or by diluting the solution to the concentration required for administration. Saline solution was used as a placebo.

(3-1) Final parameter: itching

Itching intensity was assessed using a visual analogue scale (VAS). The VAS scale is a 100 mm straight line on which patients indicate the intensity of scratching when they wake up or when they go to bed by drawing a line from 0 to 100 mm, where 0 mm means no scabies and 100 mm means the worst the degree of scratching that patients suffering from atopic dermatitis can imagine. Patients assessed their condition daily throughout the test period.

As a result, the placebo group experienced an approximately 20% reduction in VAS pruritus scores, while all CIM331 treatment groups experienced an approximately 50% reduction in VAS pruritus scores starting at week 1 post-dose and maintained this reduction even after week 4 or more after administration (see Fig. 1).

(3-2) Final parameter: dermatitis

The Eruption and Severity Index (EASI) score is a way to assess the severity and extent of atopic dermatitis. The extent and proportion of eczema in the respective affected areas was assessed at each of four sites, i.e. head and neck, upper limbs, trunk and lower limbs, and the degree of redness (erythema), thickness (induration, papules and swelling), abrasions (signs of scratching) and lichenification was graded on a scale of (0) zero, (1) mild, (2) moderate, and (3) severe. During the clinical trial period, the doctor evaluates the skin condition once every one or two weeks. The mean deviation of the EASI score at week 4 post-administration from baseline was analyzed using the visual analogue scale (VAS) for itching as a percentage reduction in itching (i.e., less than a 50% reduction group and a 50% reduction group). % or more).

As a result, in the group that experienced a 50% or greater reduction in VAS itching scores, the mean deviation in EASI scores was -11.5 points, and the reduction in EASI scores was significantly greater than in the placebo group or in the group in which there was a reduction in VAS itching scores of less than 50% (Fig. 2).

(3-3) Outcome: quality of life (QOL)

(3-3-1) Sleep

The Actiwatch (registered trademark) is a non-invasive measurement device designed to be worn on the wrist and to capture, record and store wrist movements that serve as an index of systematic movements when the user is free to move. Subjects wear this device until week 4 after insertion. Other parameters, including actual sleep time from sleep onset to awakening, sleep onset latency, and sleep efficiency were measured using an objective method. Sleep efficiency was calculated using the following equation:

As a result, although sleep efficiency was approximately 60% in all predose groups, all CIM331 treatment groups experienced an improvement in sleep efficiency starting at week 1 postdose and improved to approximately 80% at week 4 postdose (Fig. 3).

(3-3-2) DLQI Index

The Dermatology Life Quality Index DLQI is a dermatology quality of life measure of the LQI (Finlay et al. 1994) and the patient questionnaire includes 10 questions. The DLQI questions are grouped into the following six areas: symptoms and sensations, activities of daily living, leisure, work and school, personal relationships, and treatment. The DLQI index is determined by the sum of scores for all items on the questionnaire. The maximum score is 30, and the minimum is 0. A higher score means a lower LQI.

Patients answer questions every 2 or 4 weeks. As a result, at week 4 post-administration, the placebo group experienced an average decrease of 0.7 points, while the CIM331 treatment groups experienced an average decrease of 5.4 to 6.3 points.

(3-4) Final parameter: amount of topical steroid used

A topical steroid (Locoid, registered trade name, hydrocortisone butyrate) was used in combination with CIM331 for all patients. The amount of topical steroid can be adjusted accordingly depending on the patient's condition.

As a result, the placebo group tended to increase the amount of locoid used, while all CIM331 treatment groups tended to decrease the amount of locoid used at week 1 post-administration (Figure 4).

(3-5) Outcome parameter: change in serum CIM331 concentration and pharmacokinetic parameters

In fig. Figure 5 shows the changes in serum concentrations of CIM331 in Japanese patients suffering from atopic dermatitis, and Table 1 shows the pharmacokinetic parameters.

As a result, at days 4.46-5.66 (average value, the same applies to the values below) after administration of CIM331, the serum concentration of CIM331 reached its maximum value, and then a slight decrease in half-lives (t _1/2 ) was observed. at levels from day 12.6 to day 14.6. The C _max value in the 0.3 mg/kg, 1 mg/kg and 3 mg/kg dose groups was 2.20, 6.50 and 19.4 μg/ml, respectively, and the AUC _inf value was 49.2. 161 and 489 days*mcg/ml, respectively. Moreover, AUC _inf , AUC _last , and C _max values after administration of a single subcutaneous dose of CIM331 increased in a dose-proportional manner. It was also found that the serum concentration of CIM331 in a dose-dependent manner prolongs the period during which the concentration is maintained at a certain level or above. At the same time, the present trials did not clarify the relationship between the effect of suppressing itching as a result of administration of the drug CIM331 and its content in the blood plasma.

The terms used in the table mean:

AUC _inf : AUC over time period from 0 to extrapolated infinity

AUC _last : AUC during the time period from 0 to the time of the last measured plasma concentration

CL/F: apparent clearance

C _max : maximum blood concentration

MRT: average retention time of a drug in the body

t _1/2 : half-life

_Tmax : time to reach maximum blood concentration

(3-6) Search end parameter: efficiency

Based on these results, CIM331 was found to improve symptoms of pruritus, dermatitis and QOL in patients suffering from atopic dermatitis. The present trials are the first clinical outcome studies to demonstrate that an IL-31 antagonist is an effective treatment for itch associated with atopic dermatitis. Therefore, CIM331 can be expected to provide improvement in symptoms not only of atopic dermatitis-associated itch, but also of dermatitis and QOL, based on a novel mechanism of action in which the itch-itch cycle is blocked. Scratching caused by itching is known to be an exacerbation factor that worsens the rash. When scratching, mechanical damage to the skin occurs, which reduces the protective function. Foreign antigens that penetrate the epidermis increase the inflammatory response, leading to worsening symptoms of dermatitis and exacerbation of itching. This vicious cycle of scratching - worsening dermatitis symptoms - worsening itch intensity is known as the itch-itch cycle (eg, Wahlgren CF. J Dermatol; 26: 770-779 (1999); Homey B et al. J Allergy Clin Immunol; 118: 178-189 (2006)).

Example 4

Subcutaneous dosing several times in patients suffering from atopic dermatitis

(4-1) Dosing the drug several times, phase II

In the phase II multi-dose study drug arms, approximately 250 patients suffering from moderate to severe atopic dermatitis for whom topical therapy was insufficiently effective or intolerable to topical therapy received intra-abdominal administration of CIM331 or placebo as follows. CIM331 dosages per body weight and CIM331 solution concentrations for administration are also listed below. CIM331 solution was slowly administered in a volume of 20 μg/kg body weight. If a subject's body weight exceeded 120 kg, the study drug was formulated to accommodate that body weight. The test drug was prepared in the following way: the drug obtained by filling each vial with a solution of 1.53 ml containing 100 mg of CIM331 antibody in 1 ml and freeze-drying was dissolved in water for injection and thus obtained a solution for administration. This injection solution was further diluted with a separate placebo solution to the required concentration for administration.

Patients to be treated with CIM331 were patients suffering from atopic dermatitis for whom treatment with a fixed dose topical steroid or topical calcineurin inhibitor for 4 weeks or more was not sufficiently effective or for whom standard topical therapy is prohibited (due to contraindications, etc.), and which meet the following criteria:

- rash prevalence and severity index is 10 or more

- the overall static assessment by the researcher in sIGA points is 3 or more

- VASA visual analogue scale (VASA) itching score is ≥50 mm.

These clinical trials consisted of two stages. Stage A was a randomized, double-blind, placebo-controlled, parallel group study (weeks 0–12). Stage B was a double-blind extension period during which subjects continued to receive CIM331 for an additional 52 weeks (weeks 12-64). Approximately 250 subjects were randomized to one of four study drug groups (approximately 50 subjects in each group) or placebo (approximately 50 subjects) in a 1:1:1:1:1 ratio.

Stage A

- CIM331 (0.1 mg/kg) was administered subcutaneously every 4 weeks (administered on day 1, week 4 and week 8).

- CIM331 (0.5 mg/kg) was administered subcutaneously every 4 weeks (administered on day 1, week 4 and week 8).

- CIM331 (2.0 mg/kg) was administered subcutaneously every 4 weeks (administered on day 1, week 4 and week 8).

- CIM331 (2.0 mg/kg) was administered subcutaneously every 8 weeks (administered on day 1, week 4 and week 8, and placebo administered on week 4).

- placebo was administered subcutaneously every 4 weeks (administered on day 1 and week 8).

In more detail, 264 patients were administered study drug or placebo at least once in stage A, i.e. 53, 53, 54, 52 and 52 patients, respectively, in the placebo group and the groups in which patients were administered CIM331 subcutaneously every 4 weeks at a dose of 0.1 mg/kg, 0.5 mg/kg and 2.0 μ/kg, and in a group in which patients were administered CIM331 subcutaneously every 8 weeks at a dose of 2.0 mg/kg.

Stage B

Subjects assigned to placebo in stage A were randomized multiple times to receive CIM331 (0.1 mg/kg, 0.5 mg/kg, and 2.0 mg/kg) administered subcutaneously every 4 weeks for stage B.

Subjects who were randomized to receive study drug in Stage A were randomized multiple times to receive the same dose as Stage A and continued to be treated with the same regimen beginning at week 12.

- CIM331 (0.1 mg/kg) was administered subcutaneously every 4 weeks for a total of 52 weeks.

- CIM331 (0.5 mg/kg) was administered subcutaneously every 4 weeks for a total of 52 weeks.

- CIM331 (2.0 mg/kg) was administered subcutaneously every 4 weeks for a total of 52 weeks.

- CIM331 (2.0 mg/kg) was administered subcutaneously every 8 weeks for a total of 52 weeks (subjects in this group were administered alternately CIM331 and placebo every 4 weeks).

(4-2) Forced backup treatment

For patients who did not experience improvement in VAS pruritus symptoms or skin condition, the drug was prescribed as back-up therapy, subject to physician judgment, from week 4 after initial administration onwards. The definition of “no improvement in symptoms” means cases where the patient’s condition satisfies all of the following conditions:

(1) there is no improvement in the investigator's overall static assessment in sIGA scores compared to the baseline,

(2) the sIGA score is 3 or more, and

(3) the percentage improvement in VAS itch index from baseline is less than 10%, and the most recent VAS itch index was 50 mm or more.

(4-3) Final parameters:

- Itching intensity was assessed using a visual analogue scale (VAS) (Furue et al. 2013). The VAS consists of a 100 mm straight line on which patients indicate the intensity of itching over the past 24 hours by drawing a line ranging from 0 to 100 mm, with 0 mm indicating no itching and 100 mm indicating the worst degree of itching imaginable.

- The Verbal Rating Scale (VRS) for itching is a verbal scale on which subjects rate the degree of itching during the past 24 hours: (0) no itching, (1) mild itching, (2) moderate itching , (3) severe itching and (4) very severe itching (Reich et al. (2012)).

- The Eruption Extension and Severity Index (EASI) is a measure to assess the severity and extent of atopic dermatitis. The extent and proportion of eczema in the respective affected areas was assessed at each of four sites, i.e. head and neck, upper limbs, trunk and lower limbs, and the degree of redness (erythema), thickness (induration, papules and swelling), abrasions (signs of scratching) and lichenification was graded on a scale of (0) zero, (1) mild, (2) moderate, and (3) severe.

- The International Scoring System for Atopic Dermatitis (SCORAD score) is a measure for the clinical assessment of the extent and severity of eczema (according to the recommendations of the European Task Force on Atopic Dermatitis 1993).

- Static Investigator Global Assessment (sIGA) provides a comprehensive assessment of severity at the time of assessment using clinical characteristics such as erythema, infiltration, papules, exudation and crusting (scales), on a 6-point scale from no to very severe disease ( 0 - clear skin, 1 - almost clear skin, 2 - mild disease, 3 - moderate disease, 4 - severe disease, 5 - very severe disease).

- Body surface area (BSA) with atopic dermatitis lesions refers to the proportion of lesions on the entire body surface.

- VAS sleep disturbance score, in which subjects rate the degree of sleep disturbance during the past 24 hours on a scale from (0) “no sleep problems” to (10) “did not sleep at all” (Furue et al. . 2013).

- The Dermatological Life Quality Index (DLQI) is a dermatological QOL index measure (Finlay et al. 1994), and contains 10 questions. The DLQI questions are grouped into the following six areas: symptoms and sensations, activities of daily living, leisure, work and school, personal relationships, and treatment. The DLQI index is determined by the sum of scores for all items on the questionnaire. The maximum score is 30, and the minimum is 0. A higher score means a lower LQI.

- Actigraphy

The Actiwatch is a non-invasive measurement device designed to be worn on the wrist and to capture, record and store wrist movements that serve as an index of systematic movements when the user is free to move. Subjects wear this device from the start of the pre-observation period until week 4 after insertion. Other parameters, including actual sleep time from sleep onset to awakening, sleep onset latency, and sleep efficiency were measured using an objective method.

(4-4) Analysis means, analysis method, etc.

In the groups in which patients were administered CIM331 subcutaneously every 4 weeks, the percentage improvement in Pruritus VAS score at week 12 after dosing compared with that at baseline was used as the primary parameter to confirm benefit and efficacy in each dosing group. , in which patients were administered CIM331 every 4 weeks compared with a placebo group. Analysis of covariance (ANCOVA) was used as the primary method of analysis. In more detail, a model was fitted in which the percentage improvement in VAS itch score at week 12 after initiation compared with that at baseline was used as the dependent variable, treatment group was used as a fixed effect model, and VAS itch score at baseline was used as the dependent variable. administration and regions (Japan, Europe, and USA) were used as covariates. In the primary analysis using a one-sided significance level of 0.025 as the test significance level, multiplicity due to test repetition was assessed in sequential comparisons between the two groups starting at the high dose based on the principle of a closed test procedure. The sample for the primary analysis was a per-protocol (PP) sample, which excluded, for example, some subjects who experienced a major deviation from the protocol, subjects who withdrew from clinical trials early, and subjects who were administered the investigational drug. different from that prescribed in these clinical trials. All data measured after initiation of salvage therapy were excluded and missing values were replaced using the LOCF value (using the last documented value).

For patients treated with study drug or placebo in Stage A, the primary analysis sample included 46, 46, 45, 47, or 45 patients in the placebo group, respectively, in the groups receiving CIM331 subcutaneously every 4 weeks at doses of 0 .1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg, or the group in which CIM331 was administered subcutaneously every 8 weeks at a dose of 2.0 mg/kg.

Differences (least squares mean) between each of the groups in which CIM331 was administered every 4 weeks and the placebo group in percent improvement in pruritus VAS at week 12 after initiation of administration compared with this parameter at the beginning of administration, which was used as the primary outcome were -21.39% (p=0.0027), -41.16% (p<0.0001) or -40.39% (p<0.0001) in the dose group 0.1 mg/kg, 0.5 mg/kg or 2.0 mg/kg, respectively.

Moreover, since these trials are exploratory dose-finding trials, secondary analyzes can be performed in addition to the primary analysis to allow for an expanded dosing study. In this case, although the study is exploratory, a one-sided significance level of 0.025 as the test significance level was used as a control. Without limitation, in special cases, in addition to ANCOVA analysis, the use of a mixed effects model and repeated measures approach (MMRM) may be considered, and the use of pooling summary statistics regardless of the model, an analysis of the sample of all randomized patients (ITT) with using all available data obtained at the pre-designated follow-up point after administration of the study drug, and using data measured after administration of rescue therapy. Alternatively, the results of the analysis without replacing missing values with other values can be considered acceptable and examined in detail. Moreover, using the VAS itch index at a time point different from week 12 after the start of administration, or using changes in the corresponding percentage improvement in VAS itch compared to this parameter at the beginning of administration or values at different time points, it is possible to estimate the model using the proportion of cases with improvement based on their continuous value or a certain limit as the dependent variable. Important subpopulations can be considered for analysis. The secondary efficacy endpoint along with the VAS itch score could be analyzed in a similar manner.

A similar exploratory comparison could also be made in groups in which CIM331 was administered subcutaneously every 8 weeks.

Proportion of subjects with improvement: pruritus indices VAS, EASI and SCORAD

For each outcome measure, the proportion of subjects who experienced 25%, 50%, or 75% improvement from baseline was calculated.

Results for groups in which CIM331 was administered subcutaneously every 4 weeks in stage A, data measured after administration of salvage therapy in the RR population were excluded and missing values were imputed using the LOCF value. In this case, the proportion of subjects who experienced a 50% improvement in VAS pruritus score at week 12 after initiation of administration was 41%, 67%, or 59% in the 0.1 mg/kg dose group, 0 dose group, 5 mg/kg or 2.0 mg/kg, respectively, compared with 21% in the placebo group. The proportion of subjects who experienced a 75% improvement was 14%, 49%, or 44% in the 0.1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg dose group, respectively, compared with 12% in the placebo group.

Similarly, the proportion of subjects who experienced a 50% improvement in EASI Pruritus Index at week 12 after initiation of administration was 43%, 51%, or 41% in the 0.1 mg/kg dose group, in the 0.5 dose group mg/kg or 2.0 mg/kg dose group, respectively, compared with 33% in the placebo group. The proportion of subjects who experienced a 75% improvement was 23%, 37%, or 22% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or 2.0 mg dose group /kg, respectively, compared with 14% in the placebo group.

The proportion of subjects who experienced a 50% improvement in SCORAD Pruritus Index at week 12 after initiation of administration was 18%, 39%, or 31% in the 0.1 mg/kg dose group, in the 0.5 mg/kg dose group. kg or 2.0 mg/kg, respectively, compared with 15% in the placebo group. The proportion of subjects who experienced a 75% improvement was 0%, 15%, or 17% in the 0.1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg group, respectively, compared with 3% in the placebo group.

Proportion of subjects experiencing 2 or more points of improvement: sIGA and VRS scores

For each outcome measure, the proportion of subjects who had an improvement of 2 or more points from baseline to each time point was calculated.

Considering the results for the groups in which CIM331 was administered every 4 weeks in Stage A, the proportion of subjects who experienced an improvement of two or more points on the sIGA score at week 12 after initiation of administration was 21%, 30%, or 22% of the group with the 0.1 mg/kg dose, the 0.5 mg/kg dose group, or the 2.0 mg/kg dose group, respectively, compared with 12% in the placebo group.

The proportion of subjects who experienced an improvement of two or more points in VRS at week 12 after initiation of administration was 14%, 47%, or 30% in the 0.1 mg/kg dose group, in the 0.5 mg dose group /kg or in the 2.0 mg/kg dose group, respectively, compared with 5% in the placebo group.

Rate of improvement: VAS pruritus, EASI, SCORAD, sIGA, BSA atopic dermatitis lesion score, VRS pruritus and VAS sleep disturbance scores

For each outcome measure, rates of improvement from baseline to each time point were summarized using descriptive statistics.

Given the results for the groups in which CIM331 was administered every 4 weeks in stage A, all data measured after initiation of salvage therapy in the RR population were excluded. In this case, the percentage improvement in Pruritus VAS score at week 4 after administration was 39%, 55%, or 46% in the 0.1 mg/kg dose group, the 0.5 mg/kg dose group, or the with a dose of 2.0 mg/kg, respectively, compared with 12% in the placebo group. The percentage improvement at week 12 after administration was 47%, 68%, or 67% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or 2.0 mg/kg dose group. respectively, compared with 24% in the placebo group.

Similarly, the percentage improvement in EASI Pruritus Index at week 12 after administration was 34%, 54%, or 48% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or dose of 2.0 mg/kg, respectively, compared with 38% in the placebo group. The percentage improvement in SCORAD Pruritus Index at week 12 after administration was 37%, 45%, or 47% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or dose 2 group. 0 mg/kg, respectively, compared with 22% in the placebo group. The percentage improvement in sIGA at week 12 after administration was 25%, 34%, or 28% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or 2.0 dose group mg/kg, respectively, compared with 13% in the placebo group. The percentage improvement in BSA score at week 12 after administration was 25%, 26%, or 33% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or 2.0 dose group. mg/kg, respectively, compared with 31% in the placebo group. The percentage improvement in VRS at week 12 after administration was 42%, 58%, or 58% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or 2.0 dose group. mg/kg, respectively, compared with 18% in the placebo group. The percentage improvement in VAS at week 12 post-dose was 57%, 65%, or 67% in the 0.1 mg/kg dose group, 0.5 mg/kg dose group, or 2.0 dose group. mg/kg, respectively, compared with 31% in the placebo group.

Time to response: pruritus VAS, EASI, SCORAD and sIGA scores

Times from baseline to 25%, 50%, or 75% improvement on VAS, EASI, and SCORAD scores and times from baseline to 2-point improvement on sIGA scores were summarized as cumulative incidence over time using the score Kaplan-Meier method.

Based on the results for the groups in which CIM331 was administered every 4 weeks in Stage A, the time from baseline to the time at which 50% of patients achieved a 25%, 50%, or 75% improvement in VAS pruritus score was: 2 weeks. 4 weeks or not reached, respectively, in the 0.1 mg/kg dose group; 2 weeks, 2 weeks or 5 weeks, respectively, in the 0.5 mg/kg dose group; and 2 weeks, 4 weeks, or not achieved, respectively, in the 2.0 mg/kg dose group; compared with periods of 11 weeks, not achieved or not achieved, respectively, in the placebo group. Moreover, the percentage improvement of 25%, 50%, or 75% from baseline at week 12 after initiation of administration, determined using the Kaplan-Meier method, was 84%, 66%, or 38%, respectively. in the 0.1 mg/kg dose group; 95%, 80% or 68%, respectively, in the 0.5 mg/kg dose group; and 94%, 71%, or 48%, respectively, in the 2.0 mg/kg dose group; compared with 52%, 38% or 22%, respectively, in the placebo group.

Similarly, the time from baseline to the time at which 50% of patients achieved a 25%, 50%, or 75% improvement in EASI score was 2 weeks, 4 weeks, or not achieved, respectively, in the 0 dose group. .1 mg/kg; 2 weeks, 4 weeks or 12 weeks, respectively, in the 0.5 mg/kg dose group; and 2 weeks, 6 weeks, or not reached, respectively, in the 2.0 mg/kg dose group; compared with periods of 6 weeks, 12 weeks or not achieved, respectively, in the placebo group. Moreover, the percentage improvement of 25%, 50%, or 75% from baseline at week 12 after administration, as determined by the Kaplan-Meier method, was 71%, 66%, or 37%, respectively, in the group with dose 0.1 mg/kg; 84%, 73% or 53%, respectively, in the 0.5 mg/kg dose group; and 93%, 67%, or 28%, respectively, in the 2.0 mg/kg dose group; compared with values of 68%, 51% or 23%, respectively, in the placebo group.

The time from baseline to the time when 50% of patients achieved a 25%, 50%, or 75% improvement in SCORAD score was: 2 weeks, not achieved, or not achieved, respectively, in the 0.1 mg dose group /kg; 3 weeks, 10 weeks, or not reached, respectively, in the 0.5 mg/kg dose group; and 2 weeks, not achieved or not achieved, respectively, in the 2.0 mg/kg dose group; compared with 6-week periods, not achieved or not achieved, respectively, in the placebo group. Moreover, the percentage improvement of 25%, 50%, or 75% from baseline at week 12 after administration, as determined by the Kaplan-Meier method, was 78%, 46%, or 9%, respectively, in the group with dose 0.1 mg/kg; 78%, 55% or 30%, respectively, in the 0.5 mg/kg dose group; and n/a (not determined), 46% or 25%, respectively, in the 2.0 mg/kg dose group; compared with values of 57%, 40% or 6%, respectively, in the placebo group.

Considering the time from baseline to the time when 50% of patients achieved a 2-point improvement in sIGA pruritus score, such improvement was not achieved at week 12 in any of the placebo groups, the 0.1 mg/kg dose group, the 0.5 mg/kg dose group and the 2.0 mg/kg dose group. Moreover, the percentage improvement of 2 points from baseline at week 12 after initiation of administration, determined using the Kaplan-Meier method, was 36% in the 0.1 mg/kg dose group; 47% in the 0.5 mg/kg dose group or 38% in the 2.0 mg/kg dose group, compared with 30% in the placebo group.

Period before prescribing reserve therapy

Periods before initiation of salvage therapy were summarized as cumulative incidence over time using Kaplan-Meier estimation. Subjects who were not assigned to rescue therapy were censored at the early week 12 visit in stage A (or at the week 64 visit in stage B) and to account for early exclusion from clinical trials.

Based on the results for the groups in which CIM331 was administered every 4 weeks in stage A, the time from baseline to the time when 50% of patients treated with salvage therapy did not reach week 12 in any of the following groups: in the 0 dose group. 1 mg/kg, in the 0.5 mg/kg dose group, in the 2.0 mg/kg dose group. Moreover, the time from baseline to the time when 25% of patients were treated with salvage therapy was 5 weeks, 9 weeks, less than, or 9 weeks, respectively, in any of the following groups: placebo group, 0 dose group .1 mg/kg, in the group with a dose of 0.5 mg/kg, in the group with a dose of 2.0 mg/kg.

Proportion of subjects receiving reserve therapy

The proportion of subjects receiving salvage therapy at each time point was calculated.

Considering the results for the groups in which CIM331 was administered every 4 weeks in stage A, the proportion of subjects receiving salvage therapy was 26.1% in the 0.1 mg/kg dose group, 24.4% in the 0 dose group .5 mg/kg or 29.8% in the 2.0 mg/kg dose group, compared with 39.1% in the placebo group.

Actigraphy

Actigraphy results in groups in which CIM331 was administered every 4 weeks in stage A showed that the actual time from falling asleep to awakening at week 4 after administration increased by 49.5 minutes in the 0.1 mg/kg group, by 53 .1 min in the 0.5 mg/kg dose group or 48.2 min in the 2.0 mg/kg dose group, compared with an increase of 7.3 min in the placebo group. Delay in sleep onset (time from the time the patient goes to bed until falling asleep) at week 4 after administration was reduced by 17.6 minutes in the 0.1 mg/kg dose group, by 14.8 minutes in the 0 dose group. 5 mg/kg or a decrease of 12.7 minutes in the 2.0 mg/kg dose group, compared with a decrease of 4.3 minutes in the placebo group.

Moreover, in the group in which CIM331 was administered every 8 weeks in Stage A, the mean improvement in the pruritus VAS parameter at week 12 after the first administration, after which all data measured after administration of salvage therapy were excluded, was 70%.

The results of VAS pruritus score at week 12 post-dose as the primary outcome measure, as well as the EASI and sIGA scores at stage A, indicate that the anti-itch and dermatitis effect is greatest in the group in which CIM331 was administered at dose 0 .5 mg/kg/4 weeks.

Simulation of optimal dosages

Regarding dosages and to further improve ease of administration, the optimal dose and fixed dose administration based on body weight dose were evaluated by performing modeling and simulation.

First, the effects of weight-based and fixed-dose doses were compared and optimal dosing and administration were examined from a pharmacokinetic perspective. Serum drug concentrations of CIM331 fit well with a single-compartment model with first-order absorption. Moreover, body weight was integrated into the model parameters as a covariate using an allometric equation. The model parameters are shown below.

The simulation was carried out using the single-chamber model described above. In fig. Figure 10 shows the relationship between body weight and exposure. In fig. 10, Graph A shows the estimated exposure at 0.5 mg/kg or 2 mg/kg; Graphs B, C, and D show the estimated exposure at 50, 75, and 100 mg/body, respectively. The standard curves in each graph indicate the estimated upper exposure limit (1060 μg*day/mL) for the 2 mg/kg dose and the estimated lower exposure limit (44 μg*day/mL) for the 0.5 mg/kg dose.

When the dose is fixed at 50 mg, the estimated lower exposure limit for a dose of approximately 0.5 mg/kg is exceeded at 100 kg body weight, and when the dose is fixed at 100 mg, the estimated upper exposure limit for a dose of 2 mg/kg is exceeded at low body weight. Moreover, when the dosage is fixed at 75 mg, the estimated exposure decreases in the exposure interval obtained for the 0.5 mg/kg or 2 mg/kg dose. These results suggest that administration of CIM331 once every 4 weeks at a fixed dose of 50 mg (or 100 mg per body weight over 100 kg) or 75 mg will result in effects similar to those obtained in the phase II trial.

Modeling and simulation were then performed for the pruritus VAS score using PK/PD analysis. For the itch portion of the VAS, an indirect inverse model was used and the scale was transformed. The values predicted by the model well confirmed the simulation of actual measurements. The parameters predicted by the model are shown below.

The simulation was carried out using the model. In fig. Figure 11 shows the pruritus VAS score the first year after CIM331 administration.

When the fixed dose every 4 weeks was 25 mg/body or more, and preferably 50 mg/body or more, the VAS score was similar to that of 0.5 mg/kg or 2 mg/kg.

(4-5) Effect of combined administration of CIM331 and a topical steroid or similar drug

Although stage A could not use an atopic dermatitis drug other than a moisturizer in combination with CIM331, stage B could use a mild topical Mild steroid (eg, hydrocortisone, desonide, or prednisolone), a topical calcineurin inhibitor (eg , pimecrolimus or tacrolimus) or an antihistamine (eg, fexofenadine) in combination with CIM331. For the distribution and classification of topical steroids, criteria are established according to the NICE guideline CG57 "Atopic eczema in children: management of atopic eczema in children from birth up to the age of 12 years", with the addition of drugs used only in Japan and the USA. In patients who did not achieve a sufficient dermatitis-improving effect, but who did achieve a sufficient itch-improving effect with CIM331 in stage A, there was a continuous and significant dermatitis-improving effect when a topical steroid or similar drug was administered for a short or short period of time. required period in combination with CIM331 at stage B.

In a phase II dose-repeated trial, suppression of itch by CIM331 may interrupt the scratching-induced vicious cycle of decreased defense → increased inflammatory response due to foreign antigens → increased dermatitis symptoms → worsened itch, resulting in an improvement effect dermatitis. Moreover, in patients who did not achieve sufficient dermatitis-improving effect, but who did achieve sufficient itch-improving effect with CIM331 in stage A, sustained improvement in dermatitis was achieved with administration of a topical steroid or similar drug over a short period of time. period in combination with CIM331. Thus, it can be concluded that dermatitis can be improved more effectively by preventing new exacerbation of atopic dermatitis associated with the itch-scratch cycle and by suppressing the existing inflammatory response when used in combination with a topical steroid, and at the same time due to the continuous suppression of itching when CIM331 is administered.

(4-6) Expected results and beneficial effects

By administering CIM331 several times every 4 to 8 weeks, a steady-state serum concentration of CIM331 is achieved and therefore a durable antipruritic effect can be demonstrated in patients suffering from atopic dermatitis. Moreover, by maintaining the itch-improving effect, that is, blocking the itch-scratch cycle, dermatitis symptoms and QOL scores can be improved. A long-term efficacy profile can be confirmed over a total period of 64 weeks.

Moreover, given the fact that current systemic treatments for atopic dermatitis require taking the drug or applying the drug to the affected areas several times a day, or that ultraviolet irradiation treatment requires frequent visits to the clinic, i.e. one or two once a week, then using a treatment option, for example, including several doses of CIM331 every 4 or 8 weeks, can, for example, significantly reduce the burden on the patient's body associated with taking medications or visiting the clinic, and also contribute to the improvement indicator of the patient's QOL quality of life.

(4-7) CIM331 options after approval

CIM331 may be administered to, but not limited to, patients suffering from moderate to severe atopic dermatitis for whom treatment with topical therapy is insufficient or intolerable.

CIM331 may be administered multiple times subcutaneously in equal doses at equal dosing intervals, e.g., once every 2 to 12 week period, and more specifically, e.g., every 2, 3, 4, 5, 6, 7, 8. 9, 10, 11 or 12 weeks, or once every 1, 2 or 3 months.

The dose of CIM331 per body weight and the concentration of the CIM331 solution to be administered can be determined as appropriate, for example, based on the results of a phase II multiple dose trial or the results of other trials. For example, if the body weight of a patient suffering from atopic dermatitis is more than 120 kg, then the study drug can be obtained taking into account that the body weight is 120 kg. In addition, if CIM331 is contemplated to be administered to a patient suffering from atopic dermatitis at a dose expressed in mg/body, then doses of CIM331 expressed in mg/kg can be converted to doses expressed in mg/body, e.g. results from phase II trials with multiple administrations, and the appropriate doses (mg/body) can be selected and administered to the patient. In this case, although the algorithm for converting mg/kg to mg/body is not limited, it is understood that one skilled in the art can determine the dose in mg/body accordingly using the following algorithm.

Assuming that there is a minimum effective serum concentration and a maximum tolerable (empirical) serum concentration of CIM331, changing the mg/kg dose to a mg/body dose can be made based on the results of the phase II trial, taking into account that the serum concentration of CIM331 reaches the specified concentration range regardless of body weight. Moreover, since a dose in mg/body for a child with low body weight excessively increases the content of the drug in the blood plasma, a dose in mg/kg can be used in this case. Conversion of mg/body dose can be accomplished by determining the minimum effective serum concentration and maximum tolerated serum concentration of CIM331 based on the results obtained from the phase II trial followed by exposure adjustments as described above.

In a non-limiting embodiment, for an adult or pediatric patient suffering from atopic dermatitis, the single dose may be selected from the range of 0.1 to 1000 mg/body, for example 0.2 to 360 mg/body, and preferably 10 to 200 mg/body, 10 to 100 mg/body, 25 to 100 mg/body, 50 to 100 mg/body, or 50 to 75 mg/body, and can be administered several times subcutaneously at the intervals described above doses in equal quantities at equal intervals. To avoid any misunderstanding, it is precisely stated that, for example, the interval "from 0.1 to 1000 mg/body" means that all doses included in the range from 0.1 to 1000 mg/body are listed specifically and individually in increments of 0. 1 mg/body, e.g. 0.1 mg/body, 0.2 mg/body, 0.3 mg/body, 0.4 mg/body, … 49.9 mg/body, 50 mg/body, 50, 1 mg/body, 50.2 mg/body, … 99.8 mg/body, 99.9 mg/body, 100 mg/body, 100.1 mg/body, 100.2 mg/body, … 199.9 mg/body, 200 mg/body, 200.1 mg/body, … 359.8 mg/body, 359.9 mg/body, 360 mg/body, 360.1 mg/body, … 999.8 mg/body , 999.9 mg/body, as well as 1000 mg/body. Thus, it would be apparent to one skilled in the art that the range of, for example, “0.1 to 1000 mg/body” would naturally expressly and unambiguously include the doses specifically and individually indicated in the Examples section, such as 55 mg/body. body and 56.5 mg/body.

In another non-limiting embodiment, for a pediatric patient suffering from atopic dermatitis, the single dose may be selected from the range of 0.01 to 10 mg/kg, for example 0.1 to 3 mg/kg, and preferably 0.2 to 2 mg/kg and can be administered several times subcutaneously at the intervals described above between doses in equal amounts at equal intervals. To avoid any misunderstanding, it is precisely stated that, for example, the interval "from 0.01 to 10 mg/kg" means that all doses included in the range from 0.01 to 10 mg/kg are specifically and individually listed in this description in increments 0.005 mg/body, e.g. 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.03 mg/kg, 0.035 mg/kg, 0.04 mg/kg, ... 0.125 mg/kg, ... 0.49 mg/kg, 0.495 mg/kg, 0.5 mg/kg, 0.505 mg/kg, 0.51 mg/kg, ... 0.98 mg/kg, 0.985 mg/kg , 0.99 mg/kg, 0.995 mg/kg, 1 mg/kg, 1.005 mg/kg, 1.01 mg/kg, ... 1.49 mg/kg, 1.495 mg/kg, 1.5 mg/kg, 1.505 mg/kg, 1.51 mg/kg, ... 1.98 mg/kg, 1.985 mg/kg, 1.99 mg/kg, 1.995 mg/kg, 2 mg/kg, 2.005 mg/kg, 2.01 mg/kg, ... 2.99 mg/kg, 2.995 mg/kg, 3 mg/kg, 3.005 mg/kg, 3.01 mg/kg, ... 9.98 mg/kg, 9.985 mg/kg, 9.99 mg/kg, 9.995 mg/kg and 10 mg/kg. Thus, it will be apparent to one skilled in the art that, for example, the range of "0.01 to 10 mg/kg" naturally and unambiguously includes the doses specifically and individually indicated in the Examples section, such as 0.75 mg/kg and 1.245 mg/kg.

Reference example 1

Expression and purification of IgG antibodies

Antibody expression was carried out using the following method. HEK293H cell line (Invitrogen), derived from human embryonic kidney cancer cells, was suspended in DMEM (Invitrogen) containing 10% fetal bovine serum (Invitrogen). Cells were seeded onto Petri dishes for adhesive cells (diameter 10 cm, CORNING) at a cell density of 5 to 6×10 ⁵ cells/ml, and incubated in a CO ₂ incubator (37°C, 5% CO ₂ ) for all day and night. The medium was then aspirated and 6.9 ml of CHO-S-SFM-II medium (Invitrogen) was added. The resulting plasmid was introduced into cells using the lipofection method. The resulting culture supernatants were collected and centrifuged (approximately 2000 g, 5 min, room temperature) to remove cells, and sterilized by filtration through 0.22 μm MILLEX (R)-GV filters (Millipore) to obtain culture supernatants . Antibodies were purified from the resulting culture supernatants using a known procedure using an rProtein A SepharoseTM Fast Flow column (Amersham Biosciences). A spectrophotometer was used to determine the concentration of purified antibodies, and absorbance was measured at 280 nm. Antibody concentrations were calculated from the found absorbance value using the absorbance coefficient calculated according to the method described in Protein Science, 4, 2411-2423 (1995).

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LIST OF SEQUENCES

SEQUENCE LISTING

<110> CHUGAI SEIYAKU KABUSHIKI KAISHA

<120> PHARMACEUTICAL COMPOSITION FOR PREVENTION AND/OR TREATMENT

OF ATOPIC DERMATITIS COMPRISING IL-31 ANTAGONIST AS ACTIVE

INGREDIENT

<130> C1-A1507Y1P

<150> JP 2015-082699

<151> 2015-04-14

<150> JP 2016-041641

<151> 2016-03-04

<160> 15

<170> Patent In version 3.5

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Gly Tyr Ile Met Asn

15

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<223> An artificially synthesized peptide sequence

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Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe Gln

1 5 10 15

Asp

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<223> An artificially synthesized peptide sequence

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Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr

1 5 10

<210> 4

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<223> An artificially synthesized peptide sequence

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Gln Ala Ser Glu Asp Ile Tyr Ser Phe Val Ala

1 5 10

<210> 5

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<223> An artificially synthesized peptide sequence

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Asn Ala Gln Thr Glu Ala Gln

15

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<211> 9

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Gln His His Tyr Asp Ser Pro Leu Thr

15

<210> 7

<211> 121

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<223> An artificially synthesized peptide sequence

<400> 7

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 8

<211> 107

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<223> An artificially synthesized peptide sequence

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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Gln Thr Glu Ala Gln Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Asp Ser Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 9

<211> 445

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<213> Artificial sequence

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<223> An artificially synthesized peptide sequence

<400> 9

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys

210 215 220

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

290 295 300

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

<210> 10

<211> 214

<212>PRT

<213> Artificial sequence

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<223> An artificially synthesized peptide sequence

<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Gln Thr Glu Ala Gln Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Asp Ser Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 11

<211> 764

<212>PRT

<213> Homo sapiens

<400> 11

Met Cys Ile Arg Gln Leu Lys Phe Phe Thr Thr Ala Cys Val Cys Glu

1 5 10 15

Cys Pro Gln Asn Ile Leu Ser Pro Gln Pro Ser Cys Val Asn Leu Gly

20 25 30

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe

35 40 45

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr

50 55 60

Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr

65 70 75 80

Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys

85 90 95

His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser

100 105 110

Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile

115 120 125

Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr

130 135 140

Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe

145 150 155 160

Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp

165 170 175

Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu

180 185 190

Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala

195 200 205

Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln

210 215 220

Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser

225 230 235 240

Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu

245 250 255

Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu

260 265 270

Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly

275 280 285

Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro

290 295 300

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln

305 310 315 320

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser

325 330 335

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala

340 345 350

Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val

355 360 365

Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val

370 375 380

Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr

385 390 395 400

Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln

405 410 415

Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro

420 425 430

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala

435 440 445

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile

450 455 460

Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu

465 470 475 480

Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly

485 490 495

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly

500 505 510

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala

515 520 525

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr

530 535 540

Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly

545 550 555 560

Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys

565 570 575

Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro

580 585 590

Ala Glu Ser Ser Ile Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys

595 600 605

Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile

610 615 620

Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu

625 630 635 640

Val Val Asn Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala

645 650 655

Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Tyr Val

660 665 670

Thr Cys Pro Phe Arg Pro Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu

675 680 685

Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg

690 695 700

Ser Arg Met Pro Glu Gly Thr Arg Pro Glu Ala Lys Glu Gln Leu Leu

705 710 715 720

Phe Ser Gly Gln Ser Leu Val Pro Asp His Leu Cys Glu Glu Gly Ala

725 730 735

Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Ala Arg Glu Phe Leu Val

740 745 750

Ser Glu Lys Leu Pro Glu His Thr Lys Gly Glu Val

755 760

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<211> 447

<212>PRT

<213> Artificial sequence

<220>

<223> An artificially synthesized peptide sequence

<400> 12

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Asn His

20 25 30

Asp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val

35 40 45

Ser Ile Ile Asn Thr Tyr Gly Asn His Trp Tyr Ala Asn Trp Ala Ser

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Ile Asp Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Glu Thr His His Gly Ser Ser Gly Ile Asp His Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

<210> 13

<211> 217

<212>PRT

<213> Artificial sequence

<220>

<223> An artificially synthesized peptide sequence

<400> 13

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Ser Ile Tyr Ser Gly

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Asp His Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Tyr Ala Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ala Asp Tyr Ala His His

85 90 95

Ser Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr

100 105 110

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

115 120 125

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

130 135 140

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

145 150 155 160

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

165 170 175

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

180 185 190

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

195 200 205

Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 14

<211> 324

<212>PRT

<213> Artificial sequence

<220>

<223> An artificially synthesized peptide sequence

<400> 14

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

130 135 140

Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

260 265 270

Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

275 280 285

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

305 310 315 320

Ser Leu Ser Pro

<210> 15

<211> 326

<212>PRT

<213> Homo sapiens

<400> 15

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

130 135 140

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

260 265 270

Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

275 280 285

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

305 310 315 320

Ser Leu Ser Pro Gly Lys

325

<---

Claims (15)

1. A method of treating atopic dermatitis, comprising administering an IL-31 antagonist several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of 25 to 100 mg/body/4 weeks, wherein atopic dermatitis is moderate to severe atopic dermatitis in which topical therapy is ineffective or intolerable. 2. The method according to claim 1, where the IL-31 antagonist is administered at a dose of 50 to 100 mg/body/4 weeks. 3. A method of treating atopic dermatitis, comprising administering an IL-31 antagonist several times in equal amounts at equal dosing intervals to a subject suffering from or predisposed to developing atopic dermatitis, at a dose of from 0.2 to 2 mg/kg/4 weeks where the atopic dermatitis is moderate to severe atopic dermatitis and topical therapy is insufficiently effective or intolerable. 4. The method according to claim 3, where the IL-31 antagonist is administered at a dose of 0.5 mg/kg/4 weeks. 5. Method according to any one of paragraphs. 1-4, for use in the treatment of itching due to atopic dermatitis. 6. The method according to claim 5 for use in improving symptoms of sleep disturbance caused by itching. 7. Method according to any one of paragraphs. 1-6, wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling, wherein the antibody contains an amino acid variant sequence of the conserved region of the IgG2 H chain, and the amino acid variant includes glutamic acid at position 419, according to EU numbering in the sequence a conserved H chain region of SEQ ID NO: 15 found in naturally occurring IgG2, where the antibody has an increased plasma half-life compared to reference antibodies containing a conserved H chain region sequence found in naturally occurring IgG2 that is characterized by the same amino acid sequence, except for the amino acid substitution at position 419. 8. The method according to claim 7, where the antibody is characterized by an increased half-life in blood plasma as a result of a decrease in the isoelectric point value induced by replacing the amino acid at position 419 with glutamic acid. 9. Method according to any one of paragraphs. 1-8 for use in combination with a topical steroid or topical calcineurin inhibitor, wherein the IL-31 antagonist is administered before, simultaneously with, or after administration of the topical steroid or topical calcineurin inhibitor. 10. The method of claim 9, wherein administering a topical steroid or topical calcineurin inhibitor in combination with an IL-31 antagonist may reduce the dose of the topical steroid or topical calcineurin inhibitor when used in combination compared to the dose of the steroid for external use or a calcineurin inhibitor for external use when administered continuously as a single agent. 11. Method according to any one of paragraphs. 7-10, wherein the antibody is an anti-IL-31RA neutralizing antibody, and an anti-IL-31RA neutralizing antibody is selected from: (1) an anti-IL-31RA antibody comprising an H chain variable region containing CDR1 as set forth in SEQ ID NO: 1, CDR2 as set forth in SEQ ID NO: 2, and CDR3 as set forth in SEQ ID NO: 3, and an L chain variable region containing CDR1 as set forth in SEQ ID NO: 4, CDR2 as set forth in SEQ ID NO: 5, and CDR3 as set forth in SEQ ID NO: 6, (2) an anti-IL-31RA antibody comprising an H chain variable region as set forth in SEQ ID NO: 7 and an L chain variable region as set forth in SEQ ID NO: 8, and (3) an anti-IL-31RA antibody containing an H chain as set forth in SEQ ID NO: 9, and an L chain as set forth in SEQ ID NO: 10. 12. The method of claim 11, wherein the antibody does not cross-react with any mouse, rat or rabbit IL-31RA.