Pharmaceutical composition for prevention and / or treatment of atopic dermatitis containing il-31 antagonist as active ingredient

Abstract

To provide pharmaceutical compositions effective in the prevention and / or treatment of atopic dermatitis which can improve the QOL of patients.SOLUTION: A pharmaceutical composition for the prevention and / or treatment of atopic dermatitis containing IL-31 antagonist as an active ingredient is repeatedly administered at 0.1 mg to 1000 mg / body / 2 weeks, 0.1 mg to 1000 mg / body / 4 weeks, or 0.1 mg to 1000 mg / body / 8 weeks to a subject suffering from or at risk for atopic dermatitis in an equivalence and a same administration interval.SELECTED DRAWING: None

Description

[Technical Field]

[0001] In one non-limiting aspect, the present disclosure relates to a pharmaceutical composition for preventing and / or treating atopic dermatitis, which comprises an IL-31 antagonist as an active ingredient. [Background technology]

[0002] Atopic dermatitis is known to be easily exacerbated by external stimuli such as sweating, scratching, and friction, and the most important treatment goal is to suppress or alleviate itching. Atopic dermatitis is a chronic skin disease characterized by skin inflammation, rash, or eczema, and is characterized by itching (pruritus). Without intending to be bound by theory, it is thought to develop when various stimuli are added to an allergic constitution (atopic predisposition) that is prone to bronchial asthma, allergic rhinitis, and allergic dermatitis. The mechanism of atopic dermatitis development has not yet been fully elucidated, but it is believed to involve IgE-mediated cross-linking of Fcε receptors present on activated T cells, basophils, or mast cells, resulting in their activation, leading to the production of Th2-associated cytokines (e.g., IL-4, IL-13, IL-5) and chemical mediators (e.g., histamine and serotonin).

[0003] Treatments for atopic dermatitis include steroids, antihistamines, and other drug therapies, as well as PUVA therapy, which involves irradiating the affected area with UVA rays. However, previous treatments required patients to take or apply medication to the affected area several times a day, which can lead to problems with forgetting to take or apply the medication. Furthermore, UV therapy can require patients to visit a doctor as many as once or twice a week, which can be a burden on patients. Furthermore, it has been reported that the onset of itching in diseases such as atopic dermatitis is not solely due to the release of histamine, etc. (Non-Patent Document 1), and the development of therapeutic agents for atopic dermatitis based on a new mechanism of action is anticipated.

[0004] IL-31 (Interleukin-31) is a T cell cytokine. Transgenic mice overexpressing IL-31 are known to develop itching and dermatitis-like symptoms similar to atopic dermatitis (Non-Patent Document 2). Furthermore, the receptor to which IL-31 binds has been found to be a heterodimer of IL-31RA (Interleukin-31 receptor A) and OSMR (Oncostatin M receptor) (Patent Document 1), and IL-31 transmits signals intracellularly via this receptor. It has been reported that the expression of human IL-31RA is increased in the thickened epidermis of patients with atopic dermatitis (Non-Patent Document 3).

[0005] Previous studies have attempted to improve atopic dermatitis or the itching caused by it using IL-31 antagonists, and have reported successful improvement. IL-31 neutralizing antibodies and IL-31RA neutralizing antibodies have also been reported as IL-31 antagonists (Patent Documents 2 to 16). However, while some reports have shown that IL-31 protein and mRNA expression levels are elevated in the serum of patients with atopic dermatitis (Non-Patent Documents 4 and 5), others have reported that no difference in IL-31 expression levels was observed between the skin of patients with atopic dermatitis and healthy adults (Patent Document 8). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2004 / 003140 [Patent Document 2] WO2005 / 079566 [Patent Document 3] WO2006 / 063864 [Patent Document 4] WO2006 / 063865 [Patent Document 5] WO2009 / 071696 [Patent Document 6] WO2006 / 088855 [Patent Document 7] WO2006 / 088955 [Patent Document 8] WO2006 / 088956 [Patent Document 9] WO2007 / 133816 [Patent Document 10] WO2007 / 142325 [Patent Document 11] WO2009 / 072598 [Patent Document 12] WO2006 / 122079 [Patent Document 13] WO2007 / 143231 [Patent Document 14] WO2008 / 028192 [Patent Document 15] WO2009 / 072604 [Patent Document 16] WO2010 / 064697 [Non-patent literature]

[0007] [Non-Patent Document 1] J Dermatol Sci (2001) 25, 20-28 [Non-patent document 2] Nat Immunol (2004) 5, 752-760 [Non-patent document 3] J Allergy Clin Immunol (2006) 117, 418-425 [Non-patent document 4] J Allergy Clin Immunol (2008) 122, 421-423 [Non-Patent Document 5] Ann Dermatol (2011) 23, 468-473 Summary of the Invention [Problem to be solved by the invention]

[0008] In one non-limiting embodiment, an object of the present disclosure is to provide a pharmaceutical composition and the like based on a more effective administration regimen for the prevention and / or treatment of atopic dermatitis. [Means for solving the problem]

[0009] In one non-limiting embodiment, the inventors have developed a pharmaceutical composition for the prevention and / or treatment of atopic dermatitis based on a new mechanism of action. However, they are not satisfied with this and have continued to conduct research and development for many years in search of a more effective administration regimen that can reduce the burden on patients of taking medicines and visiting hospitals, and thereby contribute to improving the QOL of patients. As a result, they surprisingly discovered a more effective administration regimen that was not possible with conventional treatments for atopic dermatitis.

[0010] In one non-limiting embodiment, the present disclosure relates to: [1] A pharmaceutical composition for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient, The pharmaceutical composition comprises repeatedly administering the IL-31 antagonist at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from 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 0.1 mg to 1000 mg / body / 8 weeks. [2] The pharmaceutical composition according to [1], wherein the IL-31 antagonist is administered at a dose of 25 mg to 100 mg / body / 4 weeks. [3] The pharmaceutical composition according to [1] or [2], wherein the IL-31 antagonist is administered at a dose of 50 mg to 100 mg / body / 4 weeks. [4] A pharmaceutical composition for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient, The pharmaceutical composition comprises repeatedly administering the IL-31 antagonist at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.01 mg to 10 mg / kg every 2 weeks, 0.01 mg to 10 mg / kg every 4 weeks, or 0.01 mg to 10 mg / kg every 8 weeks. [5] The pharmaceutical composition according to [4], wherein the IL-31 antagonist is administered at a dose of 0.2 mg to 2 mg / kg every 4 weeks. [6] The pharmaceutical composition according to [4] or [5], wherein the IL-31 antagonist is administered at 0.5 mg / kg / 4 weeks. [7] The pharmaceutical composition according to any one of [1] to [6], for use in the prevention and / or treatment of pruritus caused by atopic dermatitis. [8] The pharmaceutical composition according to [7], for improving sleep disorders caused by the pruritus. [9] The pharmaceutical composition according to [8], wherein the improvement of the sleep disorder is intended to increase the time from falling asleep to waking and / or shorten sleep latency (the time from implantation to 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 antibody comprises an amino acid variant of an IgG2 H chain constant region sequence, wherein the amino acid variant comprises glutamic acid (EU numbering) at position 419 in the native IgG2 H chain constant region sequence (SEQ ID NO: 15); The pharmaceutical composition of

[10] , wherein the antibody exhibits an increased plasma half-life compared to a reference antibody comprising the H-chain constant region sequence of a native IgG2 having the same amino acid sequence as the antibody except for the amino acid mutation at position 419.

[12] The pharmaceutical composition of

[11] , wherein the antibody exhibits an increased plasma half-life due to a decrease in isoelectric point (pI) caused by the amino acid substitution at position 419 with glutamic acid.

[13] The pharmaceutical composition of

[11] or

[12] , which provides an increased plasma half-life compared to a pharmaceutical composition comprising a reference antibody comprising the same sequence of the H-chain constant region of a native IgG2 except for the amino acid mutation at position 419.

[14] The pharmaceutical composition according to any one of

[10] to

[13] , wherein the antibody does not exhibit cross-reactivity with any of mouse, rat, and rabbit IL-31RA.

[15] The pharmaceutical composition according to any one of

[10] to

[14] , wherein the antibody is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.

[16] The anti-IL-31RA neutralizing antibody is (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising an H chain variable region set forth in SEQ ID NO: 7 and an L chain variable region set forth in SEQ ID NO: 8; or (3) The pharmaceutical composition of

[15] , which is an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.

[17] The pharmaceutical composition according to any one of [1] to

[16] , for 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 according to any one of [1] to

[17] , wherein the atopic dermatitis is moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable.

[19] The pharmaceutical composition according to

[18] , wherein the topical treatment is a treatment with 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 (before application), simultaneously with (after) administration of (application of) the topical steroid or the topical calcineurin inhibitor.

[23] The pharmaceutical composition according to

[22] , wherein the IL-31 antagonist and the topical steroid or the topical calcineurin inhibitor are administered sequentially or simultaneously.

[24] The pharmaceutical composition according to

[22] or

[23] , wherein administering the topical steroid or the topical calcineurin inhibitor in combination with the IL-31 antagonist allows for a reduction in the dose (application amount) of the topical steroid or the topical calcineurin inhibitor when used in combination, compared to continuous administration (application) of the topical steroid or the topical calcineurin inhibitor alone.

[25] A combination of the pharmaceutical composition according to any one of [1] to

[21] with 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 at risk of suffering from atopic dermatitis, The IL-31 antagonist is repeatedly administered at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from 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 0.1 mg to 1000 mg / body / 8 weeks.

[27] A method for preventing and / or treating atopic dermatitis, comprising administering an IL-31 antagonist to a subject suffering from or at risk of suffering from atopic dermatitis, The IL-31 antagonist is repeatedly administered at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.01 mg to 10 mg / kg every 2 weeks, 0.01 mg to 10 mg / kg every 4 weeks, or 0.01 mg to 10 mg / kg every 8 weeks.

[28] Use of an IL-31 antagonist in the manufacture of a medicament for the prevention and / or treatment of atopic dermatitis, comprising: The IL-31 antagonist is administered repeatedly at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.1 mg to 1000 mg / body every 2 weeks, 0.1 mg to 1000 mg / body every 4 weeks, or 0.1 mg to 1000 mg / body every 8 weeks.

[29] Use of an IL-31 antagonist in the manufacture of a medicament for the prevention and / or treatment of atopic dermatitis, comprising: The IL-31 antagonist is administered repeatedly at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.01 mg to 10 mg / kg every 2 weeks, 0.01 mg to 10 mg / kg every 4 weeks, or 0.01 mg to 10 mg / kg every 8 weeks.

[30] A product comprising: (i) a container; (ii) a pharmaceutical composition in the container containing an IL-31 antagonist as an active ingredient; and (iii) a document instructing repeated administration of the IL-31 antagonist at equal doses and at the same administration intervals to a subject suffering from or at risk of suffering from 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 0.1 mg to 1000 mg / body / 8 weeks.

[31] A product comprising: (i) a container; (ii) a pharmaceutical composition in the container containing an IL-31 antagonist as an active ingredient; and (iii) a document instructing that the IL-31 antagonist be administered repeatedly at equal doses and at the same administration intervals to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.01 mg to 10 mg / kg / 2 weeks, 0.01 mg to 10 mg / kg / 4 weeks, or 0.01 mg to 10 mg / kg / 8 weeks.

[32] A pharmaceutical composition for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient, and further for improving sleep disorders caused by atopic dermatitis.

[33] The pharmaceutical composition according to

[32] , wherein the sleep disorder is caused by pruritus resulting from atopic dermatitis.

[34] The pharmaceutical composition according to

[32] or

[33] , wherein the improvement of the sleep disorder is intended to increase the time from falling asleep to waking and / or shorten sleep latency (the time from implantation to falling asleep).

[35] An IL-31 antagonist for use in the prevention and / or treatment of atopic dermatitis, wherein the IL-31 antagonist is repeatedly administered at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.1 mg to 1000 mg / body / day to 12 weeks, preferably 0.1 mg to 1000 mg / body / 2 weeks, 0.1 mg to 1000 mg / body / 4 weeks, or 0.1 mg to 1000 mg / body / 8 weeks.

[36] An IL-31 antagonist for use in the prevention and / or treatment of atopic dermatitis, wherein the IL-31 antagonist is repeatedly administered at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.01 mg to 10 mg / kg / day to 12 weeks, preferably 0.01 mg to 10 mg / kg / 2 weeks, 0.01 mg to 10 mg / kg / 4 weeks, or 0.01 mg to 10 mg / kg / 8 weeks. Any combination of part or all of one or more of the constituent elements described in any of [1] to

[36] above is also included in the present disclosure, as long as it is not technically inconsistent based on common general technical knowledge and is not contrary to the context. Therefore, a person skilled in the art can naturally and directly and unambiguously conceive of various embodiments, such as, for example, "an IL-31 antagonist for use in the prevention and / or treatment of atopic dermatitis, which is administered at a dose of 25 mg to 100 mg / body / 4 weeks or 0.2 mg to 2 mg / kg / 4 weeks in equal amounts and repeatedly at the same administration intervals to a subject suffering from or likely to suffer from atopic dermatitis, wherein the atopic dermatitis is moderate or severe atopic dermatitis that is insufficiently effective against or intolerant to treatment with a topical steroid or a topical calcineurin inhibitor." [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a graph showing the inhibitory effect on itching after a single subcutaneous administration of CIM331 or placebo in selected patients with atopic dermatitis (AD), based on a VAS score. [Figure 2] FIG. 1 is a graph showing the improvement effect of dermatitis, based on EASI score, after a single subcutaneous administration of CIM331 or placebo to certain patients with atopic dermatitis. [Figure 3] FIG. 1 is a graph showing whether or not quality of life (QOL) improved, using sleep efficiency as an index, after a single subcutaneous administration of CIM331 or placebo in patients with specified atopic dermatitis. [Figure 4] This figure shows the amount of topical steroid (Locoid) used after a single subcutaneous administration of CIM331 or placebo in patients with specified atopic dermatitis. [Figure 5] FIG. 1 shows the time course of serum CIM331 concentration after a single subcutaneous administration of CIM331 to certain patients with atopic dermatitis. [Figure 6] FIG. 1 shows the number of IL-31-induced itch behaviors after a single subcutaneous administration of 0.2 mg / kg of CIM331 to cynomolgus monkeys. [Figure 7] FIG. 1 shows the number of IL-31-induced itch behaviors after a single subcutaneous administration of 1 mg / kg of CIM331 to cynomolgus monkeys. [Figure 8] A nonlinear analytical model incorporating the Michaelis-Menten equation is shown. In the figure, the symbols represent the following: Xsc: drug amount at the subcutaneous injection site, X1: drug amount in the central compartment, X2: drug amount in the peripheral compartment, F: bioavailability, k12: drug transfer rate constant from the central compartment to the peripheral compartment, k21: drug transfer rate constant from the peripheral compartment to the central compartment, ka: absorption rate constant, kel: nonsaturable elimination rate constant, V1: distribution volume in the central compartment, Vmax: antibody elimination rate when all receptors are bound to the antibody, Km: antibody concentration binding to 50% of the total antigen, Cp: antibody concentration. [Figure 9] The predicted time course of CIM331 in human serum is shown. [Figure 10] FIG. 1 shows the relationship between body weight and exposure in a simulation of the optimal dose of CIM331 using a one-compartment model. [Figure 11] This shows the predicted pruritus VAS one year after administration of CIM331 using an indirect turnover model. DETAILED DESCRIPTION OF THE INVENTION

[0012] Preferred, non-limiting aspects of the present disclosure are described below.

[0013] All embodiments described in the following examples are intended to be considered as being equivalently described in this "Form for Carrying Out the Invention" without being bound by any patent practice, custom, laws, regulations, etc. in any country in which the patent application is intended to be granted that may attempt to restrictively interpret the contents described in the examples.

[0014] IL-31 (Interleukin-31) is a T cell cytokine, and transgenic mice overexpressing IL-31 develop dermatitis-like symptoms similar to atopic dermatitis, including persistent scratching behavior, and are known to be involved in pruritus.

[0015] The nucleic acid and amino acid sequences of human IL-31 are also known as RefSeq Accession No. NM_001014336 and RefSeq Accession No. NP_001014358, respectively.

[0016] The IL-31 receptor is a heterodimer of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) ( Nat Immunol (2004) 5, 752-60). IL-31RA, also known as NR10, is known to have multiple splicing variants ( WO00 / 075314 ). Known splicing variants include NR10.1 (652 amino acids), NR10.2 (252 amino acids), NR10.3 (662 amino acids, also known as IL-31RAv4), and IL-31RAv3 (764 amino acids). Preferred examples of IL-31RA include NR10.3 (IL-31RAv4) and IL-31RAv3. The nucleic acid and amino acid sequences of human IL-31RA (IL-31RAv4) are also known as RefSeq Accession No. NM_001242638 and RefSeq Accession No. NP_001229567, respectively. The nucleic acid and amino acid sequences of human IL-31RA (IL-31RAv3) are also known as RefSeq Accession No. NM_139017 and RefSeq Accession No. NP_620586, respectively. The nucleic acid and amino acid sequences of human OSMR are also known as RefSeq Accession No. NM_003999 and RefSeq Accession No. NP_003990, respectively.

[0017] In one embodiment, the term "IL-31 antagonist" used in the present disclosure refers to a compound that suppresses or blocks intracellular signal transduction induced by IL-31, which can also be referred to as a compound that inhibits IL-31 signaling. Such compounds may be naturally occurring compounds or artificially synthesized compounds. They may also be low-molecular-weight compounds or high-molecular-weight compounds such as proteins.

[0018] Extracellular IL-31 is known to induce intracellular signal transduction via the IL-31 receptor (a heterodimer of IL-31RA and OSMR) present on the cell surface (Nat Immunol (2004) 5, 752-760). The extracellular domain of the IL-31 receptor contains an IL-31-binding domain, and upon binding of IL-31 to this domain, the three-dimensional structure of the IL-31 receptor changes, resulting in the initiation of intracellular signal transduction from the intracellular domain of the IL-31 receptor.

[0019] One method for determining whether a compound inhibits IL-31 signaling is to examine whether the compound inhibits the binding of IL-31 to the IL-31 receptor. Examples of methods for such measurements include ELISA, flow cytometry-based assays, and surface plasmon resonance-based assays. For example, in the case of ELISA, a system is prepared in which IL-31 receptor (or IL-31RA) protein is immobilized on a plate, and the amount of IL-31 protein bound to the immobilized protein is detected with a secondary antibody such as an enzyme-labeled anti-IL-31 antibody. Addition of a compound to the system reduces the amount of detected IL-31 protein, thereby assessing whether the compound inhibits the binding of IL-31 to the IL-31 receptor. Alternatively, whether a compound inhibits IL-31 signaling can be confirmed by examining whether the compound inhibits physiological activity induced by the action of IL-31 on cells. The physiological activity is not particularly limited as long as it can be measured quantitatively or qualitatively by some method, and examples include cell proliferation activity, protein phosphorylation activity, and gene / protein expression induction activity. For example, cells expressing IL-31 receptor on their surface and whose proliferation activity is induced in response to external IL-31 stimulation can be prepared. Adding a compound to these cells can then be used to assess whether the compound inhibits IL-31 signaling by measuring whether the IL-31-induced cell proliferation activity is reduced. Such cells may be natural cells that naturally express IL-31 receptor, or genetically engineered cells artificially expressing IL-31 receptor. A suitable example of a genetically engineered cell is Ba / F3 cells expressing IL-31 receptor. As another alternative method, the method described in Dillon et al. (Nat Immunol (2004) 5, 752-760) can also be used.

[0020] In the present disclosure, the degree to which an IL-31 antagonist inhibits IL-31 signaling is not limited, but may be at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, and particularly preferably 90% or more, 95% or more, or 98% or more.

[0021] In the present disclosure, a preferred embodiment of a compound that inhibits IL-31 signaling is a protein that inhibits IL-31 signaling. The protein is not particularly limited as long as it has the property of specifically binding to IL-31 or the IL-31 receptor. Preferred examples include antibodies and antibody-like molecules (Curr Opin Biotechnol (2006) 17, 653-658, Curr Opin Struct Biol (1997) 7, 463-469, Protein Sci (2006) 15, 14-27). Antibodies include any antibody, such as monoclonal antibodies (e.g., IgG, IgM, IgE, IgA, IgD, etc.), polyclonal antibodies, modified antibodies (e.g., chimeric antibodies, humanized antibodies, glycosylated antibodies (WO99 / 54342, WO00 / 61739), etc.), antibody fragments (e.g., Fab, F(ab')2, Fv, CDR, etc.), multispecific antibodies (e.g., bispecific antibodies), and conjugated antibodies (e.g., antibodies attached with polyethylene glycol (PEG), radioisotopes, or drugs). Examples of antibody-like molecules include DARPin (WO2002 / 020565), Affibody (WO1995 / 001937), Avimer (WO2004 / 044011), and Adnectin (WO2002 / 032925). Antibodies that inhibit IL-31 signaling are more preferred. Other preferred examples of proteins that inhibit IL-31 signaling include proteins containing the extracellular domain of IL-31RA, or proteins containing each extracellular domain of the IL-31 receptor (a heterodimer of IL-31RA and OSMR).

[0022] In the present disclosure, 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) and antibodies that inhibit IL-31 signaling by 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), and antibodies that inhibit IL-31 signaling by binding to the heterodimer of IL-31RA and OSMR (anti-IL-31RA / OSMR heterodimer neutralizing antibodies). Among these anti-IL-31 receptor neutralizing antibodies, anti-IL-31RA neutralizing antibodies or anti-IL-31RA / OSMR heterodimer neutralizing antibodies are preferred, and anti-IL-31RA neutralizing antibodies are more preferred.

[0023] In a further or alternative embodiment, an antibody of the present disclosure that inhibits IL-31 signaling comprises an amino acid variant of an IgG2 H-chain constant region sequence, and the amino acid variant preferably comprises glutamic acid (EU numbering) at position 419 in the native IgG2 H-chain constant region sequence (SEQ ID NO: 15). Such modified antibodies are advantageous because they exhibit an increased plasma half-life compared to a reference antibody comprising the native IgG2 H-chain constant region sequence, which has the same amino acid sequence except for the amino acid mutation at position 419. Such an increased plasma half-life is believed to be brought about by a decrease in the isoelectric point (pI) due to the amino acid substitution at position 419 to glutamic acid (Example 2). Therefore, in one embodiment, the pharmaceutical composition of the present disclosure is advantageous because it provides an increased plasma half-life compared to a (reference) pharmaceutical composition comprising a reference antibody comprising the same H-chain constant region sequence of a native IgG2 except for the amino acid mutation at position 419. In this case, in a preferred embodiment, the antibody of the present disclosure that inhibits IL-31 signaling is any of the following anti-IL-31RA neutralizing antibodies. (1) An anti-IL-31RA antibody comprising an H-chain variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6; (2) an anti-IL-31RA antibody comprising an H chain variable region set forth in SEQ ID NO: 7 and an L chain variable region set forth in SEQ ID NO: 8; or (3) An anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.

[0024] Unless expressly stated herein and unless the context indicates otherwise, it is understood that the isoelectric point (pI) may be either the theoretical isoelectric point or the experimentally measured isoelectric point, and may also be simply referred to as "pI." For example, the isoelectric point can be measured by isoelectric focusing, which is known to those skilled in the art. The theoretical isoelectric point can also be calculated using gene and amino acid sequence analysis software (such as Genetyx). Alternatively, the isoelectric point can be measured by conducting a pharmacokinetic test of the antibody using plasma from mice, rats, rabbits, dogs, monkeys, humans, etc., in combination with a method known to those skilled in the art, such as BIACORE, cell proliferation assay, ELISA, EIA (enzyme-linked immunosorbent assay), RIA (radioimmunoassay), or fluorescent immunoassay.

[0025] Whether the plasma half-life of the antibody has increased or decreased before and after the amino acid mutation (modification) may be confirmed by conducting a pharmacokinetic test of the antibody using plasma from mice, rats, rabbits, dogs, monkeys, humans, etc., using a method known to those skilled in the art.

[0026] In yet a further or alternative embodiment, the antibody that inhibits IL-31 signaling of the present disclosure is cross-reactive with human and cynomolgus monkey IL-31RA, but preferably does not (substantially) exhibit cross-reactivity with mouse, rat, or rabbit IL-31RA.

[0027] Methods for producing antibodies are well known to those skilled in the art and can be produced, for example, by the hybridoma method (Nature (1975) 256, 495) or the phage antibody library method (Nature (1991) 352, 624-628; J Mol Biol (1991) 222, 581-597). By using an IL-31 protein, IL-31 receptor protein, or the like as an immunogen, these methods can be used to obtain a large number of anti-IL-31 antibodies and anti-IL-31 receptor antibodies. Furthermore, by screening these antibodies using the above-mentioned method for detecting compounds that inhibit IL-31 signaling, anti-IL-31 neutralizing antibodies and anti-IL-31 receptor neutralizing antibodies can be obtained. Proteins such as IL-31 and IL-31 receptor may also be prepared by genetic engineering techniques known to those skilled in the art. Specifically, the desired protein can be prepared by inserting a gene encoding the desired protein into an expression vector, introducing the vector into a suitable host cell, and then purifying the desired protein expressed in the host cell or in the culture supernatant of the host cell.

[0028] Preferred examples of anti-IL-31 neutralizing antibodies include the anti-IL-31 antibodies described in WO2006 / 122079, WO2008 / 028192, and WO2009 / 071696.

[0029] Preferred examples of anti-IL-31RA neutralizing antibodies include, but are not limited to, the anti-IL-31RA (NR10) antibody described in WO2007 / 142325, the anti-IL-31RA (NR10) antibody described in WO2009 / 072604, and the anti-IL-31RA (NR10) antibody described in WO2010 / 064697. Another preferred example is an anti-human IL-31RA (neutralizing) antibody, specifically an anti-IL-31RA (neutralizing) antibody that recognizes domain 1 and / or domain 2 of human IL-31RA. Here, domain 1 of human IL-31RA refers to the region from amino acid 53 to amino acid 152 (LPAKP-LENIA) in the amino acid sequence of SEQ ID NO: 11. Domain 2 refers to the region from amino acid 153 to amino acid 259 (KTEPP-EEEAP) in the amino acid sequence of SEQ ID NO: 11. Among anti-IL-31RA neutralizing antibodies, more preferred are, but not limited to, anti-IL-31RA antibodies comprising an H-chain (heavy chain) variable region comprising CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and an L-chain variable region comprising CDR1 set forth in SEQ ID NO: 4, CDR2 set forth in SEQ ID NO: 5, and CDR3 set forth in SEQ ID NO: 6, which are also described in WO2010 / 064697; even more preferred are anti-IL-31RA antibodies comprising an H-chain variable region set forth in SEQ ID NO: 7 and an L-chain (light chain) variable region set forth in SEQ ID NO: 8; and particularly preferred are anti-IL-31RA antibodies comprising an H-chain set forth in SEQ ID NO: 9 and an L-chain set forth in SEQ ID NO: 10.

[0030] Known methods for defining CDRs include the method of Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Ed (1991), Bethesda, MD), the method of Chothia et al. (Science (1986) 233, 755-758), and a method based on antigen-antibody contact regions (J Mol Biol (1996) 262, 732-745). Specifically, CDRs according to each method are defined as follows: CDR Kabat Chothia Contact L1 L24-L34 L24-L34 L30-L36 L2 L50-L56 L50-L56 L46-L55 L3 L89-L97 L89-L97 L89-L96 H1 H31-H35B H26-H32 / 34 H30-H35B (Kabat numbering) H1 H31-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H52-H56 H47-H58 H3 H95-H102 H95-H102 H93-H101

[0031] A preferred example of an anti-IL-31RA neutralizing antibody in the present disclosure is an anti-IL-31RA antibody that comprises, as H chain CDR1, CDR2, and CDR3, respectively, the CDR1, CDR2, and CDR3 contained in the H chain variable region set forth in SEQ ID NO: 7, and the CDR1, CDR2, and CDR3 contained in the L chain variable region set forth in SEQ ID NO: 8. The CDRs in such antibodies may be defined according to the method of Kabat et al., the method of Chothia et al., or a method based on antigen-antibody contact regions, or a combination of these methods.

[0032] Anti-IL-31RA antibodies that bind to the same epitope as the anti-IL-31RA antibodies identified by the above-mentioned H-chain and L-chain CDR sequences, H-chain and L-chain variable region sequences, and full-length H-chain and L-chain sequences are also preferred as anti-IL-31RA neutralizing antibodies. An epitope is a specific structural unit of an antigen that an antibody recognizes and binds to. When the antigen is a polypeptide, it usually consists of approximately 6 to 10 amino acids. Epitopes can be identified by methods known to those skilled in the art, such as synthesizing peptide fragments of the antigen, introducing site-specific mutations into the antigen (e.g., arginine / glutamic acid scanning; J. Biol. Chem. (1995) 270, 21619-21625; J. Biol. Chem. (2006) 281, 20464-20473), or crystallizing an antigen-antibody complex (Using Antibodies: A Laboratory Manual (1999), Cold Spring Harbor Laboratory Press, New York). In the present disclosure, "binding to the same epitope" means that the epitopes bound by two types of antibodies overlap at least partially. The degree of overlap is not limited, but is at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, particularly preferably 90% or more, and most preferably 100%.

[0033] Similarly, anti-IL-31RA antibodies whose binding to IL-31RA competes with anti-IL-31RA antibodies specified by the above-mentioned sequences of the H-chain and L-chain CDRs, the sequences of the H-chain and L-chain variable regions, and the sequences of the full-length H-chain and L-chain are also preferred as anti-IL-31RA neutralizing antibodies. Whether two types of antibodies compete with each other can be evaluated by competitive binding assays such as ELISA. Specifically, one of the two types of antibodies is pre-labeled with fluorescence or the like, and a system is prepared to detect the binding of that antibody (labeled antibody) to an antigen. A comparison is made between the presence and absence of the other unlabeled antibody (test antibody). If the amount of binding of the labeled antibody to the antigen is reduced in the presence of the test antibody, it can be determined that the test antibody and the labeled antibody compete with each other. In the present disclosure, the degree of competition is not particularly limited, but it is at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, and particularly preferably 90% or more, 95% or more, or 98% or more competition (i.e., reducing the amount of binding of the other antibody).

[0034] Nucleotide sequences and amino acid sequences encoding antibodies that inhibit IL-31 signaling (e.g., anti-IL-31 neutralizing antibodies or anti-IL-31RA neutralizing antibodies) of the present disclosure can be obtained by methods known to those skilled in the art. Amino acids contained in the amino acid sequences of the antibodies described in the present disclosure may be modified after translation (e.g., modification of N-terminal glutamine to pyroglutamic acid by pyroglutamylation is a modification well known to those skilled in the art), and even when amino acids are post-translationally modified in this way, they are naturally included in the amino acid sequences described in the present disclosure.

[0035] The atopic dermatitis in the present disclosure is not limited to, but may preferably be atopic dermatitis caused by IL-31 signaling or caused by IL-31, or may be atopic dermatitis that is responsive to prevention and / or treatment with an IL-31 antagonist. Furthermore, the pruritus in the present disclosure refers to pruritus caused by atopic dermatitis, and is not limited thereto, and may be preferably pruritus caused by atopic dermatitis resulting from IL-31 signaling or caused by IL-31. It may also be pruritus caused by atopic dermatitis that is responsive to prevention and / or treatment with an IL-31 antagonist.

[0036] Furthermore, the atopic dermatitis may be, for example, moderate to severe atopic dermatitis, preferably moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable, for which standard topical treatment is insufficiently effective or intolerable, or for which standard topical treatment cannot be performed (due to contraindications, etc.), and more preferably moderate or severe atopic dermatitis for which topical treatment is insufficiently effective or intolerable. For example, topical treatments include topical steroids (for example, glucocorticoids or derivatives thereof such as prednisolone and hydrocortisone) and topical calcineurin inhibitors (for example, tacrolimus and pimecrolimus), which are known as immunosuppressants.

[0037] Known therapeutic agents for atopic dermatitis include topical steroids and topical calcineurin inhibitors, as well as cyclosporine, methotrexate (MTX), azathioprine (AZA), and antihistamines (a variety of antihistamine preparations are known, which can be broadly divided into first-generation antihistamines and second-generation antihistamines). More specifically, the following treatments are known for treating atopic dermatitis, but are not limited to them ("Guidelines for the Management of Atopic Dermatitis," Furue et al., Journal of the Japanese Dermatological Association, 119(8), pp. 1515-1534, 2009; "Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents," Sidbury R et al., J Am Acad Dermatol. (2014), pp. 327-337; Saeki H, et al., J Dermatol. 2009, 36, pp. 563-77). (1) Cyclosporine preparation (product name: Neoral) The usual adult dose of cyclosporine is 3 mg / kg administered orally twice daily. This can be increased or decreased depending on symptoms, but the daily dose should not exceed 5 mg / kg. (2) Oral steroid preparation (product name: prednisolone tablets) The usual adult dosage is 5 to 60 mg of prednisolone (1 to 12 tablets, 0.5 to 6 g for powder) administered orally in 1 to 4 divided doses per day. Dosage may be adjusted according to age and symptoms. (3) Ultraviolet light therapy It is generally said that patients need to visit the hospital once or twice a week, but there are no definitive guidelines. (4) Antihistamine preparation (brand name: Allegra) The usual adult dosage is 60 mg of fexofenadine hydrochloride taken orally twice daily. The usual children aged 7 to 12 years are given 30 mg of fexofenadine hydrochloride taken orally twice daily, and children aged 12 years and older are given 60 mg of fexofenadine hydrochloride taken orally twice daily. The dosage may be adjusted according to symptoms. (5) Topical steroid (product name: Fulmeta) In general, apply an appropriate amount to the affected area once or several times a day. The dosage may be increased or decreased depending on the symptoms. (6) Topical steroid (product name: Locoid) Usually, apply an appropriate amount once or several times a day. The dosage may be increased or decreased depending on the symptoms. (7) Tacrolimus preparation (brand name: Protopic) In general, for adults, apply an appropriate amount to the affected area once or twice a day, up to 5g per application. (8) Pimecrolimus preparation (product name: Elidel) Usually, apply an appropriate amount twice a day. The dosage may be increased or decreased depending on the symptoms.

[0038] In one embodiment, the IL-31 antagonist of the present disclosure (e.g., an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody) may be administered in combination with the above-mentioned existing therapeutic agents or therapies. The IL-31 antagonist of the present disclosure may be administered in combination with, for example, a topical steroid or a topical calcineurin inhibitor. The IL-31 antagonist may be administered to a subject before (before application), simultaneously with, or after (after application) the administration of a topical steroid or a topical calcineurin inhibitor. As described in detail in "(4-5) Effect of combined administration of CIM331 with a topical steroid or the like" below, in patients who showed sufficient improvement in pruritus but insufficient improvement in dermatitis during Part A of the Phase II multiple-dose study, administration of CIM331 in combination with a topical steroid or the like for a short or required period after the start of Part B surprisingly demonstrated continuous and significant improvement in dermatitis. When an IL-31 antagonist is administered in combination with a topical steroid or a topical calcineurin inhibitor, the order, timing, and number of administrations are not particularly limited, as long as the continuous doses (described below) of the IL-31 antagonist of the present disclosure are equal and the administration intervals (intervals between administrations) are equal. In a non-limiting preferred embodiment, the concomitant administration of an IL-31 antagonist of the present disclosure can reduce the dose (amount applied) of the concomitantly administered topical steroid or topical calcineurin inhibitor compared to the continuous administration (application) of the topical steroid or topical calcineurin inhibitor alone (Figure 4). The amount of reduction is not particularly limited, but may be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 100% reduction compared to continuous administration (application) of a topical steroid or a topical calcineurin inhibitor alone. Topical steroids may include, but are not limited to, hydrocortisone, desonide, prednisolone, etc. Topical calcineurin inhibitors may include, but are not limited to, pimecrolimus, tacrolimus, etc.

[0039] The severity of atopic dermatitis (mild, moderate, severe, etc.) may be classified based on classification methods known to those skilled in the art for scoring the degree of skin rash or itch felt by a subject, such as Shiratori's severity criteria, the visual analogue scale (VAS) described below, the itch verbal rating scale (VRS), SCORing Atopic Dermatitis (SCORAD) by the European Task Force on Atopic Dermatitis, the Eczema Area and Severity Index (EASI) in the United States, or the static Investigator's Global Assessment (sIGA). For example, the VAS is a 100 mm line, with 0 mm representing no itching and 100 mm representing the worst imaginable itching, and the subject (patient) indicates the intensity of the itching at the time of measurement with a line between 0 and 100 mm. For example, a subject whose VAS score is 40 mm or higher may be identified as suffering from moderate to severe atopic dermatitis. In one embodiment, the VAS may be 45 mm or higher, or 50 mm or higher. Similarly, in the case of VRS, a subject classified as experiencing "moderate itching" or higher may be identified as suffering from moderate to severe atopic dermatitis (Reich et al. 2012). Alternatively, a subject whose EASI score is 10 or higher, whose sIGA score is 3 or higher, or whose total score of daytime and nighttime itching intensity based on the Shiratori severity classification is 4 or higher may be identified as suffering from moderate to severe atopic dermatitis. Alternatively, a subject with a severely inflammatory rash covering, for example, 5% or more of the body surface area may be identified as suffering from moderate to severe atopic dermatitis. Alternatively, a subject meeting one or a combination of the multiple indicators listed here may be identified as suffering from moderate to severe atopic dermatitis.

[0040] The term "subject" as used herein is not limited to, but is preferably an animal, more preferably a mammal (such as a mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey), or human, with human beings being particularly preferred. The human may be an adult (18 years of age or older) or a child (0 to under 18 years of age, e.g., 6 months to under 18 years of age).

[0041] In one aspect, the present disclosure relates to a pharmaceutical composition for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient (note that the term "prophylactic and / or therapeutic pharmaceutical composition" may be rephrased as "prophylactic agent and / or therapeutic agent"). In such cases, the IL-31 antagonist may be intended to be administered repeatedly at predetermined dosage intervals, as detailed below, in equal amounts at predetermined doses (dosage amounts), and at the same dosage intervals.

[0042] In one embodiment, the pharmaceutical compositions of the present disclosure may be used for the prevention and / or treatment of pruritus caused by atopic dermatitis.

[0043] In a further or alternative embodiment, the pharmaceutical composition of the present disclosure may be used to improve sleep disorders caused by atopic dermatitis, where the sleep disorders may be caused by pruritus caused by atopic dermatitis. The improvement in sleep disorders may be characterized, for example, by an increase in the time from sleep onset to awakening and / or a decrease in sleep latency (the time from implantation to sleep).

[0044] In yet a further or alternative embodiment, the pharmaceutical composition of the present disclosure may be used to suppress at least one symptom caused by atopic dermatitis selected from the group consisting of redness, induration, papules, edema, excoriation, and lichenification.

[0045] In one embodiment of the present disclosure, the prevention and / or treatment of atopic dermatitis may refer to, but is not limited to, administering a drug or the like to a subject currently exhibiting atopic dermatitis or various symptoms associated therewith (e.g., itching, redness, induration, papules, edema, excoriation, lichenification, decreased quality of life, or lack of sleep) to suppress one or more of these symptoms, and / or administering a drug or the like to a subject currently exhibiting atopic dermatitis or various symptoms associated therewith to prevent the onset of one or more of these symptoms or reduce the incidence thereof. Even if atopic dermatitis itself cannot be prevented and / or treated, the prevention and / or treatment of atopic dermatitis may be judged or determined to be useful for prevention and / or treatment if it improves any one of the various symptoms associated with atopic dermatitis.

[0046] A subject who may have atopic dermatitis may be, but is not limited to, a subject who has previously had atopic dermatitis and is at risk of experiencing a recurrence of symptoms, or a subject who is suspected of having atopic dermatitis before a doctor or other medical professional has diagnosed or determined that the subject has atopic dermatitis. In one embodiment, prevention and treatment of atopic dermatitis may be interpreted as synonymous in some cases.

[0047] In the test of this example in which a single subcutaneous administration of an IL-31 antagonist was administered to patients with atopic dermatitis, improvement in sleep efficiency was observed in the IL-31 antagonist administration group. Although atopic dermatitis is not necessarily a life-threatening condition, the symptoms associated with the disease significantly impact daily life. Itching, in particular, is the most characteristic symptom and is an unpleasant sensation that significantly reduces patients' quality of life (QOL). Patients have reported that itching interferes with sleep (Zuberbier T, Orlow SJ, Paller AS, Taieb A, Allen R, Hernanz-Hermosa JM, Ocampo-Candiani J, Cox M, Langeraar J, Simon JC. Patient perspective on the management of atopic dermatitis. J Allergy Clin Immunol 2006;118:226-32). Furthermore, when the patient is a child, the burden on both the child and the parents is significant. Reports suggest that parents of moderately to severely affected children spend three hours per day on treatment, losing one to two hours of sleep each day (Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial cost. Arch Dis Chil 1997;76:159-62.). Therefore, in another aspect, the present disclosure relates to a pharmaceutical composition for preventing and / or treating atopic dermatitis, comprising an IL-31 antagonist as an active ingredient, and further for improving sleep disorders caused by atopic dermatitis. Alternatively, in a further or alternative aspect, the present disclosure relates to a pharmaceutical composition for improving quality of life caused by atopic dermatitis. The improvement in sleep disorders may be characterized, for example, by an increase in the time from sleep onset to awakening and / or a decrease in sleep latency (the time from implantation to sleep).

[0048] As used herein, "repeated administration at equal doses and at equal administration intervals" may mean, in one embodiment, that the initial dose (initial dose) of an IL-31 antagonist of the present disclosure administered to a subject and subsequent subsequent doses (i.e., doses administered continuously after the initial dose) are equal in amount and at equal administration intervals (intervals between each administration). That is, for example, it may mean that the interval between the administration of the initial dose and the first subsequent dose, or the interval between the administration of the nth subsequent dose (n is an integer of 1 or more) and the n+1th subsequent dose, are all equal, and the doses are equal. Alternatively, in another embodiment, "repeated administration at equal doses and at equal administration intervals" may mean that the initial dose and subsequent doses are different, but the subsequent doses are equal in amount and at equal administration intervals (intervals between each administration). A dose (administration amount) of an IL-31 antagonist of the present disclosure, described in mg / kg or mg / body, may be considered to refer to both the initial dose and the subsequent doses if they are intended to be the same, or to the subsequent dose if they are intended to be different, unless otherwise specified and contradicted by the context. It will be understood by those skilled in the art that there may be a "tolerance range" for each determined administration interval (for example, every 4 weeks when the administration interval is determined to be every 4 weeks), and those skilled in the art can determine the tolerance range as appropriate.

[0049] In one embodiment, in the present disclosure, the number of repeated administrations may mean, for example, but is not limited to, administration of an initial dose followed by subsequent doses, for example, 1 to 10,000 or more times, more specifically, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 20, 25, 35, 40, 50, 60, 70, 80, 90, 100, 500, 1,000, 10,000, and so on.

[0050] In one embodiment, the administration interval of the pharmaceutical composition or IL-31 antagonist of the present disclosure is intended to be at least 1 day and at most 12 weeks, and 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 administration interval can also be expressed in other ways, such as once a day to once every 12 weeks, or every day to every 12 weeks.

[0051] In the present disclosure, the dosage (dose) may be, for example, a fixed dose equivalent to a body weight equivalent dose (mg / body) or a body surface area equivalent dose (mg / m 2 ) can also be expressed as For example, when the IL-31 antagonist of the present disclosure is intended to be administered at a fixed dose (mg / body) to a subject suffering from or at risk of suffering from atopic dermatitis, the dose of the IL-31 antagonist of the present disclosure may be converted from mg / kg to mg / body, and an appropriate dose (mg / body) may be set and administered to the subject. In this case, the logic for converting from mg / kg to mg / body may be determined appropriately using logic known to those skilled in the art, but is not limited thereto. An example of such logic may be as follows: Assuming that there is a minimum effective serum concentration and a maximum tolerated (empirical) serum concentration of the IL-31 antagonist disclosed herein, a change from mg / kg dosage to mg / body dosage may be considered so that the serum IL-31 antagonist concentration falls within this concentration range regardless of body weight. Such subjects may be, for example, subjects weighing less than 100 kg or less than 120 kg. Although not limited thereto, the mg / body dosage may be increased in some cases for subjects with higher body weight (e.g., more than 100 kg or more than 120 kg). Furthermore, administration in mg / kg may be considered for low-body weight children, as exposure may be significantly increased at mg / body doses.

[0052] In one non-limiting embodiment, for subjects suffering from or at risk of suffering from atopic dermatitis, for example, human adults and children, the dose is 0.1 mg to 1000 mg / body, for example, 0.2 mg to 360 mg / body, 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, 10 mg to 39 mg / body, 10 mg to 38. 5mg / body, 10mg~38mg / body, 10mg~37.5mg / body, 15mg~100mg / body, 15mg~75mg / body, 15mg~50mg / body, 15mg~40mg / body, 15mg ~39.5mg / body, 15mg~39mg / body, 15mg~38.5mg / body, 15mg~38mg / body, 15mg~37.5mg / body, 17.5mg~100mg / body, 17.5mg~75mg / body, 17.5mg~50mg / body, 17.5mg~40mg / body, 17.5mg~39.5mg / body, 17.5mg~39mg / body, 17.5mg~38.5mg / body, 17.5mg~38mg / body, 17.5mg~37.5mg / body, 20mg~100mg / body, 20mg~75mg / body, 20mg~50mg / body, 20mg~40mg / body, 20mg~39.5mg / body, 20mg g~39mg / body, 20mg~38.5mg / body, 20mg~38mg / body, 20mg~37.5mg / body, 22.5mg~100mg / body, 22.5mg~75mg / body, 22.5mg~50m g / body, 22.5mg~40mg / body, 22.5mg~39.5mg / body, 22.5mg~39mg / body, 22.5mg~38.5mg / body, 22.5mg~38mg / body, 22.5mg~37.5mg / body、25mg~500mg / body、25mg~200mg / body、25mg~120mg / body、25mg~110mg / body、25mg~100mg / body、25mg~90mg / body、25mg~80mg / body、25mg~79mg / body、25mg~78mg / body、25mg~77mg / body、25mg~76mg / body、25mg~75mg / body、25mg~74mg / body、25mg~73mg / body、25mg~72mg / body、25mg~71mg / body、25mg~70mg / body、25mg~50mg / body、30mg~50mg / body、30mg~75mg / body、30mg~100mg / body、30mg~150mg / body、30mg~200mg / body、30mg~250mg / body、30mg~300mg / body、40mg~70mg / body、40mg~71mg / body、40mg~72mg / body、40mg~73mg / body、40mg~74mg / body、40mg~75mg / body、40mg~76mg / body、40mg~77mg / body、40mg~78mg / body、40mg~79mg / body、40mg~80mg / body、40mg~90mg / body、40mg~100mg / body、40mg~110mg / body、40mg~120mg / body、42.5mg~70mg / body、42.5mg~71mg / body、42.5mg~72mg / body、42.5mg~73mg / body、42.5mg~74mg / body、42.5mg~75mg / body、42.5mg~76mg / body、42.5mg~77mg / body、42.5mg~78mg / body、42.5mg~79mg / body、42.5mg~80mg / body、42.5mg~90mg / body、42.5mg~100mg / body、42.5mg~110mg / body、42.5mg~120mg / body、45mg~70mg / body、45mg~71mg / body、45mg~72mg / body、45mg~73mg / body、45mg~74mg / body、45mg~75mg / body、45mg~76mg / body、45mg~77mg / body、45mg~78mg / body、45mg~79mg / body、45mg~80mg / body、45mg~90mg / body、45mg~100mg / body、45mg~110mg / body、45mg~120mg / body、47.5mg~70mg / body、47.5mg~71mg / body、47.5mg~72mg / body、47.5mg~73mg / body、47.5mg~74mg / body、47.5mg~75mg / body、47.5mg~76mg / body、47.5mg~77mg / body、47.5mg~78mg / body、47.5mg~79mg / body、47.5mg~80mg / body、47.5mg~90mg / body、47.5mg~100mg / body、47.5mg~110mg / body、47.5mg~120mg / body、50mg~70mg / body、50mg~71mg / body、50mg~72mg / body、50mg~73mg / body、50mg~74mg / body、50mg~75mg / body、50mg~76mg / body、50mg~77mg / body、50mg~78mg / body、50mg~79mg / body、50mg~80mg / body、50mg~90mg / body、50mg~100mg / body、50mg~110mg / body、50mg~120mg / body、50mg~150mg / body、50mg~200mg / body、50mg~250mg / body、50mg~300mg / body、52.5mg~70mg / body、52.5mg~71mg / body、52.5mg~72mg / body、52.5mg~73mg / body、52.5mg~74mg / body、52.5mg~75mg / body、52.5mg~76mg / body、52.5mg~77mg / body、52.5mg~78mg / body、52.5mg~79mg / body、52.5mg~80mg / body、52.5mg~90mg / body、52.A single dose selected from among 5 mg to 100 mg / body, 52.5 mg to 110 mg / body, 52.5 mg to 120 mg / body, 75 mg to 100 mg / body, 75 mg to 150 mg / body, 75 mg to 200 mg / body, 75 mg to 250 mg / body, 75 mg to 300 mg / body, 100 mg to 150 mg / body, 100 mg to 200 mg / body, 100 mg to 250 mg / body, 100 mg to 300 mg / body, 150 mg to 200 mg / body, 150 mg to 250 mg / body, 150 mg to 300 mg / body, 200 mg to 250 mg / body, 200 mg to 300 mg / body, and the like may be selected as the dose of the IL-31 antagonist of the present disclosure, and may be repeatedly administered in equal amounts at the same administration intervals as described above. For the avoidance of doubt, for example, when 0.1mg-1000mg / body is stated, the ranges are: 0.1mg / body, 0.2mg / body, 0.3mg / body, 0.4mg / body, 49.9mg / body, 50mg / body, 50.1mg / body, 50.2mg / body, 99.8mg / body, 99.9mg / body, 100mg / body, 100.1mg / body, 100.2mg / body, 199. All doses between 0.1 mg and 1000 mg / body inclusive increments of 0.1 mg / body, such as 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, 1000 mg / body, etc., are intended to be individually and specifically recited herein. Therefore, for example, a person skilled in the art who comes across the description of 50 mg to 200 mg / body can directly and unambiguously interpret the range as, for example, 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、60mg / body、60.5mg / body、61mg / body、61.5mg / body、62mg / 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 / body、68 mg / body、68.5 mg / body、69 mg / body、69.5 mg / body、70 mg / body、70.5 mg / body、71 mg / body、71.5 mg / body、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 / body、93 mg / body、93.5 mg / body、94 mg / body、94.5 mg / body、95 mg / body、95.5 mg / body、96 mg / body、96.5 mg / body、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 / body、118 mg / body、118.5 mg / body、119 mg / body、119.5 mg / body、120 mg / body、120.5 mg / body、121 mg / body、121.5 mg / body、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 / body、143 mg / body、143.5 mg / body、144 mg / body、144.5 mg / body、145 mg / body、145.5 mg / body、146 mg / body、146.5 mg / body、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 / body、168 mg / body、168.5 mg / body、169 mg / body、169.5 mg / body、170 mg / body、170.5 mg / body、171 mg / body、171.5 mg / body、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 / body、193 mg / body、193.5 mg / body、194 mg / body、194.5 mg / body、195 mg / body、195.5 mg / body、196 mg / body、196.5 mg / body、197 mg / body、197.5 mg / body、198 mg / body、198.5 mg / body、199 mg / body、199.5 mg / body、200mg / body etc.

[0053] Alternatively, in another non-limiting embodiment, for a subject suffering from or at risk of suffering from atopic dermatitis, for example, a human child, the dose is 0.01 mg to 10 mg / kg, for example, 0.05 mg to 7.5 mg / kg, 0.075 mg to 5 mg / kg, or 0.1 mg to 3 mg / kg, preferably, for example, 0.1 mg to 0.25 mg / kg, 0.1 mg to 0.3 mg / kg, 0.1 mg to 0.5 mg / kg, 0.1 mg to 0.75 mg / kg, 0.1 mg to 1 mg / kg, 0.1 mg to 1.5 mg / kg, 0.1 mg to 2 mg / kg, 0.1 mg to 3 mg / kg, 0.125mg~0.25mg / kg, 0.125mg~0.3mg / kg, 0.125mg~0.5mg / kg, 0.125mg~0.75mg / kg, 0.125mg~1mg / kg, 0.125mg~1.5mg / kg, 0.125mg~2mg / kg, 0. 125mg~3mg / kg, 0.2mg~0.3mg / kg, 0.2mg~0.5mg / kg, 0.2mg~0.75mg / kg, 0.2mg~1mg / kg, 0.2mg~1.5mg / kg, 0.2mg~2mg / kg, 0.2mg~3mg / kg, 0.25mg~0.3mg / kg, 0.25mg~0.5mg / kg, 0.25mg~0.75mg / kg, 0.25mg~1mg / kg, 0.25mg~1.5mg / kg, 0.25mg~2mg / kg, 0.25mg~3mg / kg, 0.3mg~0.5mg / kg, 0.3mg~0.75mg / kg, 0.3mg~1mg / kg, 0.3mg~1.5mg / kg, 0.3mg~2mg / kg, 0.3mg~3mg / kg, 0.5mg~0.75mg / kg, 0.5mg~1mg / kg, 0.5mg~1.5mg / kg, 0.5mg~2mg / kg, 0.5mg~3mg / kg , 0.75mg~1mg / kg, 0.75mg~1.5mg / kg, 0.75mg~2mg / kg, 0.75mg~3mg / kg, 1mg~1.5mg / kg, 1mg~2mg / kg, 1mg~3mg / kg, 1.5mg~2mg / kg, 1.5mg~3mg / kg, 2mg~3 mg / kg, 0.15mg~2.9mg / kg, 0.2mg~2.8mg / kg, 0.25mg~2.7mg / kg, 0.3mg~2.6mg / kg, 0.35mg~2.5mg / kg, 0.4mg~2.4mg / kg, 0.425mg~2.3mg / kg, 0.45mg~2.A single dose selected from the following may be selected as the dose of the IL-31 antagonist of the present disclosure: 2 mg / kg, 0.475 mg to 2.1 mg / kg, or 0.5 mg to 2 mg / kg, or, for example, more preferably 0.5 mg to 1.5 mg / kg, and may be repeatedly administered in equal amounts at the same administration intervals as described above. For the avoidance of doubt, for example, when 0.01mg-10mg / kg is stated, the following ranges are accepted: 0.01mg / kg, 0.015mg / kg, 0.02mg / kg, 0.025mg / kg, 0.03mg / kg, 0.035mg / kg, 0.04mg / kg, 0.125mg / kg, 0.49mg / kg, 0.495mg / kg, 0.5mg / kg, 0.505mg / kg, 0.51mg / kg, 0.98mg / kg, 0.985mg / kg, 0.99mg / kg, 0.995mg / kg, 1mg / kg, 1.005mg / kg, 1.01mg / kg, 1.49mg / kg, 1.495mg / kg, 1.5 Any dosage between 0.01 mg and 10 mg / kg in increments of 0.005 mg / kg, such as 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, 10 mg / kg, and the like, is intended to be individually and specifically set forth herein. Therefore, for example, a person skilled in the art who comes across the description of 0.1 mg to 3 mg / kg can directly and unambiguously understand, 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, 0.32mg / kg、0.33mg / kg、0.34mg / kg、0.35mg / kg、0.36mg / kg、0.37mg / kg、0.38mg / kg、0.39mg / kg、0.4mg / kg、0.41mg / kg、0.42mg / kg、0.43mg / kg、0.44mg / kg、0.45mg / kg、0.46mg / kg、0.47mg / kg、0.48mg / kg、0.49mg / kg、0.5mg / kg、0.51mg / kg、0.52mg / kg、0.53mg / kg、0.54mg / kg、0.55mg / kg、0.56mg / kg、0.57mg / kg、0.58mg / kg、0.59mg / kg、0.6mg / kg、0.61mg / kg、0.62mg / kg、0.63mg / kg、0.64mg / kg、0.65mg / kg、0.66mg / kg、0.67mg / kg、0.68mg / kg、0.69mg / kg、0.7mg / kg、0.71mg / kg、0.72mg / kg、0.73mg / kg、0.74mg / kg、0.75mg / kg、0.76mg / kg、0.77mg / kg、0.78mg / kg、0.79mg / kg、0.8mg / kg、0.81mg / kg、0.82mg / kg、0.83mg / kg、0.84mg / kg、0.85mg / kg、0.86mg / kg、0.87mg / kg、0.88mg / kg、0.89mg / kg、0.9mg / kg、0.91mg / kg、0.92mg / kg、0.93mg / kg、0.94mg / kg、0.95mg / kg、0.96mg / kg、0.97mg / kg、0.98mg / kg、0.99mg / kg、1mg / kg、1.01mg / kg、1.02mg / kg、1.03mg / kg、1.04mg / kg、1.05mg / kg、1.06mg / kg、1.07mg / kg、1.08mg / kg、1.09mg / kg、1.1mg / kg、1.11mg / kg、1.12mg / kg、1.13mg / kg、1.14mg / kg、1.15mg / kg、1.16mg / kg、1.17mg / kg、1.18mg / kg、1.19mg / kg、1.2mg / kg、1.21mg / kg、1.22mg / kg、1.23mg / kg、1.24mg / kg、1.25mg / kg、1.26mg / kg、1.27mg / kg、1.28mg / kg、1.29mg / kg、1.3mg / kg、1.31mg / kg、1.32mg / kg、1.33mg / kg、1.34mg / kg、1.35mg / kg、1.36mg / kg、1.37mg / kg、1.38mg / kg、1.39mg / kg、1.4mg / kg、1.41mg / kg、1.42mg / kg、1.43mg / kg、1.44mg / kg、1.45mg / kg、1.46mg / kg、1.47mg / kg、1.48mg / kg、1.49mg / kg、1.5mg / kg、1.51mg / kg、1.52mg / kg、1.53mg / kg、1.54mg / kg、1.55mg / kg、1.56mg / kg、1.57mg / kg、1.58mg / kg、1.59mg / kg、1.6mg / kg、1.61mg / kg、1.62mg / kg、1.63mg / kg、1.64mg / kg、1.65mg / kg、1.66mg / kg、1.67mg / kg、1.68mg / kg、1.69mg / kg、1.7mg / kg、1.71mg / kg、1.72mg / kg、1.73mg / kg、1.74mg / kg、1.75mg / kg、1.76mg / kg、1.77mg / kg、1.78mg / kg、1.79mg / kg、1.8mg / kg、1.81mg / kg、1.82mg / kg、1.83mg / kg、1.84mg / kg、1.85mg / kg、1.86mg / kg、1.87mg / kg、1.88mg / kg、1.89mg / kg、1.9mg / kg、1.91mg / kg、1.92mg / kg、1.93mg / kg、1.94mg / kg、1.95mg / kg、1.96mg / kg、1.97mg / kg、1.98mg / kg、1.99mg / kg、2mg / kg、2.01mg / kg、2.02mg / kg、2.03mg / kg、2.04mg / kg、2.05mg / kg、2.06mg / kg、2.07mg / kg、2.08mg / kg、2.09mg / kg、2.1mg / kg、2.11mg / kg、2.12mg / kg、2.13mg / kg、2.14mg / kg、2.15mg / kg、2.16mg / kg、2.17mg / kg、2.18mg / kg、2.19mg / kg、2.2mg / kg、2.21mg / kg、2.22mg / kg、2.23mg / kg、2.24mg / kg、2.25mg / kg、2.26mg / kg、2.27mg / kg、2.28mg / kg、2.29mg / kg、2.3mg / kg、2.31mg / kg、2.32mg / kg、2.33mg / kg、2.34mg / kg, 2.35mg / kg, 2.36mg / kg, 2.37mg / kg, 2.38mg / kg, 2.39mg / kg, 2.4mg / kg, 2.41mg / kg, 2.42mg / k g, 2.43mg / kg, 2.44mg / kg, 2.45mg / kg, 2.46mg / kg, 2.47mg / kg, 2.48mg / kg, 2.49mg / kg, 2.5mg / kg, 2.51m g / kg, 2.52mg / kg, 2.53mg / kg, 2.54mg / kg, 2.55mg / kg, 2.56mg / kg, 2.57mg / kg, 2.58mg / kg, 2.59mg / kg, 2 .6mg / kg, 2.61mg / kg, 2.62mg / kg, 2.63mg / kg, 2.64mg / kg, 2.65mg / kg, 2.66mg / kg, 2.67mg / kg, 2.68mg / k g, 2.69mg / kg, 2.7mg / kg, 2.71mg / kg, 2.72mg / kg, 2.73mg / kg, 2.74mg / kg, 2.75mg / kg, 2.76mg / kg, 2.77 mg / kg, 2.78mg / kg, 2.79mg / kg, 2.8mg / kg, 2.81mg / kg, 2.82mg / kg, 2.83mg / kg, 2.84mg / kg, 2.85mg / kg, 2 It is of course understood that values such as 0.86mg / kg, 2.87mg / kg, 2.88mg / kg, 2.89mg / kg, 2.9mg / kg, 2.91mg / kg, 2.92mg / kg, 2.93mg / kg, 2.94mg / kg, 2.95mg / kg, 2.96mg / kg, 2.97mg / kg, 2.98mg / kg, 2.99mg / kg, and 3mg / kg are individually and specifically listed.

[0054] Thus, an embodiment of repeated administration of the IL-31 antagonist of the present disclosure at equal and identical dose intervals at a predetermined administration interval and a predetermined dose (dosage) may be "0.1 mg to 1000 mg / body / 1 day to 12 weeks." Here, for example, "0.1 mg to 1000 mg / body / 1 day to 12 weeks" herein contemplates repeatedly administering the IL-31 antagonist of the present disclosure to a subject at equal and identical dose intervals, with a single dose selected from 0.1 mg to 1000 mg being selected as the dose of the IL-31 antagonist of the present disclosure (e.g., 100 mg / body) and an arbitrary single dose interval selected from 1 day to 12 weeks being selected as the dose interval of the IL-31 antagonist of the present disclosure (e.g., 4 weeks). For example, "100 mg / body / 4 weeks" refers to 100 mg / body of an IL-31 antagonist according to the present disclosure repeatedly administered to a subject every 4 weeks in an equal amount and at the same administration interval. Although not limited thereto, the repeated administration of an IL-31 antagonist according to the present disclosure at a predetermined administration interval and a predetermined dose (administration amount) in an equal amount and at the same administration interval is preferably 0.1 mg to 1000 mg / body / 2 to 8 weeks, and may be, for example, 0.1 mg to 1000 mg / body / 2 weeks, 0.1 mg to 1000 mg / body / 4 weeks, 0.1 mg to 1000 mg / body / 6 weeks, or 0.1 mg to 1000 mg / body / 8 weeks. Alternatively, it is more preferable that the dose is 0.2 mg to 360 mg / body / 2 to 8 weeks, for example, 0.2 mg to 360 mg / body / 2 weeks, 0.2 mg to 360 mg / body / 4 weeks, 0.2 mg to 360 mg / body / 6 weeks, or 0.The dose may be 2 mg to 360 mg per body per 8 weeks. Alternatively, for example, it is more preferably 10 mg to 200 mg per body per 2 to 8 weeks, and may be, for example, 10 mg to 200 mg per body per 2 weeks, 10 mg to 200 mg per body per 4 weeks, 10 mg to 200 mg per body per 6 weeks, or 10 mg to 200 mg per body per 8 weeks. Alternatively, for example, it is even more preferably 10 mg to 100 mg per body per 2 to 8 weeks, and may be, for example, 10 mg to 100 mg per body per 2 weeks, 10 mg to 100 mg per body per 4 weeks, 10 mg to 100 mg per body per 6 weeks, or 10 mg to 100 mg per body per 8 weeks. Alternatively, as an example, the dose may be 25 mg to 100 mg / body / 4 weeks, 25 mg to 80 mg / body / 4 weeks, 25 mg to 75 mg / body / 4 weeks, 50 mg to 100 mg / body / 4 weeks, 50 mg to 80 mg / body / 4 weeks, or 50 mg to 75 mg / body / 4 weeks, or 10 mg to 50 mg / body / 2 weeks, or 20 mg to 40 mg / body / 2 weeks. In one non-limiting embodiment, it is, for example, 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 / bo dy / 4 weeks, 54mg / body / 4 weeks, 54.5mg / body / 4 weeks, 55mg / body / 4 weeks, 55.5mg / body / 4 weeks, 56mg / body / 4 weeks, 56.5mg / body / 4 weeks, 57mg / body / 4 weeks, 57.5mg / body / 4 weeks, 58mg / body / 4 week, 58.5mg / body / 4 weeks, 59mg / body / 4 weeks, 59.5mg / body / 4 weeks, 60mg / body / 4 weeks, 60.5mg / body / 4 weeks, 61mg / body / 4 weeks, 61.5mg / body / 4 weeks, 62mg / body / 4 weeks, 62.5mg / body / 4 weeks , 63mg / body / 4 weeks, 63.5mg / body / 4 weeks, 64mg / body / 4 weeks, 64.5mg / body / 4 weeks, 65mg / body / 4 weeks, 65.5mg / body / 4 weeks, 66mg / body / 4 weeks, 66.5mg / body / 4 weeks, 67mg / body / 4 weeks, 67.5mg / body / 4 weeks, 68mg / body / 4 weeks, 68.5mg / body / 4 weeks, 69mg / body / 4 weeks, 69.5mg / body / 4 weeks, 70mg / body / 4 weeks, 70.5mg / body / 4 weeks, 71mg / body / 4 weeks, 71.5mg / body / 4 weeks, 72mg / body / 4 weeks, 72.5mg / body / 4 weeks, 73mg / body / 4 weeks, 73.5mg / body / 4 weeks, 74mg / body / 4 weeks, 74.5mg / body / 4 weeks, 75mg / body / 4 weeks, 75.5mg / body / 4 weeks, 76mg / body / 4 weeks, 76.5mg / body / 4 weeks, 77mg / body / 4 weeks, 77.5mg / body / 4 weeks, 78mg / body / 4 weeks, 78.5mg / body / 4 weeks, 79mg / body / 4 weeks, 79.5mg / body / 4 weeks, 80mg / body / 4 weeks, 80.5mg / body / 4 weeks, 81mg / body / 4 weeks, 81.5mg / body / 4 weeks, 82mg / body / 4 weeks, 82.5mg / body / 4 weeks, 83mg / body / 4 weeks, 83.5mg / body / 4 weeks, 84mg / body / 4 weeks, 84.5mg / body / 4 weeks, 85mg / body / 4 weeks, 85.5mg / body / 4 weeks, 86mg / body / 4 weeks, 86.5mg / body / 4 weeks, 87mg / body / 4 weeks, 87.5mg / body / 4 weeks, 88mg / body / 4 weeks, 88.5mg / body / 4 weeks, 89mg / body / 4 weeks, 89.5mg / body / 4 weeks, 90mg / body / 4 weeks, 90.5mg / body / 4 weeks, 91mg / body / 4 weeks, 91.5mg / body / 4 weeks, 92mg / body / 4 weeks, 92.5mg / body / 4 weeks, 93mg / body / 4 weeks, 93.5mg / body / 4 weeks , 94mg / body / 4 weeks, 94.5mg / body / 4 weeks, 95mg / body / 4 weeks, 95.5mg / body / 4 weeks, 96mg / body / 4 weeks, 96.5mg / body / 4 weeks, 97mg / body / 4 weeks, 97.5mg / body / 4 weeks, 98mg / body / 4 weeks, 98.5mg / body / 4 weeks, 99mg / body / 4 weeks, 99.5mg / body / 4 weeks, 100mg / body / 4 weeks, 100.5mg / body / 4 weeks, 101mg / body / 4 weeks, 101.5mg / body / 4 weeks, 102mg / body / 4 weeks, 102.5mg / body / 4 weeks, 103mg / body / 4 weeks, 103.5mg / body / 4 weeks, 104mg / body / 4 weeks, 104.5mg / body / 4 weeks, 105mg / body / 4 weeks, 105.5mg / body / 4 weeks, 106mg / body / 4 weeks, 106.5mg / body / 4 weeks, 107mg / body / 4 weeks, 107.5mg / body / 4 weeks, 108mg / body / 4 weeks, 108.5mg / body / 4 weeks, 109mg / body / 4 weeks, 109.5mg / body / 4 weeks, 110mg / body / 4 weeks, 110.5mg / body y / 4 weeks, 111mg / body / 4 weeks, 111.5mg / body / 4 weeks, 112mg / body / 4 weeks, 112.5mg / body / 4 weeks, 113mg / body / 4 weeks, 113.5mg / body / 4 weeks, 114mg / body / 4 weeks, 114.5mg / body / 4 weeks, 115mg / body / 4 weeks, 115.5mg / body / 4 weeks, 116mg / body / 4 weeks, 116.5mg / body / 4 weeks, 117mg / body / 4 weeks, 117.5mg / body / 4 weeks, 118mg / body / 4 weeks, 118.5mg / body / 4 weeks, 119 mg / body / 4 weeks, 119.5mg / body / 4 weeks, 120mg / body / 4 weeks, 120.5mg / body / 4 weeks, 121mg / body / 4 weeks, 121.5mg / body / 4 weeks, 122mg / body / 4 weeks, 122.5mg / body / 4 weeks, 123mg / body / 4 weeks, 123.5mg / body / 4 weeks, 124mg / body / 4 weeks, 124.5mg / body / 4 weeks, 125mg / body / 4 weeks, 125.5mg / body / 4 weeks, 126mg / body / 4 weeks, 126.5mg / body / 4 weeks, 127mg / body / 4 weeks, 127.5mg / body / 4 weeks, 128mg / body / 4 weeks, 128.5mg / body / 4 weeks, 129mg / body / 4 weeks, 129.5mg / body / 4 weeks, 130mg / body / 4 weeks, 130.5mg / body / 4 weeks, 131mg / body / 4 weeks, 131.5mg / body / 4 weeks, 132mg / body / 4 weeks, 132.5mg / body / 4 weeks, 133mg / body / 4 weeks, 133.5mg / body / 4 weeks, 134mg / body / 4 weeks, 134.5mg / body / 4 weeks, 135mg / body / 4 weeks, 135.5mg / body / 4 weeks, 136mg / body / 4 weeks, 136.5mg / body / 4 weeks, 137mg / body / 4 weeks, 137.5mg / body / 4 weeks, 138mg / body / 4 weeks, 138.5mg / body / 4 weeks, 139mg / body / 4 weeks, 139.5mg / body / 4 weeks, 140mg / body / 4 weeks, 140.5mg / body / 4 weeks, 141mg / body / 4 weeks, 141.5mg / body / 4 weeks, 142mg / body / 4 weeks, 142.5mg / body / 4 weeks, 143mg / body / 4 weeks, 143.5mg / body y / 4 weeks, 144mg / body / 4 weeks, 144.5mg / body / 4 weeks, 145mg / body / 4 weeks, 145.5mg / body / 4 weeks, 146mg / body / 4 weeks, 146.5mg / body / 4 weeks, 147mg / body / 4 weeks, 147.5mg / body / 4 weeks, 148mg / body / 4 weeks, 148.5mg / body / 4 weeks, 149mg / body / 4 weeks, 149.5mg / body / 4 weeks, 150mg / body / 4 weeks, 150.5mg / body / 4 weeks, 151mg / body / 4 weeks, 151.5mg / body / 4 weeks, 152 mg / body / 4 weeks, 152.5mg / body / 4 weeks, 153mg / body / 4 weeks, 153.5mg / body / 4 weeks, 154mg / body / 4 weeks, 154.5mg / body / 4 weeks, 155mg / body / 4 weeks, 155.5mg / body / 4 weeks, 156mg / body / 4 weeks, 156.5mg / body / 4 weeks, 157mg / body / 4 weeks, 157.5mg / body / 4 weeks, 158mg / body / 4 weeks, 158.5mg / body / 4 weeks, 159mg / body / 4 weeks, 159.5mg / body / 4 weeks, 160mg / body / 4 weeks, 160.5mg / body / 4 weeks, 161mg / body / 4 weeks, 161.5mg / body / 4 weeks, 162mg / body / 4 weeks, 162.5mg / body / 4 weeks, 163mg / body / 4 weeks, 163.5mg / body / 4 weeks, 164mg / body / 4 weeks, 164.5mg / body / 4 weeks, 165mg / body / 4 weeks, 165.5mg / body / 4 weeks, 166mg / body / 4 weeks, 166.5mg / body / 4 weeks, 167mg / body / 4 weeks, 167.5mg / body / 4 weeks, 168mg / body / 4 weeks, 168.5mg / body / 4 weeks, 169mg / body / 4 weeks, 169.5mg / body / 4 weeks, 170mg / body / 4 weeks, 170.5mg / body / 4 weeks, 171mg / body / 4 weeks, 171.5mg / body / 4 weeks, 172mg / body / 4 weeks, 172.5mg / body / 4 weeks, 173mg / body / 4 weeks, 173.5mg / body / 4 weeks, 174mg / body / 4 weeks, 174.5mg / body / 4 weeks, 175mg / body / 4 weeks, 175.5mg / body / 4 weeks, 176mg / body / 4 weeks, 176.5mg / body / 4 weeks, 177mg / body / 4 weeks, 177.5mg / body / 4 weeks, 178mg / body / 4 weeks, 178.5mg / body / 4 weeks, 179mg / body / 4 weeks, 179.5mg / body / 4 weeks, 180mg / body / 4 weeks, 180.5mg / body / 4 weeks, 181mg / body / 4 weeks, 181.5mg / body / 4 weeks, 182mg / body / 4 weeks, 182.5mg / body / 4 weeks, 183mg / body / 4 weeks, 183.5mg / body / 4 weeks, 184 mg / body / 4 weeks, 184.5mg / body / 4 weeks, 185mg / body / 4 weeks, 185.5mg / body / 4 weeks, 186mg / body / 4 weeks, 186.5mg / body / 4 weeks, 187mg / body / 4 weeks, 187.5mg / body / 4 weeks, 188mg / body / 4 weeks, 188.5mg / body / 4 weeks, 189mg / body / 4 weeks, 189.5mg / body / 4 weeks, 190mg / body / 4 weeks, 190.5mg / body / 4 weeks, 191mg / body / 4 weeks, 191.5mg / body y / 4 weeks, 192mg / body / 4 weeks, 192.5mg / body / 4 weeks, 193mg / body / 4 weeks, 193.5mg / body / 4 weeks, 194mg / body / 4 weeks, 194.5mg / body / 4 weeks, 195mg / body / 4 weeks, 195.5mg / body / 4 weeks, 196mg / body / 4 weeks, 196.5mg / body / 4 weeks, 197mg / body / 4 weeks, 197.5mg / body / 4 weeks, 198mg / body / 4 weeks, 198.5mg / body / 4 weeks, 199mg / body / 4 weeks, 199.It may be, for example, 5 mg / body / 4 weeks, 200 mg / body / 4 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, for example, 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, 83.5mg / body / 6 weeks, 84mg / body / 6 weeks, 84.5mg / body / 6 weeks, 85mg / body / 6 weeks, 85.5mg / body / 6 weeks, 86mg / body / 6 weeks, 86.5mg / body / 6 weeks, 87mg / body / 6 weeks, 87.5mg / body / 6 weeks, 88mg / body / 6 weeks, 88.5mg / body / 6 weeks, 89mg / body / 6 weeks, 89.5mg / body / 6 weeks, 90mg / body / 6 weeks, 90.5mg / body / 6 weeks, 91mg / body / 6 weeks, 91.5mg / body / 6 weeks, 92mg / body / 6 weeks week, 92.5mg / body / 6 weeks, 93mg / body / 6 weeks, 93.5mg / body / 6 weeks, 94mg / body / 6 weeks, 94.5mg / body / 6 weeks, 95mg / body / 6 weeks, 95.5mg / body / 6 weeks, 96mg / body / 6 weeks, 96.5mg / body / 6 weeks, 97mg / body / 6 weeks, 97.5mg / body / 6 weeks, 98mg / body / 6 weeks, 98.5mg / body / 6 weeks, 99mg / body / 6 weeks, 99.5mg / body / 6 weeks, 100mg / body / 6 weeks, 100.5mg / body / 6 weeks, 101mg / body / 6 weeks g / body / 6 weeks, 101.5mg / body / 6 weeks, 102mg / body / 6 weeks, 102.5mg / body / 6 weeks, 103mg / body / 6 weeks, 103.5mg / body / 6 weeks, 104mg / body / 6 weeks, 104.5mg / body / 6 weeks, 105mg / body / 6 weeks, 105.5mg / body / 6 weeks, 106mg / body / 6 weeks, 106.5mg / body / 6 weeks, 107mg / body / 6 weeks, 107.5mg / body / 6 weeks, 108mg / body / 6 weeks, 108.5mg / body / 6 weeks, 109mg / body / 6 weeks, 109.5mg / body / 6 weeks, 110mg / body / 6 weeks, 110.5mg / body / 6 weeks, 111mg / body / 6 weeks, 111.5mg / body / 6 weeks, 112mg / body / 6 weeks, 112.5mg / body / 6 weeks, 113mg / body / 6 weeks, 113.5mg / body / 6 weeks, 114mg / body / 6 weeks, 114.5mg / body / 6 weeks, 115mg / body / 6 weeks, 115.5mg / body / 6 weeks, 116mg / body / 6 weeks, 116.5mg / body / 6 weeks, 117mg / body / 6 weeks, 117.5mg / body / 6 weeks, 118mg / body / 6 weeks, 118.5mg / body / 6 weeks, 119mg / body / 6 weeks, 119.5mg / body / 6 weeks, 120mg / body / 6 weeks, 120.5mg / body / 6 weeks, 121mg / body / 6 weeks, 121.5mg / body / 6 weeks, 122mg / body / 6 weeks, 122.5mg / body / 6 weeks, 123mg / body / 6 weeks, 123.5mg / body / 6 weeks, 124mg / body / 6 weeks, 124.5mg / body / 6 weeks, 125mg / body / 6 weeks, 125.5mg / body / 6 weeks, 126mg / body / 6 weeks, 126.5mg / body / 6 weeks, 127mg / body / 6 weeks, 127.5mg / body / 6 weeks, 128mg / body / 6 weeks, 128.5mg / body / 6 weeks, 129mg / body / 6 weeks, 129.5mg / body / 6 weeks, 130mg / body / 6 weeks, 130.5mg / body / 6 weeks, 131mg / body / 6 weeks, 131.5mg / body / 6 weeks, 132mg / body / 6 weeks, 132.5mg / body / 6 weeks, 13 3mg / body / 6 weeks, 133.5mg / body / 6 weeks, 134mg / body / 6 weeks, 134.5mg / body / 6 weeks, 135mg / body / 6 weeks, 135.5mg / body / 6 weeks, 136mg / body / 6 weeks, 136.5mg / body / 6 weeks, 137mg / body / 6 weeks, 137.5mg / body / 6 weeks, 138mg / body / 6 weeks, 138.5mg / body / 6 weeks, 139mg / body / 6 weeks, 139.5mg / body / 6 weeks, 140mg / body / 6 weeks, 140.5mg / body dy / 6 weeks, 141mg / body / 6 weeks, 141.5mg / body / 6 weeks, 142mg / body / 6 weeks, 142.5mg / body / 6 weeks, 143mg / body / 6 weeks, 143.5mg / body / 6 weeks, 144mg / body / 6 weeks, 144.5mg / body / 6 weeks, 145mg / body / 6 weeks, 145.5mg / body / 6 weeks, 146mg / body / 6 weeks, 146.5mg / body / 6 weeks, 147mg / body / 6 weeks, 147.5mg / body / 6 weeks, 148mg / body / 6 weeks, 1. 48.5mg / body / 6 weeks, 149mg / body / 6 weeks, 149.5mg / body / 6 weeks, 150mg / body / 6 weeks, 150.5mg / body / 6 weeks, 151mg / body / 6 weeks, 151.5mg / body / 6 weeks, 152mg / body / 6 weeks, 152.5mg / body / 6 weeks, 153mg / body / 6 weeks, 153.5mg / body / 6 weeks, 154mg / body / 6 weeks, 154.5mg / body / 6 weeks, 155mg / body / 6 weeks, 155.5mg / body / 6 weeks, 156mg / body / 6 weeks, 156.5mg / body ody / 6 weeks, 157mg / body / 6 weeks, 157.5mg / body / 6 weeks, 158mg / body / 6 weeks, 158.5mg / body / 6 weeks, 159mg / body / 6 weeks, 159.5mg / body / 6 weeks, 160mg / body / 6 weeks, 160.5mg / body / 6 weeks, 161mg / body / 6 weeks, 161.5mg / body / 6 weeks, 162mg / body / 6 weeks, 162.5mg / body / 6 weeks, 163mg / body / 6 weeks, 163.5mg / body / 6 weeks, 164mg / body / 6 weeks, 164.5mg / body / 6 weeks, 65mg / body / 6 weeks, 165.5mg / body / 6 weeks, 166mg / body / 6 weeks, 166.5mg / body / 6 weeks, 167mg / body / 6 weeks, 167.5mg / body / 6 weeks, 168mg / body / 6 weeks, 168.5mg / body / 6 weeks, 169mg / body / 6 weeks, 169.5mg / body / 6 weeks, 170mg / body / 6 weeks, 170.5mg / body / 6 weeks, 171mg / body / 6 weeks, 171.5mg / body / 6 weeks, 172mg / body / 6 weeks, 172.5mg / body / 6 weeks, 173mg / body y / 6 weeks, 173.5mg / body / 6 weeks, 174mg / body / 6 weeks, 174.5mg / body / 6 weeks, 175mg / body / 6 weeks, 175.5mg / body / 6 weeks, 176mg / body / 6 weeks, 176.5mg / body / 6 weeks, 177mg / body / 6 weeks, 177.5mg / body / 6 weeks, 178mg / body / 6 weeks, 178.5mg / body / 6 weeks, 179mg / body / 6 weeks, 179.5mg / body / 6 weeks, 180mg / body / 6 weeks, 180.5mg / body / 6 weeks, 181mg / body / 6 weeks, 181.It may be, for example, 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, 200 mg / body / 6 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, for example, 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, 63.5mg / body / 8 weeks, 64mg / body / 8 weeks, 64.5mg / body / 8 weeks, 65mg / body / 8 weeks, 65.5mg / body / 8 weeks, 66mg / body / 8 weeks, 66.5mg / body / 8 weeks, 67mg / body / 8 weeks, 67.5mg / body / 8 weeks, 68mg / body / 8 weeks, 68.5mg / body / 8 weeks, 69mg / body / 8 weeks, 69.5mg / body / 8 weeks, 70mg / body / 8 weeks, 70.5mg / body / 8 weeks, 71mg / body / 8 weeks, 71.5mg / body / 8 weeks, 72mg / body / 8 weeks, 72.5mg / body / 8 weeks, 73mg / body / 8 weeks, 73.5mg / body / 8 weeks, 74mg / body / 8 weeks, 74.5mg / body / 8 weeks, 75mg / body / 8 weeks, 75.5mg / body / 8 weeks, 76mg / body / 8 weeks, 76.5mg / body / 8 weeks, 77mg / body / 8 weeks, 77.5mg / body / 8 weeks, 78mg / body / 8 weeks, 78.5mg / body / 8 weeks, 79mg / body / 8 weeks, 79.5mg / body / 8 weeks, 80mg / body / 8 weeks, 80.5mg / body / 8 weeks, 81 mg / body / 8 weeks, 81.5mg / body / 8 weeks, 82mg / body / 8 weeks, 82.5mg / body / 8 weeks, 83mg / body / 8 weeks, 83.5mg / body / 8 weeks, 84mg / body / 8 weeks, 84.5mg / body / 8 weeks, 85mg / body / 8 weeks, 85.5mg / body / 8 weeks, 86mg / body / 8 weeks, 86.5mg / body / 8 weeks, 87mg / body / 8 weeks, 87.5mg / body / 8 weeks, 88mg / body / 8 weeks, 88.5mg / body / 8 weeks, 89mg / body / 8 weeks, 89.5mg / body y / 8 weeks, 90mg / body / 8 weeks, 90.5mg / body / 8 weeks, 91mg / body / 8 weeks, 91.5mg / body / 8 weeks, 92mg / body / 8 weeks, 92.5mg / body / 8 weeks, 93mg / body / 8 weeks, 93.5mg / body / 8 weeks, 94mg / body / 8 weeks, 94.5mg / body / 8 weeks, 95mg / body / 8 weeks, 95.5mg / body / 8 weeks, 96mg / body / 8 weeks, 96.5mg / body / 8 weeks, 97mg / body / 8 weeks, 97.5mg / body / 8 weeks, 98mg / body / 8 weeks, 98.5mg / body / 8 weeks, 99mg / body / 8 weeks, 99.5mg / body / 8 weeks, 100mg / body / 8 weeks, 100.5mg / body / 8 weeks, 101mg / body / 8 weeks, 101.5mg / body / 8 weeks, 102mg / body / 8 weeks, 102.5mg / body / 8 weeks, 103mg / body / 8 weeks, 103.5mg / body / 8 weeks, 104mg / body / 8 weeks, 104.5mg / body / 8 weeks, 105mg / body / 8 weeks, 105.5mg / body / 8 weeks, 106mg / body / 8 weeks, 106.5mg / body / 8 weeks, 107mg / body / 8 weeks, 107.5mg / body / 8 weeks, 108mg / body / 8 weeks, 108.5mg / body / 8 weeks, 109mg / body / 8 weeks, 109.5mg / body / 8 weeks, 110mg / body / 8 weeks, 110.5mg / body / 8 weeks, 111mg / body / 8 weeks, 111.5mg / body / 8 weeks, 112mg / body / 8 weeks, 112.5mg / body / 8 weeks, 113mg / body / 8 weeks, 113.5mg / body / 8 weeks, 114mg / body / 8 weeks, 114.5mg / body / 8 weeks, 115mg / body / 8 weeks g / body / 8 weeks, 115.5mg / body / 8 weeks, 116mg / body / 8 weeks, 116.5mg / body / 8 weeks, 117mg / body / 8 weeks, 117.5mg / body / 8 weeks, 118mg / body / 8 weeks, 118.5mg / body / 8 weeks, 119mg / body / 8 weeks, 119.5mg / body / 8 weeks, 120mg / body / 8 weeks, 120.5mg / body / 8 weeks, 121mg / body / 8 weeks, 121.5mg / body / 8 weeks, 122mg / body / 8 weeks, 122.5mg / body / 8 weeks, 123mg / body / 8 weeks, 123.5mg / body / 8 weeks, 124mg / body / 8 weeks, 124.5mg / body / 8 weeks, 125mg / body / 8 weeks, 125.5mg / body / 8 weeks, 126mg / body / 8 weeks, 126.5mg / body / 8 weeks, 127mg / body / 8 weeks, 127.5mg / body / 8 weeks, 128mg / body / 8 weeks, 128.5mg / body / 8 weeks, 129mg / body / 8 weeks, 129.5mg / body / 8 weeks, 130mg / body / 8 weeks, 130.5mg / body / 8 weeks, 131mg / body / 8 weeks, 131.5mg / body / 8 weeks, 132mg / body / 8 weeks, 132.5mg / body / 8 weeks, 133mg / body / 8 weeks, 133.5mg / body / 8 weeks, 134mg / body / 8 weeks, 134.5mg / body / 8 weeks, 135mg / body / 8 weeks, 135.5mg / body / 8 weeks, 136mg / body / 8 weeks, 136.5mg / body / 8 weeks, 137mg / body / 8 weeks, 137.5mg / body / 8 weeks, 138mg / body / 8 weeks, 138.5mg / body / 8 weeks, 139mg / body / 8 weeks, 139.5mg / body y / 8 weeks, 140mg / body / 8 weeks, 140.5mg / body / 8 weeks, 141mg / body / 8 weeks, 141.5mg / body / 8 weeks, 142mg / body / 8 weeks, 142.5mg / body / 8 weeks, 143mg / body / 8 weeks, 143.5mg / body / 8 weeks, 144mg / body / 8 weeks, 144.5mg / body / 8 weeks, 145mg / body / 8 weeks, 145.5mg / body / 8 weeks, 146mg / body / 8 weeks, 146.5mg / body / 8 weeks, 147mg / body / 8 weeks, 147.5mg / body / 8 weeks, 148 mg / body / 8 weeks, 148.5mg / body / 8 weeks, 149mg / body / 8 weeks, 149.5mg / body / 8 weeks, 150mg / body / 8 weeks, 150.5mg / body / 8 weeks, 151mg / body / 8 weeks, 151.5mg / body / 8 weeks, 152mg / body / 8 weeks, 152.5mg / body / 8 weeks, 153mg / body / 8 weeks, 153.5mg / body / 8 weeks, 154mg / body / 8 weeks, 154.5mg / body / 8 weeks, 155mg / body / 8 weeks, 155.5mg / body / 8 weeks, 156mg / body / 8 weeks, 156.5mg / body / 8 weeks, 157mg / body / 8 weeks, 157.5mg / body / 8 weeks, 158mg / body / 8 weeks, 158.5mg / body / 8 weeks, 159mg / body / 8 weeks, 159.5mg / body / 8 weeks, 160mg / body / 8 weeks, 160.5mg / body / 8 weeks, 161mg / body / 8 weeks, 161.5mg / body / 8 weeks, 162mg / body / 8 weeks, 162.5mg / body / 8 weeks, 163mg / body / 8 weeks, 163.5mg / body / 8 weeks, 164mg / body / 8 weeks, 164.5mg / body / 8 weeks, 165mg / body / 8 weeks, 165.5mg / body / 8 weeks, 166mg / body / 8 weeks, 166.5mg / body / 8 weeks, 167mg / body / 8 weeks, 167.5mg / body / 8 weeks, 168mg / body / 8 weeks, 168.5mg / body / 8 weeks, 169mg / body / 8 weeks, 169.5mg / body / 8 weeks, 170mg / body / 8 weeks, 170.5mg / body / 8 weeks, 171mg / body / 8 weeks, 171.5mg / body / 8 weeks, 172mg / body / 8 weeks, 172.5mg / body y / 8 weeks, 173mg / body / 8 weeks, 173.5mg / body / 8 weeks, 174mg / body / 8 weeks, 174.5mg / body / 8 weeks, 175mg / body / 8 weeks, 175.5mg / body / 8 weeks, 176mg / body / 8 weeks, 176.5mg / body / 8 weeks, 177mg / body / 8 weeks, 177.5mg / body / 8 weeks, 178mg / body / 8 weeks, 178.5mg / body / 8 weeks, 179mg / body / 8 weeks, 179.5mg / body / 8 weeks, 180mg / body / 8 weeks, 180.5mg / body / 8 weeks, 181 mg / body / 8 weeks, 181.5mg / body / 8 weeks, 182mg / body / 8 weeks, 182.5mg / body / 8 weeks, 183mg / body / 8 weeks, 183.5mg / body / 8 weeks, 184mg / body / 8 weeks, 184.5mg / body / 8 weeks, 185mg / body / 8 weeks, 185.5mg / body / 8 weeks, 186mg / body / 8 weeks, 186.5mg / body / 8 weeks, 187mg / body / 8 weeks, 187.5mg / body / 8 weeks, 188mg / body / 8 weeks, 188.5mg / body / 8 weeks, 189mg / body / 8 weeks, 189.5mg / body / 8 weeks, 190mg / body / 8 weeks, 190.5mg / body / 8 weeks, 191mg / body / 8 weeks, 191.5mg / body / 8 weeks, 192mg / body / 8 weeks, 192.5mg / body / 8 weeks, 193mg / body / 8 weeks, 193.5mg / body / 8 weeks, 194mg / body / 8 weeks, 194.5mg / body / 8 weeks, 195mg / body / 8 weeks, 195.5mg / body / 8 weeks, 196mg / body / 8 weeks, 196.5mg / body / 8 weeks, 197mg / body / 8 weeks, 197.It may be, for example, 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, 200 mg / body / 8 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, for example, 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...5mg / body / 10 weeks, 79mg / body / 10 weeks, 79.5mg / body / 10 weeks, 80mg / body / 10 weeks, 80.5mg / body / 10 weeks, 81mg / body / 10 weeks, 81.5mg / body / 10 weeks, 82mg / body / 10 weeks, 82.5mg / body / 10 weeks, 83mg / body / 10 weeks, 83.5mg / body / 10 weeks, 84mg / body / 10 weeks, 84.5mg / body / 10 weeks, 85mg / body / 10 weeks, 85.5mg / body / 10 weeks, 86mg / body / 10 weeks, 86.5mg / body ody / 10 weeks, 87mg / body / 10 weeks, 87.5mg / body / 10 weeks, 88mg / body / 10 weeks, 88.5mg / body / 10 weeks, 89mg / body / 10 weeks, 89.5mg / body / 10 weeks, 90mg / body / 10 weeks, 90.5mg / body / 10 weeks, 91mg / body / 10 weeks, 91.5mg / body / 10 weeks, 92mg / body / 10 weeks, 92.5mg / body / 10 weeks, 93mg / body / 10 weeks, 93.5mg / body / 10 weeks, 94mg / body / 10 weeks, 94.5mg / body / 10 week, 95mg / body / 10 weeks, 95.5mg / body / 10 weeks, 96mg / body / 10 weeks, 96.5mg / body / 10 weeks, 97mg / body / 10 weeks, 97.5mg / body / 10 weeks, 98mg / body / 10 weeks, 98.5mg / body / 10 weeks, 99mg / body / 10 weeks, 99.5mg / body / 10 weeks, 100mg / body / 10 weeks, 100.5mg / body / 10 weeks, 101mg / body / 10 weeks, 101.5mg / body / 10 weeks, 102mg / body / 10 weeks, 102.5mg / body / 1 0 week, 103mg / body / 10 weeks, 103.5mg / body / 10 weeks, 104mg / body / 10 weeks, 104.5mg / body / 10 weeks, 105mg / body / 10 weeks, 105.5mg / body / 10 weeks, 106mg / body / 10 weeks, 106.5mg / body / 10 weeks, 107mg / body / 10 weeks, 107.5mg / body / 10 weeks, 108mg / body / 10 weeks, 108.5mg / body / 10 weeks, 109mg / body / 10 weeks, 109.5mg / body / 10 weeks, 110mg / body / 10 weeks, 110.5mg / body / 10 weeks, 111mg / body / 10 weeks, 111.5mg / body / 10 weeks, 112mg / body / 10 weeks, 112.5mg / body / 10 weeks, 113mg / body / 10 weeks, 113.5mg / body / 10 weeks, 114mg / body / 10 weeks, 114.5mg / body / 10 weeks, 115mg / body / 10 weeks, 115.5mg / body / 10 weeks, 116mg / body / 10 weeks, 116.5mg / body / 10 weeks, 117mg / body / 10 weeks, 117.5mg / body / 10 weeks, 118mg / body / 10 weeks, 118.5mg / body / 10 weeks, 119mg / body / 10 weeks, 119.5mg / body / 10 weeks, 120mg / body / 10 weeks, 120.5mg / body / 10 weeks, 121mg / body / 10 weeks, 121.5mg / body / 10 weeks, 122mg / body / 10 weeks, 122.5mg / body / 10 weeks, 123mg / body / 10 weeks, 123.5mg / body / 10 weeks, 124mg / body / 10 weeks, 124.5mg / body / 10 weeks, 125mg / body / 10 weeks, 125.5mg / 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, 134mg / body / 10 weeks, 134.5mg / body / 10 weeks, 135mg / body / 10 weeks, 135.5mg / body / 10 weeks, 136mg / body / 10 weeks, 136.5mg / body / 10 weeks, 137mg / body / 10 weeks, 137.5mg / body / 10 weeks, 138mg / body / 10 weeks, 138.5mg / body / 10 weeks, 139mg / body / 10 weeks, 139.5mg / body / 10 weeks, 140mg / body / 10 weeks, 140.5mg / body / 10 weeks, 141mg / body / 10 weeks, 141.5mg / body / 10 weeks, 142mg / body / 10 weeks, 142.5mg / body / 10 weeks, 143mg / body / 10 weeks, 143.5mg / body / 10 weeks, 144mg / body / 10 weeks, 144.5mg / body / 10 weeks, 14. 5mg / body / 10 weeks, 145.5mg / body / 10 weeks, 146mg / body / 10 weeks, 146.5mg / body / 10 weeks, 147mg / body / 10 weeks, 147.5mg / body / 10 weeks, 148mg / body / 10 weeks, 148.5mg / body / 10 weeks, 149mg / body / 10 weeks, 149.5mg / body / 10 weeks, 150mg / body / 10 weeks, 150.5mg / body / 10 weeks, 151mg / body / 10 weeks, 151.5mg / body / 10 weeks, 152mg / body / 10 weeks, 152.5mg / body / 10 weeks, 153mg / body / 10 weeks, 153.5mg / body / 10 weeks, 154mg / body / 10 weeks, 154.5mg / body / 10 weeks, 155mg / body / 10 weeks, 155.5mg / body / 10 weeks, 156mg / body / 10 weeks, 156.5mg / body / 10 weeks, 157mg / body / 10 weeks, 157.5mg / body / 10 weeks, 158mg / body / 10 weeks, 158.5mg / body / 10 weeks, 159mg / body / 10 weeks, 159.5mg / body / 10 weeks, 160mg / body / 10 weeks, 160.5mg / body / 10 weeks, 161mg / body / 10 weeks, 161.5mg / body / 10 weeks, 162mg / body / 10 weeks, 162.5mg / body / 10 weeks, 163mg / body / 10 weeks, 163.5mg / body / 10 weeks, 164mg / body / 10 weeks, 164.5mg / body / 10 weeks, 165mg / body / 10 weeks, 165.5mg / body / 10 weeks, 166mg / body / 10 weeks, 166.5mg / body / 10 weeks, 167mg / body / 10 weeks, 167.5mg / body / 10 week, 168mg / body / 10 weeks, 168.5mg / body / 10 weeks, 169mg / body / 10 weeks, 169.5mg / body / 10 weeks, 170mg / body / 10 weeks, 170.5mg / body / 10 weeks, 171mg / body / 10 weeks, 171.5mg / body / 10 weeks, 172mg / body / 10 weeks, 172.5mg / body / 10 weeks, 173mg / body / 10 weeks, 173.5mg / body / 10 weeks, 174mg / body / 10 weeks, 174.5mg / body / 10 weeks, 175mg / 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, 200 mg / body / 10 weeks, etc. may be. Or, in a non-limiting embodiment, it is, for example, 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, 55.5mg / body / 12 weeks, 56mg / body / 12 weeks, 56.5mg / body / 12 weeks, 57mg / body / 12 weeks, 57.5mg / body / 12 weeks, 58mg / body / 12 weeks, 58.5mg / body / 12 weeks, 59mg / body / 12 weeks, 59.5mg / body / 12 weeks, 60mg / body / 12 weeks, 60.5mg / body / 12 weeks, 61mg / body / 12 weeks, 61.5mg / body / 12 weeks, 62mg / body / 12 weeks, 62.5mg / body / 12 weeks, 63mg / body / 12 weeks, 63.5mg / body y / 12 weeks, 64mg / body / 12 weeks, 64.5mg / body / 12 weeks, 65mg / body / 12 weeks, 65.5mg / body / 12 weeks, 66mg / body / 12 weeks, 66.5mg / body / 12 weeks, 67mg / body / 12 weeks, 67.5mg / body / 12 weeks, 68mg / body / 12 weeks, 68.5mg / body / 12 weeks, 69mg / body / 12 weeks, 69.5mg / body / 12 weeks, 70mg / body / 12 weeks, 70.5mg / body / 12 weeks, 71mg / body / 12 weeks, 71.5mg / 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, 80.5mg / body / 12 weeks, 81mg / body / 12 weeks, 81.5mg / body / 12 weeks, 82mg / body / 12 weeks, 82.5mg / body / 12 weeks, 83mg / body / 12 weeks, 83.5mg / body / 12 weeks, 84mg / body / 12 weeks, 84.5mg / body / 12 weeks, 85mg / body / 12 weeks, 85.5mg / body / 12 weeks, 86mg / body / 12 weeks, 86.5mg / body / 12 weeks, 87mg / body / 12 weeks, 87.5mg / body / 12 weeks, 88mg / body / 12 weeks, 88.5mg / body / 12 weeks, 89mg / body / 12 weeks, 89.5mg / body / 12 weeks, 90mg / body / 12 weeks, 90.5mg / body / 12 weeks, 91mg / body / 12 weeks, 91.5mg / body / 12 weeks, 92mg / body / 12 weeks, 92.5mg / body / 12 weeks, 93mg / body / 12 weeks, 93.5mg / body / 12 weeks, 94mg / body / 12 weeks, 94.5mg / body / 12 weeks, 95mg / body / 12 weeks, 95.5mg / body / 12 weeks, 96mg / body / 12 weeks, 96.5mg / body / 12 weeks g / body / 12 weeks, 97mg / body / 12 weeks, 97.5mg / body / 12 weeks, 98mg / body / 12 weeks, 98.5mg / body / 12 weeks, 99mg / body / 12 weeks, 99.5mg / body / 12 weeks, 100mg / body / 12 weeks, 100.5mg / body / 12 weeks, 101mg / body / 12 weeks, 101.5mg / body / 12 weeks, 102mg / body / 12 weeks, 102.5mg / body / 12 weeks, 103mg / body / 12 weeks, 103.5mg / body / 12 weeks, 104mg / body / 12 weeks , 104.5mg / body / 12 weeks, 105mg / body / 12 weeks, 105.5mg / body / 12 weeks, 106mg / body / 12 weeks, 106.5mg / body / 12 weeks, 107mg / body / 12 weeks, 107.5mg / body / 12 weeks, 108mg / body / 12 weeks, 108.5mg / body / 12 weeks, 109mg / body / 12 weeks, 109.5mg / body / 12 weeks, 110mg / body / 12 weeks, 110.5mg / body / 12 weeks, 111mg / body / 12 weeks, 111.5mg / body / 12 weeks, 112mg / body / 12 weeks, 112.5mg / body / 12 weeks, 113mg / body / 12 weeks, 113.5mg / body / 12 weeks, 114mg / body / 12 weeks, 114.5mg / body / 12 weeks, 115mg / body / 12 weeks, 115.5mg / body / 12 weeks, 116mg / body / 12 weeks, 116.5mg / body / 12 weeks, 117mg / body / 12 weeks, 117.5mg / body / 12 weeks, 118mg / body / 12 weeks, 118.5mg / body / 12 weeks, 119mg / body / 12 weeks, 119.5mg / body / 12 weeks, 120mg / body / 12 weeks, 120.5mg / body / 12 weeks, 121mg / body / 12 weeks, 121.5mg / body / 12 weeks, 122mg / body / 12 weeks, 122.5mg / body / 12 weeks, 123mg / body / 12 weeks, 123.5mg / body / 12 weeks, 124mg / body / 12 weeks, 124.5mg / body / 12 weeks, 125mg / body / 12 weeks, 125.5mg / body / 12 weeks, 126mg / body / 12 weeks, 126.5mg / body / 12 weeks, 127mg / body / 12 weeks, 127.5mg / body / 12 weeks, 128mg / body / 12 weeks, 128.5mg / body / 12 weeks, 129mg / body / 12 weeks, 129.5mg / body / 12 weeks, 130mg / body / 12 weeks, 130.5mg / body / 12 weeks, 131mg / body / 12 weeks, 131.5mg / body / 12 weeks, 132mg / body / 12 weeks, 132.5mg / body / 12 weeks, 133mg / body / 12 weeks, 133.5mg / body / 12 weeks, 134mg / body / 12 weeks, 134.5mg / 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, 143mg / body / 12 weeks, 143.5mg / body / 12 weeks, 144mg / body / 12 weeks, 144.5mg / body / 12 weeks, 145mg / body / 12 weeks, 145.5mg / body / 12 weeks, 146mg / body / 12 weeks, 146.5mg / body / 12 weeks, 147mg / body / 12 weeks, 147.5mg / body / 12 weeks, 148mg / body / 12 weeks, 148.5mg / body / 12 weeks, 149mg / body / 12 weeks, 149.5mg / body / 12 weeks, 150mg / body / 12 weeks, 150.5mg / body / 12 weeks, 151mg / body / 12 weeks, 151.5mg / body / 12 weeks, 152mg / body / 12 weeks, 152.5mg / body / 12 weeks, 153mg / body / 12 weeks, 153.5mg / body / 12 weeks, 154mg / body / 12 weeks, 154.5mg / body / 12 weeks, 155mg / body / 12 weeks, 155.5mg / body / 12 weeks, 156mg / body / 12 weeks, 156.5mg / body / 12 weeks, 157mg / body / 12 weeks, 157.5mg / body / 12 weeks, 158mg / body / 12 weeks, 158.5mg / body / 12 weeks, 159mg / body / 12 weeks, 159.5mg / body / 12 weeks, 160mg / body / 12 weeks, 160.5mg / body / 12 weeks, 161mg / body / 12 weeks, 161.5mg / body / 12 weeks, 162mg / body / 12 weeks, 162.5mg / body / 12 weeks, 163mg / body / 12 weeks, 163.5mg / body / 12 weeks, 164mg / body / 12 weeks, 164.5mg / body / 12 weeks, 165mg / body / 12 weeks, 165.5mg / 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, 174mg / body / 12 weeks, 174.5mg / body / 12 weeks, 175mg / body / 12 weeks, 175.5mg / body / 12 weeks, 176mg / body / 12 weeks, 176.5mg / body / 12 weeks, 177mg / body / 12 weeks, 177.5mg / body / 12 weeks, 178mg / body / 12 weeks, 178.5mg / body / 12 weeks, 179mg / body / 12 weeks, 179.5mg / body / 12 weeks, 180mg / body / 12 weeks, 180.5mg / body / 12 weeks, 181mg / body / 12 weeks, 181.5mg / body / 12 weeks, 182mg / body / 12 weeks, 182.5mg / body / 12 weeks, 183mg / body / 12 weeks, 183.5mg / body / 12 weeks, 184mg / body / 12 weeks, 184.5mg / body / 12 weeks, 185mg / body / 12 weeks, 185.5mg / body / 12 weeks, 186mg / body / 12 weeks, 186.5mg / body / 12 weeks, 187mg / body / 12 weeks, 187.5mg / body / 12 weeks, 188mg / body / 12 weeks, 188.5mg / body / 12 weeks, 189mg / body / 12 weeks, 189.5mg / body / 12 weeks, 190mg / body / 12 weeks, 190.5mg / body / 12 weeks, 191mg / body / 12 weeks g / body / 12 weeks, 191.5mg / body / 12 weeks, 192mg / body / 12 weeks, 192.5mg / body / 12 weeks, 193mg / body / 12 weeks, 193.5mg / body / 12 weeks, 194mg / body / 12 weeks, 194.5mg / body / 12 weeks, 195mg / body / 12 weeks, 195.5mg / body / 12 weeks, 196mg / body / 12 weeks, 196.5mg / body / 12 weeks, 197mg / body / 12 weeks, 197.5mg / body / 12 weeks, 198mg / body / 12 weeks, 198.5mg / body / 12 weeks, 199mg / body / 12 weeks, 199.5mg / body / 12 weeks, 200mg / body / 12 weeks, etc. The non-limited dosage is 25mg~100mg / body / 4 weeks, 50mg~100mg / body / 4 weeks and 50mg~75mg / body / 4 weeks. Non-limited non-limited use of 10mg~50mg / body / 2 weeks and 20mg~40mg / body / 2 weeks.

[0055] Alternatively, an embodiment of repeated administration of the IL-31 antagonist of the present disclosure at an equal amount and at the same administration interval at a predetermined administration interval and a predetermined dose (administration amount) may be "0.01 mg to 10 mg / kg / 1 day to 12 weeks." Here, for example, "0.01 mg to 10 mg / kg / 1 day to 12 weeks" herein contemplates repeatedly administering the IL-31 antagonist of the present disclosure to a subject at an equal amount and at the same administration interval, with a single dose selected from 0.01 mg to 10 mg being selected as the administration amount of the IL-31 antagonist of the present disclosure and an arbitrary administration interval selected from 1 day to 12 weeks being selected as the administration interval (e.g., 4 weeks) of the IL-31 antagonist of the present disclosure. Although not limited thereto, the repeated administration of an IL-31 antagonist of the present disclosure at equal and identical doses at predetermined administration intervals (dosage) is preferably 0.01 mg to 10 mg / kg / 2 to 8 weeks, and may be, for example, 0.01 mg to 10 mg / kg / 2 weeks, 0.01 mg to 10 mg / kg / 4 weeks, 0.01 mg to 10 mg / kg / 6 weeks, or 0.01 mg to 10 mg / kg / 8 weeks. Alternatively, the dose is more preferably 0.1 mg to 3 mg / kg / 2 to 8 weeks, and may be, for example, 0.1 mg to 3 mg / kg / 2 weeks, 0.1 mg to 3 mg / kg / 4 weeks, 0.1 mg to 3 mg / kg / 6 weeks, or 0.1 mg to 3 mg / kg / 8 weeks. Alternatively, as an example, a dose of 0.2 mg to 2 mg / kg / 2 to 8 weeks is more preferable, and may be, for example, 0.2 mg to 2 mg / kg / 2 weeks, 0.2 mg to 2 mg / kg / 4 weeks, 0.2 mg to 2 mg / kg / 6 weeks, or 0.2 mg to 2 mg / kg / 8 weeks. Alternatively, as an example, a dose of 0.5 mg to 1.5 mg / kg / 4 to 8 weeks is even more preferable, and may be, for example, 0.5 mg to 1.5 mg / kg / 4 weeks, 0.5 mg to 1.5 mg / kg / 6 weeks, or 0.5 mg to 1.5 mg / kg / 8 weeks. In one non-limiting embodiment, it is, for example, 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, 0.18mg / kg / 4 weeks, 0.19mg / kg / 4 weeks, 0.2mg / kg / 4 weeks, 0.21mg / kg / 4 weeks, 0.22mg / kg / 4 weeks, 0.23mg / kg / 4 weeks, 0.24mg / kg / 4 weeks, 0.25mg / kg / 4 weeks, 0.26mg / kg / 4 weeks, 0.27mg / kg / 4 weeks, 0.28mg / kg / 4 weeks, 0.29mg / kg / 4 weeks, 0.3mg / kg / 4 weeks, 0.31mg / kg / 4 weeks, 0.32mg / kg / 4 weeks, 0.33mg / kg / 4 weeks, 0.34mg / kg / 4 weeks, 0.35mg / kg / 4 weeks, 0.36mg / kg / 4 weeks, 0.37mg / kg / 4 weeks g / kg / 4 weeks, 0.38mg / kg / 4 weeks, 0.39mg / kg / 4 weeks, 0.4mg / kg / 4 weeks, 0.41mg / kg / 4 weeks, 0.42mg / kg / 4 weeks, 0.43mg / kg / 4 weeks, 0.44mg / kg / 4 weeks, 0.45mg / kg / 4 weeks, 0.46mg / kg / 4 weeks, 0.47mg / kg / 4 weeks, 0.48mg / kg / 4 weeks, 0.49mg / kg / 4 weeks, 0.5mg / kg / 4 weeks, 0.51mg / kg / 4 weeks, 0.52mg / kg / 4 weeks, 0.53mg / kg / 4 weeks, 0.54mg / kg / 4 weeks, 0.55mg / kg / 4 weeks, 0.56mg / kg g / 4 weeks, 0.57mg / kg / 4 weeks, 0.58mg / kg / 4 weeks, 0.59mg / kg / 4 weeks, 0.6mg / kg / 4 weeks, 0.61mg / kg / 4 weeks, 0.62mg / kg / 4 weeks, 0.63mg / kg / 4 weeks, 0.64mg / kg / 4 weeks, 0.65mg / kg / 4 weeks, 0.66mg / kg / 4 weeks, 0.67mg / kg / 4 weeks, 0.68mg / kg / 4 weeks, 0.69mg / kg / 4 weeks, 0.7mg / kg / 4 weeks, 0.71mg / kg / 4 weeks, 0.72mg / kg / 4 weeks, 0.73mg / kg / 4 weeks, 0.74mg / kg / 4 weeks, 0.75mg / kg / 4 weeks. week, 0.76mg / kg / 4 weeks, 0.77mg / kg / 4 weeks, 0.78mg / kg / 4 weeks, 0.79mg / kg / 4 weeks, 0.8mg / kg / 4 weeks, 0.81mg / kg / 4 weeks, 0.82mg / kg / 4 weeks, 0.83mg / kg / 4 weeks, 0.84mg / kg / 4 weeks, 0.85mg / kg / 4 weeks, 0.86mg / kg / 4 weeks, 0.87mg / kg / 4 weeks, 0.88mg / kg / 4 weeks, 0.89mg / kg / 4 weeks, 0.9mg / kg / 4 weeks, 0.91mg / kg / 4 weeks, 0.92mg / kg / 4 weeks, 0.93mg / kg / 4 weeks, 0.94mg / kg / 4 weeks, 0.95mg / kg / 4 weeks, 0.96mg / kg / 4 weeks, 0.97mg / kg / 4 weeks, 0.98mg / kg / 4 weeks, 0.99mg / kg / 4 weeks, 1mg / kg / 4 weeks, 1.01mg / kg / 4 weeks, 1.02mg / kg / 4 weeks, 1.03mg / kg / 4 weeks, 1.04mg / kg / 4 weeks, 1.05mg / kg / 4 weeks, 1.06mg / kg / 4 weeks, 1.07mg / kg / 4 weeks, 1.08mg / kg / 4 weeks, 1.09mg / kg / 4 weeks, 1.1mg / kg / 4 weeks, 1.11mg / kg / 4 weeks, 1.12mg / kg / 4 weeks, 1.13mg / kg / 4 weeks, 1.14mg / kg / 4 weeks, 1.15mg / kg / 4 weeks, 1.16mg / kg / 4 weeks, 1.17mg / kg / 4 weeks, 1.18mg / kg / 4 weeks, 1.19mg / kg / 4 weeks, 1.2mg / kg / 4 weeks, 1.21mg / kg / 4 weeks, 1.22mg / kg / 4 weeks, 1.23mg / kg / 4 weeks, 1.24mg / kg / 4 weeks, 1.25mg / kg / 4 weeks, 1.26mg / kg / 4 weeks, 1.27mg / kg / 4 weeks, 1.28mg / kg / 4 weeks, 1.29mg / kg / 4 weeks, 1.3mg / kg / 4 weeks, 1.31mg / kg / 4 weeks, 1.32mg / kg / 4 weeks, 1.33mg / kg / 4 weeks, 1.34mg / kg / 4 weeks, 1.35mg / kg / 4 weeks, 1.36mg / kg / 4 weeks, 1.37mg / kg / 4 weeks, 1.38mg / kg / 4 weeks, 1.39mg / kg / 4 weeks, 1.4mg / kg / 4 weeks, 1.41mg / kg / 4 weeks, 1.42mg / kg / 4 weeks, 1.43mg / kg / 4 weeks, 1.44mg / kg / 4 weeks, 1.45mg / kg / 4 weeks, 1.46mg / kg / 4 weeks, 1.47mg / kg / 4 weeks, 1.48mg / kg / 4 weeks, 1.49mg / kg / 4 weeks, 1.5mg / kg / 4 weeks, 1.51mg / kg / 4 weeks, 1.52mg / kg / 4 weeks , 1.53mg / kg / 4 weeks, 1.54mg / kg / 4 weeks, 1.55mg / kg / 4 weeks, 1.56mg / kg / 4 weeks, 1.57mg / kg / 4 weeks, 1.58mg / kg / 4 weeks, 1.59mg / kg / 4 weeks, 1.6mg / kg / 4 weeks, 1.61mg / kg / 4 weeks, 1.62mg / kg / 4 weeks, 1.63mg / kg / 4 weeks, 1.64mg / kg / 4 weeks, 1.65mg / kg / 4 weeks, 1.66mg / kg / 4 weeks, 1.67mg / kg / 4 weeks, 1.68mg / kg / 4 weeks, 1.69mg / kg / 4 weeks, 1.7mg / kg / 4 weeks, 1.71mg / kg / 4 weeks, 1.72mg / kg / 4 weeks, 1.73mg / kg / 4 weeks, 1.74mg / kg / 4 weeks, 1.75mg / kg / 4 weeks, 1.76mg / kg / 4 weeks, 1.77mg / kg / 4 weeks, 1.78mg / kg / 4 weeks, 1.79mg / kg / 4 weeks, 1.8mg / kg / 4 weeks, 1.81mg / kg / 4 weeks, 1.82mg / kg / 4 weeks, 1.83mg / kg / 4 weeks, 1.84mg / kg / 4 weeks, 1.85mg / kg / 4 weeks, 1.86mg / kg / 4 weeks, 1.87mg / kg / 4 weeks, 1.88mg / kg / 4 weeks, 1.89mg / kg / 4 weeks, 1.9mg / kg / 4 weeks, 1.91mg / kg / 4 weeks g / kg / 4 weeks, 1.92mg / kg / 4 weeks, 1.93mg / kg / 4 weeks, 1.94mg / kg / 4 weeks, 1.95mg / kg / 4 weeks, 1.96mg / kg / 4 weeks, 1.97mg / kg / 4 weeks, 1.98mg / kg / 4 weeks, 1.99mg / kg / 4 weeks, 2mg / kg / 4 weeks, 2.01mg / kg / 4 weeks, 2.02mg / kg / 4 weeks, 2.03mg / kg / 4 weeks, 2.04mg / kg / 4 weeks, 2.05mg / kg / 4 weeks, 2.06mg / kg / 4 weeks, 2.07mg / kg / 4 weeks, 2.08mg / kg / 4 weeks, 2.09mg / kg / 4 weeks, 2.1mg / kg / 4 weeks, 2.11mg / kg / 4 weeks, 2.12mg / kg / 4 weeks, 2.13mg / kg / 4 weeks, 2.14mg / kg / 4 weeks, 2.15mg / kg / 4 weeks, 2.16mg / kg / 4 weeks, 2.17mg / kg / 4 weeks, 2.18mg / kg / 4 weeks, 2.19mg / kg / 4 weeks, 2.2mg / kg / 4 weeks, 2.21mg / kg / 4 weeks, 2.22mg / kg / 4 weeks, 2.23mg / kg / 4 weeks, 2.24mg / kg / 4 weeks, 2.25mg / kg / 4 weeks, 2.26mg / kg / 4 weeks, 2.27mg / kg / 4 weeks, 2.28mg / kg / 4 weeks, 2.29mg / kg / 4 weeks , 2.3mg / kg / 4 weeks, 2.31mg / kg / 4 weeks, 2.32mg / kg / 4 weeks, 2.33mg / kg / 4 weeks, 2.34mg / kg / 4 weeks, 2.35mg / kg / 4 weeks, 2.36mg / kg / 4 weeks, 2.37mg / kg / 4 weeks, 2.38mg / kg / 4 weeks, 2.39mg / kg / 4 weeks, 2.4mg / kg / 4 weeks, 2.41mg / kg / 4 weeks, 2.42mg / kg / 4 weeks, 2.43mg / kg / 4 weeks, 2.44mg / kg / 4 weeks, 2.45mg / kg / 4 weeks, 2.46mg / kg / 4 weeks, 2.47mg / kg / 4 weeks, 2.48mg / kg / 4 weeks, 2.49mg / kg / 4 weeks, 2.5mg / kg / 4 weeks, 2.51mg / kg / 4 weeks, 2.52mg / kg / 4 weeks, 2.53mg / kg / 4 weeks, 2.54mg / kg / 4 weeks, 2.55mg / 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, 2.6 2mg / kg / 4 weeks, 2.63mg / kg / 4 weeks, 2.64mg / kg / 4 weeks, 2.65mg / kg / 4 weeks, 2.66mg / kg / 4 weeks, 2.67mg / kg / 4 weeks, 2.68mg / 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, 2.7 5mg / kg / 4 weeks, 2.76mg / kg / 4 weeks, 2.77mg / kg / 4 weeks, 2.78mg / kg / 4 weeks, 2.79mg / kg / 4 weeks, 2.8mg / kg / 4 weeks, 2.81mg / 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, 2.8 The dose may be 8 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, 3 mg / kg / 4 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, for example, 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, 0.2mg / kg / 6 weeks, 0.21mg / kg / 6 weeks, 0.22mg / kg / 6 weeks, 0.23mg / kg / 6 weeks, 0.24mg / kg / 6 weeks, 0.25mg / 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, 0.32mg / kg / 6 weeks, 0.33mg / kg / 6 weeks, 0.34mg / kg / 6 weeks, 0.35mg / kg / 6 weeks, 0.36mg / kg / 6 weeks, 0.37mg / kg / 6 weeks, 0.38mg / kg / 6 weeks, 0.39mg / kg / 6 weeks, 0.4mg / kg / 6 weeks, 0.41mg / kg / 6 weeks, 0.42mg / kg / 6 weeks, 0.43mg / kg / 6 weeks, 0.44mg / kg / 6 weeks, 0.45mg / kg / 6 weeks, 0.46mg / kg / 6 weeks, 0.47mg / kg / 6 weeks, 0.48mg / kg / 6 weeks, 0.49mg / kg / 6 weeks, 0.5mg / kg / 6 weeks, 0.51mg / kg / 6 weeks g / kg / 6 weeks, 0.52mg / kg / 6 weeks, 0.53mg / kg / 6 weeks, 0.54mg / kg / 6 weeks, 0.55mg / kg / 6 weeks, 0.56mg / kg / 6 weeks, 0.57mg / kg / 6 weeks, 0.58mg / kg / 6 weeks, 0.59mg / kg / 6 weeks, 0.6mg / kg / 6 weeks, 0.61mg / kg / 6 weeks, 0.62mg / kg / 6 weeks, 0.63mg / kg / 6 weeks, 0.64mg / kg / 6 weeks, 0.65mg / kg / 6 weeks, 0.66mg / kg / 6 weeks, 0.67mg / kg / 6 weeks, 0.68mg / kg / 6 weeks, 0.69mg / kg / 6 weeks, 0.7mg / kg g / 6 weeks, 0.71mg / kg / 6 weeks, 0.72mg / kg / 6 weeks, 0.73mg / kg / 6 weeks, 0.74mg / kg / 6 weeks, 0.75mg / kg / 6 weeks, 0.76mg / kg / 6 weeks, 0.77mg / kg / 6 weeks, 0.78mg / kg / 6 weeks, 0.79mg / kg / 6 weeks, 0.8mg / kg / 6 weeks, 0.81mg / kg / 6 weeks, 0.82mg / kg / 6 weeks, 0.83mg / kg / 6 weeks, 0.84mg / kg / 6 weeks, 0.85mg / kg / 6 weeks, 0.86mg / kg / 6 weeks, 0.87mg / kg / 6 weeks, 0.88mg / kg / 6 weeks, 0.89mg / kg / 6 weeks, 0.9mg / kg / 6 weeks, 0.91mg / kg / 6 weeks, 0.92mg / kg / 6 weeks, 0.93mg / kg / 6 weeks, 0.94mg / kg / 6 weeks, 0.95mg / kg / 6 weeks, 0.96mg / kg / 6 weeks, 0.97mg / kg / 6 weeks, 0.98mg / kg / 6 weeks, 0.99mg / kg / 6 weeks, 1mg / kg / 6 weeks, 1.01mg / kg / 6 weeks, 1.02mg / kg / 6 weeks, 1.03mg / kg / 6 weeks, 1.04mg / kg / 6 weeks, 1.05mg / kg / 6 weeks, 1.06mg / kg / 6 weeks, 1.07mg / kg / 6 weeks, 1.08mg / kg / 6 weeks, 1.09mg / kg / 6 weeks, 1.1mg / kg / 6 weeks, 1.11mg / kg / 6 weeks, 1.12mg / kg / 6 weeks, 1.13mg / kg / 6 weeks, 1.14mg / kg / 6 weeks, 1.15mg / kg / 6 weeks, 1.16mg / kg / 6 weeks, 1.17mg / kg / 6 weeks, 1.18mg / kg / 6 weeks, 1.19mg / kg / 6 weeks, 1.2mg / kg / 6 weeks, 1.21mg / kg / 6 weeks, 1.22mg / kg / 6 weeks, 1.23mg / kg / 6 weeks, 1.24mg / kg / 6 weeks, 1.25mg / kg / 6 weeks, 1.26mg / kg / 6 weeks, 1.27mg / kg / 6 weeks, 1.28mg / kg / 6 weeks g / kg / 6 weeks, 1.29mg / kg / 6 weeks, 1.3mg / kg / 6 weeks, 1.31mg / kg / 6 weeks, 1.32mg / kg / 6 weeks, 1.33mg / kg / 6 weeks, 1.34mg / kg / 6 weeks, 1.35mg / kg / 6 weeks, 1.36mg / kg / 6 weeks, 1.37mg / kg / 6 weeks, 1.38mg / kg / 6 weeks, 1.39mg / kg / 6 weeks, 1.4mg / kg / 6 weeks, 1.41mg / kg / 6 weeks, 1.42mg / kg / 6 weeks, 1.43mg / kg / 6 weeks, 1.44mg / kg / 6 weeks, 1.45mg / kg / 6 weeks, 1.46mg / kg / 6 weeks, 1.47mg / kg g / 6 weeks, 1.48mg / kg / 6 weeks, 1.49mg / kg / 6 weeks, 1.5mg / kg / 6 weeks, 1.51mg / kg / 6 weeks, 1.52mg / kg / 6 weeks, 1.53mg / kg / 6 weeks, 1.54mg / kg / 6 weeks, 1.55mg / kg / 6 weeks, 1.56mg / kg / 6 weeks, 1.57mg / kg / 6 weeks, 1.58mg / kg / 6 weeks, 1.59mg / kg / 6 weeks, 1.6mg / kg / 6 weeks, 1.61mg / kg / 6 weeks, 1.62mg / kg / 6 weeks, 1.63mg / kg / 6 weeks, 1.64mg / kg / 6 weeks, 1.65mg / kg / 6 weeks, 1.66mg / kg / 6 weeks week, 1.67mg / kg / 6 weeks, 1.68mg / kg / 6 weeks, 1.69mg / kg / 6 weeks, 1.7mg / kg / 6 weeks, 1.71mg / kg / 6 weeks, 1.72mg / kg / 6 weeks, 1.73mg / kg / 6 weeks, 1.74mg / kg / 6 weeks, 1.75mg / kg / 6 weeks, 1.76mg / kg / 6 weeks, 1.77mg / kg / 6 weeks, 1.78mg / kg / 6 weeks, 1.79mg / kg / 6 weeks, 1.8mg / kg / 6 weeks, 1.81mg / kg / 6 weeks, 1.82mg / kg / 6 weeks, 1.83mg / kg / 6 weeks, 1.84mg / kg / 6 weeks, 1.85mg / kg / 6 weeks, 1.86mg / kg / 6 weeks, 1.87mg / kg / 6 weeks, 1.88mg / kg / 6 weeks, 1.89mg / kg / 6 weeks, 1.9mg / kg / 6 weeks, 1.91mg / kg / 6 weeks, 1.92mg / kg / 6 weeks, 1.93mg / kg / 6 weeks, 1.94mg / kg / 6 weeks, 1.95mg / kg / 6 weeks, 1.96mg / kg / 6 weeks, 1.97mg / kg / 6 weeks, 1.98mg / kg / 6 weeks, 1.99mg / kg / 6 weeks, 2mg / kg / 6 weeks, 2.01mg / kg / 6 weeks, 2.02mg / kg / 6 weeks, 2.03mg / kg / 6 weeks, 2.04mg / kg / 6 weeks, 2.05mg / kg / 6 weeks, 2.06mg / kg / 6 weeks, 2.07mg / kg / 6 weeks, 2.08mg / kg / 6 weeks, 2.09mg / kg / 6 weeks, 2.1mg / kg / 6 weeks, 2.11mg / kg / 6 weeks, 2.12mg / kg / 6 weeks, 2.13mg / kg / 6 weeks, 2.14mg / kg / 6 weeks, 2.15mg / kg / 6 weeks, 2.16mg / kg / 6 weeks, 2.17mg / kg / 6 weeks, 2.18mg / kg / 6 weeks, 2.19mg / kg / 6 weeks, 2.2mg / kg / 6 weeks, 2.21mg / kg / 6 weeks, 2.22mg / kg / 6 weeks, 2.23mg / kg / 6 weeks, 2.24mg / kg / 6 weeks, 2.25mg / kg / 6 weeks, 2.26mg / kg / 6 weeks, 2.27mg / kg / 6 weeks, 2.28mg / kg / 6 weeks, 2.29mg / kg / 6 weeks, 2.3mg / kg / 6 weeks, 2.31mg / kg / 6 weeks, 2.32mg / kg / 6 weeks, 2.33mg / kg / 6 weeks, 2.34mg / kg / 6 weeks, 2.35mg / kg / 6 weeks, 2.36mg / kg / 6 weeks, 2.37mg / kg / 6 weeks, 2.38mg / kg / 6 weeks, 2.39mg / kg / 6 weeks, 2.4mg / kg / 6 weeks, 2.41mg / kg / 6 weeks, 2.42mg / kg / 6 weeks, 2.43mg / kg / 6 weeks , 2.44mg / kg / 6 weeks, 2.45mg / kg / 6 weeks, 2.46mg / kg / 6 weeks, 2.47mg / kg / 6 weeks, 2.48mg / kg / 6 weeks, 2.49mg / kg / 6 weeks, 2.5mg / kg / 6 weeks, 2.51mg / kg / 6 weeks, 2.52mg / kg / 6 weeks, 2.53mg / kg / 6 weeks, 2.54mg / kg / 6 weeks, 2.55mg / kg / 6 weeks, 2.56mg / kg / 6 weeks, 2.57mg / kg / 6 weeks, 2.58mg / kg / 6 weeks, 2.59mg / kg / 6 weeks, 2.6mg / kg / 6 weeks, 2.61mg / kg / 6 weeks, 2.62mg / kg / 6 weeks, 2.63mg / kg / 6 weeks, 2.64mg / kg / 6 weeks, 2.65mg / kg / 6 weeks, 2.66mg / kg / 6 weeks, 2.67mg / kg / 6 weeks, 2.68mg / kg / 6 weeks, 2.69mg / kg / 6 weeks, 2.7mg / kg / 6 weeks, 2.71mg / kg / 6 weeks, 2.72mg / 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, 2.8 2 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, 3 mg / kg / 6 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, e.g., For example, 0.1mg / kg / 8 weeks, 0.11mg / kg / 8 weeks, 0.12mg / kg / 8 weeks, 0.125mg / kg / 8 weeks, 0.13mg / kg / 8 weeks, 0.14mg / kg / 8 weeks, 0.15mg / kg / 8 weeks, 0.16mg / kg / 8 weeks, 0.17mg / kg / 8 weeks, 0.18mg / kg / 8 weeks, 0.19mg / kg / 8 weeks, 0.2mg / kg / 8 weeks, 0.21mg / kg / 8 weeks, 0.22mg / kg / 8 weeks, 0.23mg / kg / 8 weeks, 0.24mg / kg / 8 weeks, 0.25mg / kg / 8 weeks, 0.26mg / kg / 8 weeks, 0.27mg / kg / 8 weeks, 0.28mg / kg / 8 weeks, 0.29mg / kg / 8 weeks, 0.3mg / kg / 8 weeks, 0.31mg / kg / 8 weeks, 0.32mg / kg / 8 weeks, 0.33mg / kg / 8 weeks, 0.34mg / kg / 8 weeks, 0.35mg / kg / 8 weeks, 0.36mg / kg / 8 weeks, 0.37mg / 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 m g / 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 .57mg / kg / 8 weeks, 0.58mg / kg / 8 weeks, 0.59mg / kg / 8 weeks, 0.6mg / kg / 8 weeks, 0.61mg / kg / 8 weeks, 0.62mg / kg / 8 weeks, 0.63mg / kg / 8 weeks, 0.64mg / kg / 8 weeks, 0.65mg / kg / 8 weeks, 0.66mg / 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, 0.86mg / kg / 8 weeks, 0.87mg / kg / 8 weeks, 0.88mg / kg / 8 weeks, 0.89mg / kg / 8 weeks, 0.9mg / kg / 8 weeks, 0.91mg / kg / 8 weeks, 0.92mg / kg / 8 weeks, 0.93mg / kg / 8 weeks, 0.94mg / kg / 8 weeks, 0.95mg / kg / 8 weeks, 0.96mg / kg / 8 weeks, 0.97mg / kg / 8 weeks, 0.98mg / kg / 8 weeks, 0.99mg / kg / 8 weeks, 1mg / kg / 8 weeks, 1.01mg / kg / 8 weeks, 1.02mg / kg / 8 weeks, 1.03mg / kg / 8 weeks, 1.04mg / kg / 8 weeks, 1.05mg / kg / 8 weeks, 1.06mg / kg / 8 weeks, 1.07mg / kg / 8 weeks, 1.08mg / kg / 8 weeks, 1.09mg / kg / 8 weeks, 1.1mg / kg / 8 weeks, 1.11mg / kg / 8 weeks, 1.12mg / kg / 8 weeks, 1.13mg / kg / 8 weeks, 1.14mg / kg / 8 weeks, 1.15mg / kg / 8 weeks, 1.16mg / kg / 8 weeks, 1.17mg / kg / 8 weeks, 1.18mg / kg / 8 weeks, 1.19mg / kg / 8 weeks, 1.2mg / kg / 8 weeks, 1.21mg / kg / 8 weeks, 1.22mg / kg / 8 weeks, 1.23mg / kg / 8 weeks, 1.24mg / kg / 8 weeks, 1.25mg / kg / 8 weeks, 1.26mg / kg / 8 weeks, 1.27mg / kg / 8 weeks, 1.28mg / kg / 8 weeks, 1.29mg / kg / 8 weeks, 1.3mg / kg / 8 weeks, 1.31mg / kg / 8 weeks, 1.32mg / kg / 8 weeks, 1.33mg / kg / 8 weeks, 1.34mg / kg / 8 weeks, 1.35mg / kg / 8 weeks, 1.36mg / kg / 8 weeks, 1.37mg / kg / 8 weeks, 1.38mg / kg / 8 weeks, 1.39mg / kg / 8 weeks, 1.4mg / kg / 8 weeks, 1.41mg / kg / 8 weeks, 1.42mg / kg / 8 weeks, 1.43mg / kg / 8 weeks , 1.44mg / kg / 8 weeks, 1.45mg / kg / 8 weeks, 1.46mg / kg / 8 weeks, 1.47mg / kg / 8 weeks, 1.48mg / kg / 8 weeks, 1.49mg / kg / 8 weeks, 1.5mg / kg / 8 weeks, 1.51mg / kg / 8 weeks, 1.52mg / kg / 8 weeks, 1.53mg / kg / 8 weeks, 1.54mg / kg / 8 weeks, 1.55mg / kg / 8 weeks, 1.56mg / kg / 8 weeks, 1.57mg / kg / 8 weeks, 1.58mg / kg / 8 weeks, 1.59mg / kg / 8 weeks, 1.6mg / kg / 8 weeks, 1.61mg / kg / 8 weeks, 1.62mg / kg / 8 weeks, 1.63mg / kg / 8 weeks, 1.64mg / kg / 8 weeks, 1.65mg / kg / 8 weeks, 1.66mg / kg / 8 weeks, 1.67mg / kg / 8 weeks, 1.68mg / kg / 8 weeks, 1.69mg / kg / 8 weeks, 1.7mg / kg / 8 weeks, 1.71mg / kg / 8 weeks, 1.72mg / kg / 8 weeks, 1.73mg / kg / 8 weeks, 1.74mg / kg / 8 weeks, 1.75mg / kg / 8 weeks, 1.76mg / kg / 8 weeks, 1.77mg / kg / 8 weeks, 1.78mg / kg / 8 weeks, 1.79mg / kg / 8 weeks, 1.8mg / kg / 8 weeks, 1.81mg / kg / 8 weeks, 1.82mg / kg / 8 weeks g / kg / 8 weeks, 1.83mg / kg / 8 weeks, 1.84mg / kg / 8 weeks, 1.85mg / kg / 8 weeks, 1.86mg / kg / 8 weeks, 1.87mg / kg / 8 weeks, 1.88mg / kg / 8 weeks, 1.89mg / kg / 8 weeks, 1.9mg / kg / 8 weeks, 1.91mg / kg / 8 weeks, 1.92mg / kg / 8 weeks, 1.93mg / kg / 8 weeks, 1.94mg / kg / 8 weeks, 1.95mg / kg / 8 weeks, 1.96mg / kg / 8 weeks, 1.97mg / kg / 8 weeks, 1.98mg / kg / 8 weeks, 1.99mg / kg / 8 weeks, 2mg / kg / 8 weeks, 2.01mg / kg / 8 weeks, 2.02mg / kg / 8 weeks, 2.03mg / kg / 8 weeks, 2.04mg / kg / 8 weeks, 2.05mg / kg / 8 weeks, 2.06mg / kg / 8 weeks, 2.07mg / kg / 8 weeks, 2.08mg / kg / 8 weeks, 2.09mg / kg / 8 weeks, 2.1mg / kg / 8 weeks, 2.11mg / kg / 8 weeks, 2.12mg / kg / 8 weeks, 2.13mg / kg / 8 weeks, 2.14mg / kg / 8 weeks, 2.15mg / kg / 8 weeks, 2.16mg / kg / 8 weeks, 2.17mg / kg / 8 weeks, 2.18mg / kg / 8 weeks, 2.19mg / kg / 8 weeks, 2.2mg / kg / 8 weeks, 2.21mg / kg / 8 weeks, 2.22mg / kg / 8 weeks, 2.23mg / kg / 8 weeks, 2.24mg / kg / 8 weeks, 2.25mg / kg / 8 weeks, 2.26mg / kg / 8 weeks, 2.27mg / kg / 8 weeks, 2.28mg / kg / 8 weeks, 2.29mg / kg / 8 weeks, 2.3mg / kg / 8 weeks, 2.31mg / kg / 8 weeks, 2.32mg / kg / 8 weeks, 2.33mg / kg / 8 weeks, 2.34mg / kg / 8 weeks, 2.35mg / kg / 8 weeks, 2.36mg / kg / 8 weeks, 2.37mg / kg / 8 weeks, 2.38mg / kg / 8 weeks, 2.39mg / kg / 8 weeks, 2.4mg / kg / 8 weeks, 2.41mg / kg / 8 weeks, 2.42mg / kg / 8 weeks, 2.43mg / kg / 8 weeks, 2.44mg / kg / 8 weeks, 2.45mg / kg / 8 weeks, 2.46mg / kg / 8 weeks, 2.47mg / 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 .63mg / kg / 8 weeks, 2.64mg / kg / 8 weeks, 2.65mg / kg / 8 weeks, 2.66mg / kg / 8 weeks, 2.67mg / kg / 8 weeks, 2.68mg / kg / 8 weeks, 2.69mg / kg / 8 weeks, 2.7mg / 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, It may be 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, 3 mg / kg / 8 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, for example, 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, 0.22mg / kg / 10 weeks, 0.23mg / kg / 10 weeks, 0.24mg / kg / 10 weeks, 0.25mg / kg / 10 weeks, 0.26mg / kg / 10 weeks, 0.27mg / kg / 10 weeks, 0.28mg / kg / 10 weeks, 0.29mg / kg / 10 weeks, 0.3mg / kg / 10 weeks, 0.31mg / kg / 10 weeks, 0.32mg / kg / 10 weeks, 0.33mg / kg / 10 weeks, 0.34mg / kg / 10 weeks, 0.35mg / kg / 10 weeks, 0.36mg / kg / 10 weeks, 0.37mg / kg / 10 weeks, 0.38mg / kg / 10 weeks, 0.39mg / kg / 10 weeks, 0. 0.4mg / kg / 10 weeks, 0.41mg / kg / 10 weeks, 0.42mg / kg / 10 weeks, 0.43mg / kg / 10 weeks, 0.44mg / kg / 10 weeks, 0.45mg / kg / 10 weeks, 0.46mg / kg / 10 weeks, 0.47mg / kg / 10 weeks, 0.48mg / kg / 10 weeks, 0.49mg / kg / 10 weeks, 0.5mg / kg / 10 weeks, 0.51mg / kg / 10 weeks, 0.52mg / kg / 10 weeks, 0.53mg / kg / 10 weeks, 0.54mg / kg / 10 weeks, 0.55mg / kg / 10 weeks, 0.56mg / kg / 10 weeks, 0.57mg / kg / 10 weeks, 0. 0.58mg / kg / 10 weeks, 0.59mg / kg / 10 weeks, 0.6mg / kg / 10 weeks, 0.61mg / kg / 10 weeks, 0.62mg / kg / 10 weeks, 0.63mg / kg / 10 weeks, 0.64mg / kg / 10 weeks, 0.65mg / kg / 10 weeks, 0.66mg / kg / 10 weeks, 0.67mg / kg / 10 weeks, 0.68mg / kg / 10 weeks, 0.69mg / kg / 10 weeks, 0.7mg / kg / 10 weeks, 0.71mg / kg / 10 weeks, 0.72mg / kg / 10 weeks, 0.73mg / kg / 10 weeks, 0.74mg / kg / 10 weeks, 0.75mg / kg / 10 weeks, 0 .76mg / kg / 10 weeks, 0.77mg / kg / 10 weeks, 0.78mg / kg / 10 weeks, 0.79mg / kg / 10 weeks, 0.8mg / kg / 10 weeks, 0.81mg / kg / 10 weeks, 0.82mg / kg / 10 weeks, 0.83mg / kg / 10 weeks, 0.84mg / kg / 10 weeks, 0.85mg / kg / 10 weeks, 0.86mg / kg / 10 weeks, 0.87mg / kg / 10 weeks, 0.88mg / kg / 10 weeks, 0.89mg / kg / 10 weeks, 0.9mg / kg / 10 weeks, 0.91mg / kg / 10 weeks, 0.92mg / kg / 10 weeks, 0.93mg / kg / 10 weeks, 0.94mg / kg / 10 weeks, 0.95mg / kg / 10 weeks, 0.96mg / kg / 10 weeks, 0.97mg / kg / 10 weeks, 0.98mg / kg / 10 weeks, 0.99mg / kg / 10 weeks, 1mg / kg / 10 weeks, 1.01mg / kg / 10 weeks, 1.02mg / kg / 10 weeks, 1.03mg / kg / 10 weeks, 1.04mg / kg / 10 weeks, 1.05mg / kg / 10 weeks, 1.06mg / kg / 10 weeks, 1.07mg / kg / 10 weeks, 1.08mg / kg / 10 weeks, 1.09mg / kg / 10 weeks, 1.1mg / kg / 10 weeks, 1.11mg / kg / 10 weeks, 1.1 2mg / kg / 10 weeks, 1.13mg / kg / 10 weeks, 1.14mg / kg / 10 weeks, 1.15mg / kg / 10 weeks, 1.16mg / kg / 10 weeks, 1.17mg / kg / 10 weeks, 1.18mg / kg / 10 weeks, 1.19mg / kg / 10 weeks, 1.2mg / kg / 10 weeks, 1.21mg / kg / 10 weeks, 1.22mg / kg / 10 weeks, 1.23mg / kg / 10 weeks, 1.24mg / kg / 10 weeks, 1.25mg / kg / 10 weeks, 1.26mg / kg / 10 weeks, 1.27mg / kg / 10 weeks, 1.28mg / kg / 10 weeks, 1.29mg / kg / 10 weeks, 1. 3mg / kg / 10 weeks, 1.31mg / kg / 10 weeks, 1.32mg / kg / 10 weeks, 1.33mg / kg / 10 weeks, 1.34mg / kg / 10 weeks, 1.35mg / kg / 10 weeks, 1.36mg / kg / 10 weeks, 1.37mg / kg / 10 weeks, 1.38mg / kg / 10 weeks, 1.39mg / kg / 10 weeks, 1.4mg / kg / 10 weeks, 1.41mg / kg / 10 weeks, 1.42mg / kg / 10 weeks, 1.43mg / kg / 10 weeks, 1.44mg / kg / 10 weeks, 1.45mg / kg / 10 weeks, 1.46mg / kg / 10 weeks, 1.47mg / kg / 10 weeks, 1. 48mg / kg / 10 weeks, 1.49mg / kg / 10 weeks, 1.5mg / kg / 10 weeks, 1.51mg / kg / 10 weeks, 1.52mg / kg / 10 weeks, 1.53mg / kg / 10 weeks, 1.54mg / kg / 10 weeks, 1.55mg / kg / 10 weeks, 1.56mg / kg / 10 weeks, 1.57mg / kg / 10 weeks, 1.58mg / kg / 10 weeks, 1.59mg / kg / 10 weeks, 1.6mg / kg / 10 weeks, 1.61mg / kg / 10 weeks, 1.62mg / kg / 10 weeks, 1.63mg / kg / 10 weeks, 1.64mg / kg / 10 weeks, 1.65mg / kg / 10 weeks, 1.66mg / kg / 10 weeks, 1.67mg / kg / 10 weeks, 1.68mg / kg / 10 weeks, 1.69mg / kg / 10 weeks, 1.7mg / kg / 10 weeks, 1.71mg / kg / 10 weeks, 1.72mg / kg / 10 weeks, 1.73mg / kg / 10 weeks, 1.74mg / kg / 10 weeks, 1.75mg / kg / 10 weeks, 1.76mg / kg / 10 weeks, 1.77mg / kg / 10 weeks, 1.78mg / kg / 10 weeks, 1.79mg / kg / 10 weeks, 1.8mg / kg / 10 weeks, 1.81mg / kg / 10 weeks, 1.82mg / kg / 10 weeks, 1.83mg / kg / 10 weeks, 1 .84mg / kg / 10 weeks, 1.85mg / kg / 10 weeks, 1.86mg / kg / 10 weeks, 1.87mg / kg / 10 weeks, 1.88mg / kg / 10 weeks, 1.89mg / kg / 10 weeks, 1.9mg / kg / 10 weeks, 1.91mg / kg / 10 weeks, 1.92mg / kg / 10 weeks, 1.93mg / kg / 10 weeks, 1.94mg / kg / 10 weeks, 1.95mg / kg / 10 weeks, 1.96mg / kg / 10 weeks, 1.97mg / kg / 10 weeks, 1.98mg / kg / 10 weeks, 1.99mg / kg / 10 weeks, 2.01mg / kg / 10 weeks, 2.0 2mg / kg / 10 weeks, 2.03mg / kg / 10 weeks, 2.04mg / kg / 10 weeks, 2.05mg / kg / 10 weeks, 2.06mg / kg / 10 weeks, 2.07mg / kg / 10 weeks, 2.08mg / kg / 10 weeks, 2.09mg / kg / 10 weeks, 2.1mg / kg / 10 weeks, 2.11mg / kg / 10 weeks, 2.12mg / kg / 10 weeks, 2.13mg / kg / 10 weeks, 2.14mg / kg / 10 weeks, 2.15mg / kg / 10 weeks, 2.16mg / kg / 10 weeks, 2.17mg / kg / 10 weeks, 2.18mg / kg / 10 weeks, 2.19mg / kg / 10 weeks, 2. 2mg / kg / 10 weeks, 2.21mg / kg / 10 weeks, 2.22mg / kg / 10 weeks, 2.23mg / kg / 10 weeks, 2.24mg / kg / 10 weeks, 2.25mg / kg / 10 weeks, 2.26mg / kg / 10 weeks, 2.27mg / kg / 10 weeks, 2.28mg / kg / 10 weeks, 2.29mg / kg / 10 weeks, 2.3mg / kg / 10 weeks, 2.31mg / kg / 10 weeks, 2.32mg / kg / 10 weeks, 2.33mg / kg / 10 weeks, 2.34mg / kg / 10 weeks, 2.35mg / kg / 10 weeks, 2.36mg / kg / 10 weeks, 2.37mg / kg / 10 weeks, 2.38mg / kg / 10 weeks, 2.39mg / kg / 10 weeks, 2.4mg / kg / 10 weeks, 2.41mg / kg / 10 weeks, 2.42mg / kg / 10 weeks, 2.43mg / kg / 10 weeks, 2.44mg / kg / 10 weeks, 2.45mg / kg / 10 weeks, 2.46mg / kg / 10 weeks, 2.47mg / kg / 10 weeks, 2.48mg / kg / 10 weeks, 2.49mg / kg / 10 weeks, 2.5mg / kg / 10 weeks, 2.51mg / kg / 10 weeks, 2.52mg / kg / 10 weeks, 2.53mg / kg / 10 weeks , 2.54mg / kg / 10 weeks, 2.55mg / kg / 10 weeks, 2.56mg / kg / 10 weeks, 2.57mg / kg / 10 weeks, 2.58mg / kg / 10 weeks, 2.59mg / kg / 10 weeks, 2.6mg / kg / 10 weeks, 2.61mg / kg / 10 week, 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 / k g / 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, 3 mg / kg / 10 weeks, etc. Alternatively, in one non-limiting embodiment, it may be, for example, 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, 0.15mg / kg / 12 weeks, 0.16mg / kg / 12 weeks, 0.17mg / kg / 12 weeks, 0.18mg / kg / 12 weeks, 0.19mg / kg / 12 weeks, 0.2mg / kg / 12 weeks, 0.21mg / kg / 12 weeks, 0.22mg / kg / 12 weeks, 0.23mg / kg / 12 weeks, 0.24mg / kg / 12 weeks, 0.25mg / kg / 12 weeks, 0.26mg / kg / 12 weeks, 0.27mg / kg / 12 weeks, 0.28mg / kg / 12 weeks, 0.29mg / kg / 12 weeks, 0.3mg / kg / 12 weeks, 0.3 1mg / kg / 12 weeks, 0.32mg / kg / 12 weeks, 0.33mg / kg / 12 weeks, 0.34mg / kg / 12 weeks, 0.35mg / kg / 12 weeks, 0.36mg / kg / 12 weeks, 0.37mg / kg / 12 weeks, 0.38mg / kg / 12 weeks, 0.39mg / kg / 12 weeks, 0.4mg / kg / 12 weeks, 0.41mg / kg / 12 weeks, 0.42mg / kg / 12 weeks, 0.43mg / kg / 12 weeks, 0.44mg / kg / 12 weeks, 0.45mg / kg / 12 weeks, 0.46mg / kg / 12 weeks, 0.4 7mg / kg / 12 weeks, 0.48mg / kg / 12 weeks, 0.49mg / kg / 12 weeks, 0.5mg / kg / 12 weeks, 0.51mg / kg / 12 weeks, 0.52mg / kg / 12 weeks, 0.53mg / kg / 12 weeks, 0.54mg / kg / 12 weeks, 0.55mg / kg / 12 weeks, 0.56mg / kg / 12 weeks, 0.57mg / kg / 12 weeks, 0.58mg / kg / 12 weeks, 0.59mg / kg / 12 weeks, 0.6mg / kg / 12 weeks, 0.61mg / kg / 12 weeks, 0.62mg / kg / 12 weeks, 0.63 mg / kg / 12 weeks, 0.64mg / kg / 12 weeks, 0.65mg / kg / 12 weeks, 0.66mg / kg / 12 weeks, 0.67mg / kg / 12 weeks, 0.68mg / kg / 12 weeks, 0.69mg / kg / 12 weeks, 0.7mg / kg / 12 weeks, 0.71mg / kg / 12 weeks, 0.72mg / kg / 12 weeks, 0.73mg / kg / 12 weeks, 0.74mg / kg / 12 weeks, 0.75mg / kg / 12 weeks, 0.76mg / kg / 12 weeks, 0.77mg / kg / 12 weeks, 0.78mg / kg / 12 weeks, 0.7. 9mg / kg / 12 weeks, 0.8mg / kg / 12 weeks, 0.81mg / kg / 12 weeks, 0.82mg / kg / 12 weeks, 0.83mg / kg / 12 weeks, 0.84mg / kg / 12 weeks, 0.85mg / kg / 12 weeks, 0.86mg / kg / 12 weeks, 0.87mg / kg / 12 weeks, 0.88mg / kg / 12 weeks, 0.89mg / kg / 12 weeks, 0.9mg / kg / 12 weeks, 0.91mg / kg / 12 weeks, 0.92mg / kg / 12 weeks, 0.93mg / kg / 12 weeks, 0.94mg / kg / 12 weeks, 0.95mg / kg / 12 weeks, 0.96mg / kg / 12 weeks, 0. 97mg / kg / 12 weeks, 0.98mg / kg / 12 weeks, 0.99mg / kg / 12 weeks, 1mg / kg / 12 weeks, 1.01mg / kg / 12 weeks, 1.02mg / kg / 12 weeks, 1.03mg / kg / 12 weeks, 1.04mg / kg / 12 weeks, 1.05mg / kg / 12 weeks, 1.06mg / kg / 12 weeks, 1.07mg / kg / 12 weeks, 1.08mg / kg / 12 weeks, 1.09mg / kg / 12 weeks, 1.1mg / kg / 12 weeks, 1.11mg / kg / 12 weeks, 1.12mg / kg / 12 weeks, 1.13mg / kg / 12 weeks, 1.14mg / kg / 12 weeks, 1.1 5mg / kg / 12 weeks, 1.16mg / kg / 12 weeks, 1.17mg / kg / 12 weeks, 1.18mg / kg / 12 weeks, 1.19mg / kg / 12 weeks, 1.2mg / kg / 12 weeks, 1.21mg / kg / 12 weeks, 1.22mg / kg / 12 weeks, 1.23mg / kg / 12 weeks, 1.24mg / kg / 12 weeks, 1.25mg / kg / 12 weeks, 1.26mg / kg / 12 weeks, 1.27mg / kg / 12 weeks, 1.28mg / kg / 12 weeks, 1.29mg / kg / 12 weeks, 1.3mg / kg / 12 weeks, 1.31mg / kg / 12 weeks, 1.32mg / kg / 12 weeks, 1. 33mg / kg / 12 weeks, 1.34mg / kg / 12 weeks, 1.35mg / kg / 12 weeks, 1.36mg / kg / 12 weeks, 1.37mg / kg / 12 weeks, 1.38mg / kg / 12 weeks, 1.39mg / kg / 12 weeks, 1.4mg / kg / 12 weeks, 1.41mg / kg / 12 weeks, 1.42mg / kg / 12 weeks, 1.43mg / kg / 12 weeks, 1.44mg / kg / 12 weeks, 1.45mg / kg / 12 weeks, 1.46mg / kg / 12 weeks, 1.47mg / kg / 12 weeks, 1.48mg / kg / 12 weeks, 1.49mg / kg / 12 weeks, 1.5mg / kg / 12 weeks, 1.51mg / kg / 12 weeks, 1.52mg / kg / 12 weeks, 1.53mg / kg / 12 weeks, 1.54mg / kg / 12 weeks, 1.55mg / kg / 12 weeks, 1.56mg / kg / 12 weeks, 1.57mg / kg / 12 weeks, 1.58mg / kg / 12 weeks, 1.59mg / kg / 12 weeks, 1.6mg / kg / 12 weeks, 1.61mg / kg / 12 weeks, 1.62mg / kg / 12 weeks, 1.63mg / kg / 12 weeks, 1.64mg / kg / 12 weeks, 1.65mg / kg / 12 weeks, 1.66mg / kg / 12 weeks, 1.67mg / kg / 12 weeks, 1.68mg / kg / 12 weeks, 1.69mg / kg / 12 weeks, 1.7mg / kg / 12 weeks, 1.71mg / kg / 12 weeks, 1.72mg / kg / 12 weeks, 1.73mg / kg / 12 weeks, 1.74mg / kg / 12 weeks, 1.75mg / kg / 12 weeks, 1.76mg / kg / 12 weeks, 1.77mg / kg / 12 weeks, 1.78mg / kg / 12 weeks, 1.79mg / kg / 12 weeks, 1.8mg / kg / 12 weeks, 1.81mg / kg / 12 weeks, 1.82mg / kg / 12 weeks, 1.83mg / kg / 12 weeks, 1.84mg / kg / 12 weeks, 1.85mg / kg / 12 weeks, 1.86mg / kg / 12 weeks, 1.87mg / kg / 12 weeks, 1.88mg / kg / 12 weeks, 1.89mg / kg / 12 weeks, 1.9mg / kg / 12 weeks, 1.91mg / kg / 12 weeks, 1.92mg / kg / 12 weeks, 1.93mg / kg / 12 weeks, 1.94mg / kg / 12 weeks, 1.95mg / kg / 12 weeks, 1.96mg / kg / 12 weeks, 1.97mg / kg / 12 weeks, 1.98mg / kg / 12 weeks, 1.99mg / kg / 12 weeks, 2mg / kg / 12 weeks, 2.01mg / kg / 12 weeks, 2.02mg / kg / 12 weeks, 2.03mg / kg / 12 weeks, 2.04mg / kg / 12 weeks, 2. 05mg / kg / 12 weeks, 2.06mg / kg / 12 weeks, 2.07mg / kg / 12 weeks, 2.08mg / kg / 12 weeks, 2.09mg / kg / 12 weeks, 2.1mg / kg / 12 weeks, 2.11mg / kg / 12 weeks, 2.12mg / kg / 12 weeks, 2.13mg / kg / 12 weeks, 2.14mg / kg / 12 weeks, 2.15mg / kg / 12 weeks, 2.16mg / kg / 12 weeks, 2.17mg / kg / 12 weeks, 2.18mg / kg / 12 weeks, 2.19mg / kg / 12 weeks, 2.2mg / kg / 12 weeks, 2.21mg / kg / 12 weeks, 2.22mg / kg / 12 weeks, 2.23mg / kg / 12 weeks, 2.24mg / kg / 12 weeks, 2.25mg / kg / 12 weeks, 2.26mg / kg / 12 weeks, 2.27mg / kg / 12 weeks, 2.28mg / kg / 12 weeks, 2.29mg / kg / 12 weeks, 2.3mg / kg / 12 weeks, 2.31mg / kg / 12 weeks, 2.32mg / kg / 12 weeks, 2.33mg / kg / 12 weeks, 2.34mg / kg / 12 weeks, 2.35mg / kg / 12 weeks, 2.36mg / kg / 12 weeks, 2.37mg / kg / 12 weeks, 2.38mg / kg / 12 weeks, 2.39mg / kg / 12 weeks, 2.4mg / kg / 12 weeks. 41mg / kg / 12 weeks, 2.42mg / kg / 12 weeks, 2.43mg / kg / 12 weeks, 2.44mg / kg / 12 weeks, 2.45mg / kg / 12 weeks, 2.46mg / kg / 12 weeks, 2.47mg / kg / 12 weeks, 2.48mg / kg / 12 weeks, 2.49mg / kg / 12 weeks, 2.5mg / kg / 12 weeks, 2.51mg / kg / 12 weeks, 2.52mg / kg / 12 weeks, 2.53mg / kg / 12 weeks, 2.54mg / kg / 12 weeks, 2.55mg / kg / 12 weeks, 2.56mg / kg / 12 weeks, 2.57mg / kg / 12 weeks, 2.58mg / kg / 12 weeks, 2 .59mg / kg / 12 weeks, 2.6mg / kg / 12 weeks, 2.61mg / kg / 12 weeks, 2.62mg / kg / 12 weeks, 2.63mg / kg / 12 weeks, 2.64mg / kg / 12 weeks, 2.65mg / kg / 12 weeks, 2.66mg / kg / 12 weeks, 2.67mg / kg / 12 weeks, 2.68mg / kg / 12 weeks, 2.69mg / kg / 12 weeks, 2.7mg / kg / 12 weeks, 2.71mg / kg / 12 weeks, 2.72mg / kg / 12 weeks, 2.73mg / kg / 12 weeks, 2.74mg / kg / 12 weeks, 2.75mg / kg / 12 weeks, 2.76mg / kg / 12 weeks, 2 .77mg / kg / 12 weeks, 2.78mg / kg / 12 weeks, 2.79mg / kg / 12 weeks, 2.8mg / kg / 12 weeks, 2.81mg / kg / 12 weeks, 2.82mg / kg / 12 weeks, 2.83mg / kg / 12 weeks, 2.84mg / kg / 12 weeks, 2.85mg / kg / 12 weeks, 2.86mg / kg / 12 weeks, 2.87mg / kg / 12 weeks, 2.88mg / kg / 12 weeks, 2.89mg / kg / 12 weeks, 2.9mg / kg / 12 weeks, 2.91mg / kg / 12 weeks, 2.92mg / kg / 12 weeks, 2.93mg / kg / 12 weeks, 2.94mg / kg / 12 weeks, 2.The dose may be 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, 3 mg / kg / 12 weeks, etc.

[0056] The IL-31 antagonist of the present disclosure can be repeatedly administered at the same administration interval and at the same dose (dosage) as described above to a subject suffering from or at risk of suffering from atopic dermatitis, thereby continuously suppressing or ameliorating one or more of atopic dermatitis and / or various symptoms associated therewith (e.g., itching, redness, induration, papules, edema, excoriation, lichenification, decreased quality of life, or sleep deprivation, etc.). The doses administered in equal amounts and the administration intervals that provide the same dose are determined taking into consideration, for example, efficacy and safety.

[0057] In one embodiment, the method of administering the pharmaceutical composition of the present disclosure to a subject can be selected from oral administration and parenteral administration. Typically, but not limited to, when the active ingredient is a low-molecular-weight compound, oral or parenteral administration may be used, while when the active ingredient is a high-molecular-weight compound, parenteral administration is preferred. Examples of parenteral administration include injection, nasal administration, pulmonary administration, and transdermal administration, and examples of injection include intravenous injection, intramuscular injection, intraperitoneal injection, and subcutaneous injection. These administration methods allow the pharmaceutical composition of the present disclosure to be administered systemically or locally. For example, subcutaneous administration by subcutaneous injection is preferred.

[0058] In one embodiment, the pharmaceutical compositions of the present disclosure can be formulated by combining the active ingredient, an IL-31 antagonist, with a pharmaceutically acceptable carrier and then using known methods. For example, the IL-31 antagonist can be formulated by appropriately combining it with a pharmaceutically acceptable carrier or vehicle, such as sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc. Examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, inorganic salts, etc. The amount of the active ingredient in these formulations can be appropriately determined within the recommended dosage range.

[0059] In another embodiment, the present disclosure relates to a method for preventing and / or treating atopic dermatitis, comprising administering an IL-31 antagonist to a subject suffering from or at risk of suffering from atopic dermatitis. In such cases, the IL-31 antagonist may be repeatedly administered at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.1 mg to 1000 mg / body / day to 12 weeks, preferably 0.1 mg to 1000 mg / body / 2 weeks, 0.1 mg to 1000 mg / body / 4 weeks, or 0.1 mg to 1000 mg / body / 8 weeks. Alternatively, the IL-31 antagonist may be repeatedly administered at the same dose and at the same administration interval to a subject suffering from or at risk of suffering from atopic dermatitis at a dose of 0.01 mg to 10 mg / kg / day to 12 weeks, preferably 0.01 mg to 10 mg / kg / 2 weeks, 0.01 mg to 10 mg / kg / 4 weeks, or 0.01 mg to 10 mg / kg / 8 weeks. Furthermore, in such preventive and / or therapeutic methods, the IL-31 antagonist may be administered before, simultaneously with, or after administration of a topical steroid or a topical calcineurin inhibitor.

[0060] In another aspect, the present disclosure provides a product comprising at least (i) a container (e.g., an injection); (ii) a pharmaceutical composition in the container containing an IL-31 antagonist as an active ingredient; and (iii) a written document instructing repeated administration of the IL-31 antagonist at equal doses and at the same administration intervals to a subject suffering from or at risk of suffering from atopic dermatitis, at a dose of 0.1 mg to 1000 mg / body / day for 12 weeks or 0.01 mg to 10 mg / kg / day for 12 weeks. The product may also be packaged with other items, such as a label, a syringe, needles, a pharmaceutically acceptable medium, an alcohol wipe, and a bandage, as appropriate. The container may be, for example, a bottle, glass vial, or syringe, and may be made of various materials such as glass or plastic. The container contains the pharmaceutical composition, and the opening and closing port is sealed, for example, with a rubber stopper. The container is affixed with a label indicating, for example, that the pharmaceutical composition is used for the prevention or treatment of a selected condition. The label may optionally describe the use of the IL-31 antagonist in combination with a topical steroid or a topical calcineurin inhibitor.

[0061] All technical documents cited herein are incorporated herein by reference in their entirety.

[0062] In this specification, the meaning of the term "and / or" is understood to include any combination of the terms before and after the phrase "and / or", where "and" and "or" are combined as appropriate.

[0063] The terms used in this specification are used to describe specific embodiments and should not be understood as being intended to limit the invention. Unless otherwise defined, the terms used in this specification (including technical and scientific terms) should be interpreted as having the same meaning as commonly understood by those skilled in the art to which this disclosure belongs, and should not be interpreted in an idealized or overly formal sense.

[0064] The term "comprises" as used in this specification intends that the stated items (components, steps, elements, numbers, etc.) are present, unless the context clearly dictates otherwise, and does not exclude the presence of other items (components, steps, elements, numbers, etc.).

[0065] Embodiments of the present disclosure may be described with reference to schematic diagrams, which may be exaggerated for clarity of illustration.

[0066] Numerical values described herein may be understood as values having a certain range according to the common general knowledge of those skilled in the art, unless the context dictates otherwise. For example, the term "1 mg" is understood to mean "approximately 1 mg" and is understood to encompass a certain amount of variation based on the description of the present specification and the common general knowledge of those skilled in the art. Furthermore, when the term "1 to 5 times" is used herein, it may be understood that each value is specifically described, such as "1 time, 2 times, 3 times, 4 times, 5 times," unless the context dictates otherwise. Furthermore, when the term "20 times, ... 25 times" is used herein, it may be understood that each value is specifically described, such as "20 times, 21 times, 22 times, 23 times, 24 times, 25 times," unless the context dictates otherwise. Furthermore, in this specification, for example, when it is stated that "1 to 5000 pg / mL" is used, it is not limited to "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, 100 pg / mL, 110 pg / mL, 120 pg / mL, 130 pg / mL, 140 pg / mL, 150 pg / mL, 160 pg / mL, 170 pg / mL, 180 pg / mL, 190 pg / mL, 210 pg / mL, 220 pg / mL, 230 pg / mL, 240 pg / mL, 250 pg / mL, 260 pg / mL, 270 pg / mL, 280 pg / mL, 290 pg / mL, 300 pg / mL, 310 pg / mL, 320 pg / mL, 330 pg / mL, 340 pg / mL, 350 pg / mL, 360 pg / mL, 370 pg / mL, 380 pg / mL, 390 pg / mL, 400 pg / mL, 410 pg / 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".Furthermore, for example, when a description is made of "10 pg / mL, . . . 15 pg / mL," it may be understood that each value is individually and specifically described, such as "10 pg / mL, 11 pg / mL, 12 pg / mL, 13 pg / mL, 14 pg / mL, 15 pg / mL," unless the context indicates otherwise. Therefore, a person skilled in the art would naturally understand that, for example, a description of "1 to 5000 pg / mL" directly and unambiguously describes values such as 100 pg / mL, 224 pg / mL, 1500 pg / mL, etc. Unless the context indicates otherwise, the numerical values described herein may be interpreted in the same manner as appropriate, and similarly, it may be naturally understood by a person skilled in the art that each value is individually and specifically described directly and unambiguously. [Example]

[0067] The present disclosure will be specifically described below using examples, but the present disclosure is not limited to these examples.

[0068] [Example 1] Preparation of anti-human IL-31RA antibody CIM331 (H chain, SEQ ID NO: 9; L chain, SEQ ID NO: 10), an anti-human IL-31RA antibody also described in WO2010 / 064697, was produced by methods known to those skilled in the art, in accordance with the description of the aforementioned patent document. As also described in WO2010 / 064697, CIM331 has neutralizing activity against human IL-31RA and cynomolgus monkey IL-31RA.

[0069] [Example 2] Modification of antibody amino acid residues Antibodies in which at least one amino acid residue that can be exposed on the antibody surface has been modified to lower the isoelectric point (pI) of the antibody (hereinafter also referred to as "pI-reduced antibodies") may reduce intracellular uptake of the antibody or delay elimination of the antibody from plasma, as described or suggested in WO2009 / 041643. The anti-human IL-31RA antibody CIM331 was produced by substituting multiple amino acid residues in the CDRs that can increase or decrease the pI as described in WO2009 / 041643 (e.g., K62Q, K64Q, and G65D in the H-chain variable region; R24Q, N27aD, and L54E (Kabat numbering) in the L-chain variable region).

[0070] It has recently been discovered that the pI can also be increased or decreased by substituting amino acid residues in the antibody constant region. Such a method is described, for example, in WO2014 / 145159.

[0071] To confirm the effect of amino acid residue substitutions in the antibody constant region on pI, an anti-human IgE antibody was produced by the method of Reference Example 1. Specifically, a conventional antibody, Ab1, was produced, consisting of Ab1H (SEQ ID NO: 12) as the heavy chain and Ab1L (SEQ ID NO: 13) as the light chain. The theoretical isoelectric points (pI) of the antibodies thus prepared were calculated using GENETYX-SV / RC Ver. 9.1.0 (GENETYX CORPORATION) by methods known to those skilled in the art (Skoog, B. and Wichman, A. 1986. Calculation of the isoelectric points of polypeptides from the amino acid composition. Trends in analytical chemistry, Vol. 5, No. 4, pp. 82-83). Note that calculations were performed assuming that all cysteine side chains in the antibody molecule form disulfide bonds, excluding the contribution of the pKa of the cysteine side chains. The theoretical pI of Ab1 was 6.77.

[0072] The Ab1 thus constructed is an antibody having a human native IgG1 constant region. Ab1H, the heavy chain of Ab1, was modified in the Fc region by altering proline at position 238 (EU numbering) to aspartic acid and serine at position 298 (EU numbering) to alanine to create Ab1H-P600. Furthermore, a Q419K (EU numbering) mutation, which substitutes an uncharged amino acid for a positively charged amino acid, was introduced into the Fc region of Ab1H-P600 to create an Fc variant (Ab1H-P850) using the method described in Reference Example 1. Ab1L (SEQ ID NO: 13) was used as the light chain.

[0073] For antibodies containing the constructed Fc variant (Ab1H-P850), a binding experiment between soluble human FcγR2b (also referred to as "human FcγRIIb" or "hFcγR2b") and antigen-antibody complexes was performed using a Biacore T200 (GE Healthcare). Soluble human FcγR2b was prepared as a His-tagged molecule using methods known to those skilled in the art. An appropriate amount of anti-His antibody was immobilized on a sensor chip CM5 (GE Healthcare) by the amine coupling method using a His capture kit (GE Healthcare), and human FcγR2b was captured onto the immobilized antibody. Next, the antibody-antigen complex and running buffer (as a reference solution) were injected and allowed to interact with the human FcγR2b captured on the sensor chip. The running buffer was 20 mM N-(2-acetamido)-2-aminoethanesulfonic acid, 150 mM NaCl, 1.2 mM CaCl2, 0.05% (w / v) Tween 20, pH 7.4, and the soluble human FcγRIIb was also diluted with this buffer. 10 mM glycine-HCl, pH 1.5 was used to regenerate the sensor chip. All measurements were performed at 25°C. Analysis was performed based on binding (RU) calculated from the sensorgram obtained from the measurements, and the binding amount at P600 was expressed as a relative value, with the binding amount at P600 set at 1.00. Parameters were calculated using Biacore T100 Evaluation Software (GE Healthcare).

[0074] Comparison of Ab1H-P600 and Ab1H-P850 showed that Ab1H-P850 had enhanced binding to hFcγR2b immobilized on a Biacore sensor chip (the value for Ab1H-P850 was 2.22, where the value for Ab1H-P600 was 1.00). Furthermore, Biacore confirmed that the affinity of Ab1H-P850 for hFcγR2b itself was comparable to that of Ab1H-P600 for hFcγR2b itself (data not shown).

[0075] Without being bound by any particular theory, this result can be explained as follows. The Biacore sensor chip is known to be negatively charged, and its charge state can be considered to be similar to that of a cell membrane surface. In other words, the binding of antigen-antibody complexes to hFcγR2b immobilized on the negatively charged Biacore sensor chip is expected to be similar to the binding of antigen-antibody complexes to hFcγR2b present on the negatively charged cell membrane surface. Here, an antibody containing an Fc variant (Ab1H-P850) in which a pI-increasing modification was introduced at position 419 of the Fc region exhibits a more positively biased Fc region charge compared to an antibody containing Ab1H-P600 before the modification was introduced. Therefore, it is conceivable that the Coulombic interaction between the Fc region (positive charge) and the sensor chip (negative charge) is strengthened by the amino acid modification that increases the pI. Furthermore, since this effect is expected to occur similarly on the surface of a cell membrane, which also has a negative charge, it is expected to accelerate the rate of intracellular uptake in vivo. Conversely, by using an Fc variant in which an amino acid that lowers the pI (e.g., aspartic acid or glutamic acid) has been introduced at position 419 of the Fc region, the charge of the Fc region becomes more negative compared to before the alteration was introduced, and the pI-lowering amino acid alteration weakens the Coulombic interaction between the Fc region (negative charge) and the cell membrane surface (negative charge), which is expected to slow the rate of intracellular uptake in vivo and increase the plasma half-life of the antibody. Note that, while Ab1 is an antibody that has human native IgG1 as its constant region, the amino acid residue at position 419 (EU numbering) is glutamine (Q) in all of human native IgG1 to IgG4, and therefore, it will be understood by those skilled in the art that the same results can be observed regardless of the type of IgG. The amino acid sequence of CIM331 has an amino acid mutation in which Gln(Q)419 is replaced with Glu(E).

[0076] A notable finding was made in nonclinical studies of CIM331 prior to clinical trials. Specifically, the antigen-antibody interaction of CIM331 with mouse, rat, and rabbit IL-31RA was evaluated using Biacore (Biacore T100 (GE Healthcare)) by methods known to those skilled in the art. The results showed that CIM331 did not exhibit cross-reactivity with mouse, rat, or rabbit IL-31RA (Sakurai T, Esaki K. Cross-reactivity of CH5427227 with NR10 (IL-31RA) from mice, rats, and rabbits (Study No. TOX08-0198S). Chugai Pharmaceutical Co., Ltd. In-house report, 2010.). Therefore, even those skilled in the art had to predict the effects of CIM331 in humans, as described below, by actually administering CIM331 to humans to confirm the effects, or by administering it to a human model that exhibits cross-reactivity (e.g., cynomolgus monkeys) and then extrapolating the results to humans.

[0077] Example 3A Subcutaneous administration of CIM331 suppresses IL-31-induced pruritus in cynomolgus monkeys We investigated the effect of subcutaneous administration of CIM331 on pruritus induced by intravenous administration of cynomolgus monkey IL-31 in cynomolgus monkeys. The number of pruritic behaviors was measured as an index of pruritic reactivity. The number of pruritic behaviors was determined by visually observing the monkeys' behavior (over 2 hours) recorded with a video camera, and counting each scratching of a body part with a forelimb or hind limb as one pruritic behavior. However, pruritic behaviors that ended after one or two occurrences were considered accidental and were excluded from the number of pruritic behaviors. First, before CIM331 administration, the behavior of individual cynomolgus monkeys without IL-31 administration was videotaped (for 2 hours). Afterwards, the video was replayed and the number of itch-inducing behaviors without IL-31 administration was counted using the method described above. Cynomolgus monkeys received a single subcutaneous dose of 0.2 or 1 mg / kg of CIM331, and the number of pruritic behaviors after administration of cynomolgus IL-31 was measured to assess the effects of subcutaneous CIM331. Cynomolgus monkeys received a single subcutaneous dose of 0.2 mg / kg of CIM331, and then received intravenous administration of 1 μg / kg of cynomolgus IL-31 before and 3, 15, 28, 42, 56, and 93 days after subcutaneous CIM331 administration. After administration of cynomolgus IL-31, individual behavior was videotaped (2 hours). Similarly, cynomolgus monkeys received a single subcutaneous dose of 1 mg / kg CIM331, followed by intravenous administration of 1 μg / kg cynomolgus IL-31 before and 28, 42, 56, 77, 79, 81, 84, and 93 days after subcutaneous administration of CIM331. After administration of cynomolgus IL-31, individual behavior was videotaped (2 hours). The video was then replayed and the number of pruritic behaviors after administration of cynomolgus IL-31 was measured using the method described above.

[0078] Before CIM331 administration, the number of itch-inducing behaviors increased with cynomolgus IL-31 administration compared to before CIM331 administration, confirming that itch was induced. Furthermore, a single subcutaneous administration of CIM331 to cynomolgus monkeys was confirmed to decrease the number of itch-inducing behaviors after cynomolgus IL-31 administration. A single subcutaneous administration of 0.2 mg / kg CIM331 to cynomolgus monkeys reduced the mean number of itch-related behaviors after cynomolgus IL-31 administration compared to before CIM331 administration, and the mean number of itch-related behaviors after cynomolgus IL-31 administration was still reduced 42 days later (Figure 6). Furthermore, a single subcutaneous administration of 1 mg / kg CIM331 reduced the mean number of itch-related behaviors after cynomolgus IL-31 administration even 77 days after CIM331 administration (Figure 7).

[0079] To determine the human dosage, the effective plasma concentration of CIM331 was determined based on the results of an in vivo cynomolgus monkey IL-31-induced pruritus model, in which systemic pruritus was induced in cynomolgus monkeys by administration of cynomolgus monkey IL-31. In this study, CIM331 was administered intravenously to the same cynomolgus monkey at doses ranging from 3 μg / kg to 100 μg / kg in incremental increments (3, 10, 40, 60, and 100 μg / kg) to increase the plasma concentration. Blood samples were taken the day after each dose to measure plasma CIM331 concentrations. Itching behavior induced by intravenous administration of 1 μg / kg of cynomolgus monkey IL-31 was videotaped and the number of pruritic events was counted for 2 hours after administration. The number of pruritic behaviors was determined by visually observing the monkeys' behavior (over 2 hours) recorded with a video camera. Scratching a part of the body with either the forelimbs or hindlimbs was counted as one pruritic behavior. However, pruritic behaviors that ended after one or two occurrences were considered accidental and were excluded from the count. CIM331 was administered intravenously at gradually increasing doses, resulting in a dose-dependent increase in the mean plasma CIM331 concentration on the day after administration. CIM331 demonstrated a clear inhibitory effect on IL-31-induced pruritus in cynomolgus monkeys from 40 μg / kg administration onward (mean plasma concentration on the day after administration was 670 ng / mL). This mean plasma concentration of 670 ng / mL was used as the estimated effective serum concentration of CIM331 in humans.It has been reported that the pharmacokinetics of antibodies are similar in humans and cynomolgus monkeys (Jennifer Q. Dong et al., Quantitative Prediction of Human Pharmacokinetics for Monoclonal Antibodies. Clin Pharmacokinet 2011;50(2):131-142; Jie Ling et al., Interspecies Scaling of Therapeutic Monoclonal Antibodies: Initial Look. J Clin Pharmacol 2009:49(12):1382-1402; Rong Deng et al., Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data. mAbs 2011:3(1):61-66). Therefore, PK parameters obtained by nonlinear analysis of plasma CIM331 concentration profiles in cynomolgus monkey PK studies were used to predict PK parameters in humans. For the nonlinear analysis, a nonlinear analysis model incorporating the Michaelis-Menten equation (Figure 8) was used.

[0080] The mean plasma CIM331 concentrations after intravenous and subcutaneous administration of CIM331 at 0.04 mg / kg, 0.2 mg / kg, and 1.0 mg / kg in cynomolgus monkeys were simultaneously fitted to the above model to calculate optimal parameters. The resulting parameters were used to predict the serum concentration of CIM331 when administered to humans. When administered to humans at 1 mg / kg, it was predicted that serum concentrations of CIM331 would be maintained at 670 ng / mL or higher, the estimated effective serum concentration in humans, for 56 days (Figure 9). The predicted optimal clinical dose was 1 mg / kg, which is expected to reliably maintain the inhibitory effect of CIM331 on IL-31 signaling for at least one month.

[0081] Example 3B A single subcutaneous injection in patients with atopic dermatitis In the test drug group of the Phase I single-dose study, 36 patients with atopic dermatitis who met the following criteria received a single subcutaneous injection of CIM331 at doses of 0.3 mg / kg, 1 mg / kg, or 3 mg / kg of body weight or placebo in the abdomen (9 patients per group). Patients selected for CIM331 administration were atopic dermatitis patients who met the following criteria despite having been treated with topical steroids for 12 weeks or more. Eczema Area Severity Index of 10 or more and severe inflammation of the skin covering 5% or more of the body surface area - The total score of the daytime and nighttime itching severity rating based on the Shiratori severity classification is 4 or higher - Itch VAS mean value ≧ 50mm The investigational drug was a 1 mL solution containing 100 mg of CIM331 antibody per mL, or diluted to the desired administration concentration. Physiological saline was used as a placebo.

[0082] (3-1) Evaluation item: Itching The intensity of itching was assessed using a visual analog scale (VAS). The VAS is a 100 mm line, with 0 mm representing no itching and 100 mm representing the most severe itching the patient has ever experienced due to atopic dermatitis. Patients indicate the intensity of their itching upon waking and at bedtime by drawing a line between 0 and 100 mm. Patients recorded their itching every day during the study period. As a result, the VAS decreased by approximately 20% in the placebo group, whereas in the CIM331-treated groups, the VAS decreased from one week after administration in all dose groups, and the decrease was maintained at approximately 50% even after four weeks of administration (Figure 1).

[0083] (3-2) Evaluation item: Dermatitis The Eczema Area Severity Index (EASI) score is a tool for measuring the severity and extent of atopic dermatitis. The degree and proportion of eczema in typical affected areas were assessed for each of four areas: head and neck, upper limbs, trunk, and lower limbs. The degree of redness (erythema), thickness (induration, papules, edema), scratching (excoriation), and lichenification were assessed using a scale of none (0), mild (1), moderate (2), or severe (3). During the clinical trial, physicians assessed the scores weekly or biweekly. The mean change in EASI score from baseline at 4 weeks after treatment was analyzed by the reduction rate of pruritus VAS score at 4 weeks after treatment (i.e., the group with a reduction rate of less than 50% and the group with a reduction rate of 50% or more). As a result, in the group with a reduction in itch VAS score of 50% or more, the mean change in EASI score was -11.5 points, which was a larger reduction in EASI score compared to the group with a reduction of less than 50% or the placebo group (Figure 2).

[0084] (3-3) Evaluation item: Quality of life (QOL) (3-3-1) Sleep The Actiwatch® is a non-invasive wrist-worn device designed to capture, record, and store ambulatory wrist movements, which are indicators of whole-body movement. Subjects wore the device until Week 4 after administration. Other parameters, including actual time from sleep onset to wakefulness, sleep latency, and sleep efficiency, were measured objectively. Sleep efficiency was calculated using the following formula:

number

[0085] (3-4) Evaluation item: Amount of topical steroid used Topical steroids (Locoid (registered trademark); hydrocortisone butyrate ester) were also used in all patients. The amount of topical steroids used could be increased or decreased depending on the patient's condition. As a result, the amount of Locoid used tended to increase in the placebo group, whereas the amount used in the CIM331 group showed a tendency to decrease from one week after administration in all dose groups (Figure 4).

[0086] (3-5) Evaluation items: serum concentration and pharmacokinetic parameters of CIM331 The time course of serum CIM331 concentrations in Japanese patients with atopic dermatitis is shown in Figure 5, and the pharmacokinetic parameter values are shown in Table 1.

[0087] [Table 1]

[0088] As a result, CIM331 reached its maximum serum concentration 4.46 to 5.66 days (mean, same below) after administration of CIM331, and then its serum elimination half-life (t 1 / 2 ) Slow disappearance was observed in 12.6 to 14.6 days. C in the 0.3 mg / kg, 1 mg / kg, and 3 mg / kg groups max were 2.20, 6.50, and 19.4 μg / mL, respectively, and AUC infThe AUC values after a single subcutaneous administration of CIM331 were 49.2, 161, and 489 μg / mL, respectively. inf , AUC last and C max The serum CIM331 concentration increased in proportion to the dose. There was a dose-dependent tendency for the duration of time during which the concentration remained above a certain level. Furthermore, the relationship between the exposure and the suppressive effect of CIM331 administration was not clear in this study. In the table, the terms have the following meanings: AUC inf : AUC extrapolated from time 0 to infinity AUC last : AUC from time 0 to the last quantifiable plasma concentration time point CL / F: Apparent clearance C max : Maximum blood concentration MRT: Mean residence time t 1 / 2 : Elimination half-life T max : Time to reach maximum blood concentration

[0089] (3-6) Exploratory endpoint: Efficacy These results demonstrated that CIM331 improved pruritus, dermatitis, and quality of life in patients with atopic dermatitis. This study is the first clinical trial report demonstrating the efficacy of an IL-31 antagonist for treating pruritus caused by atopic dermatitis. Based on its novel mechanism of action, blocking the Itch-Scratch Cycle, CIM331 is expected to improve not only pruritus caused by atopic dermatitis, but also dermatitis and quality of life. Itchy eczema is known to be an exacerbating factor for eczema. Itch-scratch damage mechanically damages the skin, weakening its barrier function. Foreign antigens penetrate the epidermis, enhancing the inflammatory response, leading to worsening dermatitis and pruritus. This vicious cycle of itching-worsening dermatitis-worsening pruritus is known as the Itch Scratch Cycle (e.g., Wahlgren CF. J Dermatol 1999;26:770-9; Homey B, et al. J Allergy Clin Immunol 2006;118:178-89).

[0090] [Example 4] Repeated subcutaneous administration in patients with atopic dermatitis (4-1) Phase II multiple-dose study In the test drug group of the Phase II multiple-dose study, approximately 250 patients with moderate to severe atopic dermatitis who have not responded adequately to or are intolerant to topical treatment will receive subcutaneous administration of either CIM331 or placebo in the abdomen as follows: The CIM331 dose and administration solution concentration per body weight will be as follows, and the CIM331 will be administered slowly at a volume of 20 μL / kg of body weight. If the subject weighs more than 120 kg, the investigational drug will be prepared assuming a body weight of 120 kg. The investigational drug will be prepared by lyophilizing a solution containing 100 mg of CIM331 antibody per mL, filled in 1.53 mL per vial, and reconstituting it with water for injection to form the administration solution, which will then be further diluted with a separately prepared placebo solution to achieve the desired administration concentration.

[0091] [Table 2]

[0092] Patients eligible for CIM331 were selected from atopic dermatitis patients who had not achieved sufficient results after four or more weeks of continuous, fixed use of topical steroids or topical calcineurin inhibitors, or who were intolerant to standard topical treatments, or who could not undergo standard topical treatments (due to contraindications, etc.), and who met the following criteria: Eczema Area Severity Index of 10 or more sIGA score 3 or higher - Itch VAS ≥ 50mm

[0093] The clinical trial consisted of two parts. Part A was a randomized, double-blind, placebo-controlled, parallel-group study (Week 0–Week 12). Part B was the double-blind treatment extension period, during which subjects continued to receive CIM331 for an additional 52 weeks (Week 12–Week 64). Approximately 250 subjects in Part A were randomly assigned in a 1:1:1:1:1 ratio to one of four treatment groups (approximately 50 subjects per group) or a placebo group (approximately 50 subjects). Part A CIM331 (0.1 mg / kg), administered subcutaneously every 4 weeks (administered on Day 1, Week 4, and Week 8) CIM331 (0.5 mg / kg), administered subcutaneously every 4 weeks (administered on Day 1, Week 4, and Week 8) CIM331 (2.0 mg / kg), administered subcutaneously every 4 weeks (administered on Day 1, Week 4, and Week 8) CIM331 (2.0 mg / kg) administered subcutaneously every 8 weeks (Day 1 and Week 8, plus placebo on Week 4) Placebo administered subcutaneously every 4 weeks (Day 1, Week 4, and Week 8) More specifically, in Part A, 264 patients received at least one dose of the investigational drug or placebo: 53, 53, 54, 52, and 52 patients in the groups receiving subcutaneous administration of placebo, 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg every 4 weeks, and 2.0 mg / kg every 8 weeks, respectively. Part B Participants assigned to the placebo group in Part A will be re-randomized to receive CIM331 (0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg) subcutaneously every 4 weeks in Part B. Subjects randomly assigned to the investigational drug group in Part A will be reassigned to the same dose group as in Part A and will continue the same treatment from Week 12 onwards. CIM331 (0.1 mg / kg), subcutaneously administered every 4 weeks for a total of 52 weeks CIM331 (0.5 mg / kg), subcutaneously administered every 4 weeks for a total of 52 weeks CIM331 (2.0 mg / kg), subcutaneously administered every 4 weeks for a total of 52 weeks CIM331 (2.0 mg / kg) administered subcutaneously every 8 weeks for a total of 52 weeks (subjects in this group were given CIM331 and placebo alternately every 4 weeks).

[0094] (4-2) Rescue treatment For subjects who do not show improvement in pruritus VAS or skin symptoms, topical medications will be allowed as rescue treatment at the discretion of the physician after 4 weeks of the first administration. "No improvement" is defined as (1) no improvement in sIGA score from baseline, (2) sIGA score ≥ 3; (3) The improvement rate of pruritus VAS from baseline is less than 10%, and the most recent pruritus VAS is 50 mm or more This applies when all of the above are met.

[0095] (4-3) Evaluation items: The intensity of itching was assessed using a visual analog scale (VAS) (Furue et al. 2013). The VAS is a 100 mm line, with 0 mm representing no itching and 100 mm representing the worst itching imaginable. Patients indicate the intensity of their itching over the past 24 hours by drawing a line between 0 and 100 mm. The Itch Verbal Rating Scale (VRS) is a 5-point scale in which subjects rate the intensity of their itch over the past 24 hours: no itch (0), mild itch (1), moderate itch (2), severe itch (3), or very severe itch (4) (Reich et al. 2012). The Eczema Area Severity Index (EASI) score is a tool for measuring the severity and extent of atopic dermatitis. It assesses the extent and proportion of eczema in representative affected areas in each of four areas: head and neck, upper limbs, trunk, and lower limbs. The EASI score assesses the degree of redness (erythema), thickness (induration, papules, edema), scratching (excoriation), and lichenification, with a scale of 0 (none), 1 (mild), 2 (moderate), or 3 (severe). SCORing Atopic Dermatitis (SCORAD) is a clinical tool for assessing the extent and severity of eczema (European Task Force on Atopic Dermatitis 1993). The static Investigator's Global Assessment (sIGA) assesses the overall severity of disease at the time of assessment using the clinical characteristics of erythema, infiltration, papules, exudation, and crusts on a 6-point scale ranging from clear to very severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease, 5 = very severe disease). The body surface area (BSA) of atopic dermatitis lesions indicates the proportion of the entire body that is occupied by the lesions. The sleep disturbance visual analog scale (VAS) asks participants to rate the severity of their sleep disturbance during the past 24 hours on a scale ranging from “no sleep problems” (0) to “could not sleep at all” (10) (Furue et al. 2013). The Dermatology Life Quality Index (DLQI) (Finlay et al. 1994) is a 10-question quality of life assessment tool for dermatology. The DLQI questions are divided into the following six categories: Symptoms / emotions, daily activities, leisure, work / school, relationships, treatment. The DLQI is calculated by adding up the scores for all questions. The maximum is 30 and the minimum is 0. The higher the score, the lower the QOL. Actigraphy The Actiwatch is a non-invasive wrist-worn device designed to capture, record, and store ambulatory wrist movements, which are indicators of whole-body movement. Subjects will wear the device from the start of the pre-observation period through Week 4. Other parameters, including actual time from sleep onset to wakefulness, sleep latency, and sleep efficiency, will be measured objectively.

[0096] (4-4) Analysis means, analysis method, etc.: The primary endpoint for the group receiving subcutaneous CIM331 every four weeks will be the improvement rate of pruritus VAS scores after 12 weeks of treatment compared to baseline, and the superiority and efficacy of each dose group receiving CIM331 once every four weeks compared to placebo will be confirmed. Analysis of covariance (ANCOVA) will be used as the primary analysis method. Specifically, the improvement rate of pruritus VAS scores after 12 weeks of treatment compared to baseline will be used as the response variable, and a model will be fitted with treatment group as a fixed effect and pruritus VAS scores at baseline and region (Japan, Europe, USA) as covariates. In the primary analysis, a one-sided significance level of 0.025 will be used, and two-group comparisons will be performed sequentially, starting from the highest dose, based on the principle of a closed testing procedure to account for multiplicity due to repeated testing. The primary analysis population will be the per-protocol (PP) population, which excludes some subjects with serious protocol deviations, subjects who discontinued the trial early, and subjects who received an investigational drug other than that assigned. All data measured after receiving rescue treatment will be excluded, and missing values will be imputed using LOCF (Last Observation Value Carrying Forward after Baseline).

[0097] Among patients who received the investigational drug or placebo in Part A, the primary analysis population consisted of 46, 46, 45, 47, and 45 patients in the groups receiving placebo, 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg subcutaneously every 4 weeks, and 2.0 mg / kg subcutaneously every 8 weeks. In the 4-weekly administration group, the differences from placebo in the primary endpoint, the rate of improvement (least squares mean) from the start of pruritus VAS score after 12 weeks of administration, were -21.39% (p=0.0027), -41.16% (p<0.0001), and -40.39% (p<0.0001) for 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg, respectively. Furthermore, because this is an exploratory dose-finding study, secondary analyses may be conducted in addition to the primary analysis to comprehensively evaluate the dose. In such cases, although this is an exploratory study, the one-sided significance level of 0.025 is recommended. While not intended to be limiting, specific methods other than ANCOVA may be used, such as the mixed-effects model repeated measures approach (MMRM), model-independent summary statistics, an intent-to-treat (ITT) analysis set using all available data obtained at specified observation time points after administration of the investigational drug, data measured after rescue treatment, or analyses without imputing missing values. Furthermore, for the pruritus VAS, time points other than 12 weeks after the start of treatment may be used, or model analyses using the change in the improvement rate compared to the start of treatment or values at each time point, with these continuous values or the proportion of improved cases based on a certain threshold as the response variable, may also be evaluated. Important subpopulations may be considered in such analyses. Secondary efficacy endpoints other than the pruritus VAS may also be analyzed in a similar manner. Exploratory comparisons can also be made with CIM331 administered subcutaneously every 8 weeks.

[0098] -Percentage of subjects who improved: Itch VAS, EASI, SCORAD The percentage of subjects who achieved a 25%, 50%, and 75% improvement from baseline to each time point for each item will be calculated. In Part A, for the 4-weekly treatment groups, when all data measured after rescue treatment in the PP population were excluded and missing values were imputed using LOCF, the proportion of subjects who achieved a 50% improvement in the pruritus VAS at 12 weeks of treatment was 21% in the placebo group, compared with 41%, 67%, and 59% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively. The proportion of subjects who achieved a 75% improvement was 12% in the placebo group, compared with 14%, 49%, and 44% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively. Similarly, after 12 weeks of treatment, the proportion of subjects achieving a 50% improvement in EASI was 33% in the placebo group, compared with 43%, 51%, and 41% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively. The proportion of subjects achieving a 75% improvement was 14% in the placebo group, compared with 23%, 37%, and 22% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively. After 12 weeks of treatment, the percentage of subjects achieving a 50% improvement on SCORAD was 15% in the placebo group, compared with 18%, 39%, and 31% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively. The percentage of subjects achieving a 75% improvement was 3% in the placebo group, compared with 0%, 15%, and 17% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively.

[0099] Percentage of subjects who improved by 2 or more points: sIGA, pruritus VRS The proportion of subjects who improved by 2 or more points from baseline to each time point for each item will be calculated. In Part A, the results for the four-weekly administration group showed that 12 weeks after the start of treatment, the percentage of subjects who improved by ≥2 points on the sIGA was 12% in the placebo group, compared with 21%, 30%, and 22% in the 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively. At 12 weeks after the start of treatment, the percentage of subjects whose pruritus VRS improved by 2 or more points was 5% in the placebo group, while it was 14%, 47%, and 30% in the 0.1 mg / kg group, 0.5 mg / kg group, and 2.0 mg / kg group, respectively.

[0100] Improvement level: Itching VAS, EASI, SCORAD, sIGA, BSA of atopic dermatitis lesions, Itching VRS, Sleep disturbance VAS The degree of improvement from baseline to each time point for each item will be summarized using descriptive statistics. In Part A, the results for the 4-weekly treatment groups showed that, excluding all data measured after rescue treatment in the PP population, the improvement rates of pruritus VAS at 4 weeks of treatment were 12% in the placebo group, 39% in the 0.1 mg / kg group, 55% in the 0.5 mg / kg group, and 46% in the 2.0 mg / kg group. At 12 weeks of treatment, the improvement rates were 24% in the placebo group, 47% in the 0.1 mg / kg group, 68% in the 0.5 mg / kg group, and 67% in the 2.0 mg / kg group. Similarly, the EASI improvement rate after 12 weeks was 34% in the 0.1 mg / kg group, 54% in the 0.5 mg / kg group, and 48% in the 2.0 mg / kg group compared with 38% in the placebo group. The SCORAD improvement rate after 12 weeks was 37% in the 0.1 mg / kg group, 45% in the 0.5 mg / kg group, and 47% in the 2.0 mg / kg group compared with 22% in the placebo group. The sIGA improvement rate after 12 weeks was 25% in the 0.1 mg / kg group, 34% in the 0.5 mg / kg group, and 28% in the 2.0 mg / kg group compared with 13% in the placebo group. The BSA improvement rate after 12 weeks was 25% in the 0.1 mg / kg group, 26% in the 0.5 mg / kg group, and 33% in the 2.0 mg / kg group compared with 31% in the placebo group. The improvement rates for pruritus VRS after 12 weeks of treatment were 42% in the 0.1 mg / kg group, 58% in the 0.5 mg / kg group, and 58% in the 2.0 mg / kg group, compared with 18% in the placebo group.The improvement rates for sleep disturbance VAS after 12 weeks of treatment were 57% in the 0.1 mg / kg group, 65% in the 0.5 mg / kg group, and 67% in the 2.0 mg / kg group, compared with 31% in the placebo group.

[0101] Time to response: Itch VAS, EASI, SCORAD, sIGA Time to achieve 25%, 50%, and 75% improvement from baseline on the pruritus VAS, EASI, and SCORAD, and time to achieve a 2-point improvement from baseline on the sIGA, will be summarized as cumulative incidence over time using Kaplan-Meier estimates. In Part A, the results for the 4-weekly treatment groups showed that the time to 50% of patients achieving 25%, 50%, and 75% improvement from baseline on the pruritus VAS was 11 weeks, not achieved, and not achieved, respectively, in the placebo group, compared with 2 weeks and 4 weeks, respectively, in the 0.1 mg / kg group, 2 weeks, 2 weeks, and 5 weeks, respectively, in the 0.5 mg / kg group, and 2 weeks and 4 weeks, respectively, in the 2.0 mg / kg group. Furthermore, the Kaplan-Meier estimates of the achievement rates of 25%, 50%, and 75% improvement from baseline at 12 weeks after the start of treatment were 52%, 38%, and 22%, respectively, in the placebo group, compared with 84%, 66%, and 38%, respectively, in the 0.1 mg / kg group, 95%, 80%, and 68%, respectively, in the 0.5 mg / kg group, and 94%, 71%, and 48%, respectively, in the 2.0 mg / kg group. Similarly, the time to 50% of patients achieving a 25%, 50%, or 75% improvement from baseline in the EASI was 6 weeks, 12 weeks, and not achieved, respectively, in the placebo group, compared with 2 weeks and 4 weeks in the 0.1 mg / kg group, 2 weeks, 4 weeks, and 12 weeks in the 0.5 mg / kg group, and 2 weeks and 6 weeks in the 2.0 mg / kg group. Using Kaplan-Meier estimates, the rates of achieving a 25%, 50%, and 75% improvement from baseline at 12 weeks after the start of treatment were 68%, 51%, and 23%, respectively, in the placebo group, compared with 71%, 66%, and 37%, respectively, in the 0.1 mg / kg group, 84%, 73%, and 53%, respectively, in the 0.5 mg / kg group, and 93%, 67%, and 28%, respectively, in the 2.0 mg / kg group. In SCORAD, the time to 50% of patients achieving 25%, 50%, and 75% improvement from baseline was 6 weeks, not achieved, and not achieved, respectively, in the placebo group, compared with 2 weeks, not achieved, and not achieved, respectively, in the 0.1 mg / kg group, 3 weeks, not achieved, and 10 weeks, respectively, in the 0.5 mg / kg group, and 2 weeks, not achieved, and not achieved, respectively, in the 2.0 mg / kg group. Furthermore, the Kaplan-Meier estimates of the achievement rates of 25%, 50%, and 75% improvement from baseline at 12 weeks after the start of treatment were 57%, 40%, and 6%, respectively, in the placebo group, compared with 78%, 46%, and 9%, respectively, in the 0.1 mg / kg group, 78%, 55%, and 30%, respectively, in the 0.5 mg / kg group, and NE (not calculable), 46%, and 25%, respectively, in the 2.0 mg / kg group. In the sIGA, the time to 50% of patients achieving a 2-point improvement from baseline was not achieved by week 12 in any of the placebo, 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups. Furthermore, the rate of achieving a 2-point improvement from baseline at 12 weeks after the start of treatment using Kaplan-Meier estimates was 30% in the placebo group, compared with 36% in the 0.1 mg / kg group, 47% in the 0.5 mg / kg group, and 38% in the 2.0 mg / kg group.

[0102] - The period until receiving rescue treatment Time to rescue treatment will be summarized as cumulative incidence over time using Kaplan-Meier estimates. Subjects who did not receive rescue treatment will be censored at the Week 12 visit in Part A (or Week 64 visit in Part B) or at early discontinuation of the study, whichever comes first. In Part A, the results for the every-four-weekly administration group showed that the time from baseline to receiving rescue therapy for 50% of patients was not reached by 12 weeks in the placebo, 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups. The time from baseline to receiving rescue therapy for 25% of patients was 5 weeks, 9 weeks, not reached, and 9 weeks in the placebo, 0.1 mg / kg, 0.5 mg / kg, and 2.0 mg / kg groups, respectively.

[0103] Percentage of subjects receiving rescue treatment The proportion of subjects receiving rescue treatment at each time point will be calculated. In Part A, the results for the every-four-weekly administration groups showed that the proportion of subjects receiving rescue treatment was 39.1% in the placebo group, 26.1% in the 0.1 mg / kg group, 24.4% in the 0.5 mg / kg group, and 29.8% in the 2.0 mg / kg group. Actigraphy Actigraphy results for the 4-weekly treatment groups in Part A showed that the actual time from sleep onset to wakefulness increased by 49.5 minutes in the 0.1 mg / kg group, 53.1 minutes in the 0.5 mg / kg group, and 48.2 minutes in the 2.0 mg / kg group after 4 weeks of treatment, compared with an increase of 7.3 minutes in the placebo group. Sleep latency (time from implantation to sleep) decreased by 17.6 minutes in the 0.1 mg / kg group, 14.8 minutes in the 0.5 mg / kg group, and 12.7 minutes in the 2.0 mg / kg group after 4 weeks of treatment, compared with a decrease of 4.3 minutes in the placebo group.

[0104] In addition, in the group receiving CIM331 once every 8 weeks in Part A, the mean improvement rate from the start of pruritus VAS 12 weeks after administration, excluding all data measured after receiving rescue treatment, was 70%.

[0105] Based on the results of the primary endpoint, the pruritus VAS at 12 weeks of administration, and the results of Part A regarding dermatitis indices such as EASI and sIGA, it was considered that the effects on pruritus and dermatitis were greatest in the 0.5 mg / kg / 4-week administration group.

[0106] Simulation of optimal dosage Regarding dosage, from the viewpoint of further improving convenience, modeling and simulation were performed to evaluate the optimal dosage at a fixed dose based on the dosage per body weight. First, we compared exposure between doses based on body weight and fixed doses, and considered the optimal dose from a pharmacokinetic perspective. Serum drug concentrations of CIM331 fit well with a one-compartment model with a first-order absorption process. Body weight was also incorporated as a covariate into the model parameters using the allometry equation. The model parameters are shown below.

[0107] [Table 3]

[0108] Simulations were performed using the one-compartment model, and the relationship between body weight and exposure is shown in Figure 10. A in the figure shows the expected exposure when administered at 0.5 mg / kg or 2 mg / kg, while B, C, and D show the expected exposure when administered at 50, 75, and 100 mg / body, respectively. The reference lines in the figure indicate the upper limit of the expected exposure for 2 mg / kg (1060 μg*day / mL) and the lower limit of the exposure for 0.5 mg / kg (44 μg*day / mL). A fixed dose of 50 mg was expected to exceed the lower limit of exposure at approximately 0.5 mg / kg in subjects with a body weight of less than 100 kg, and a fixed dose of 100 mg was expected to exceed the upper limit of exposure at 2 mg / kg in subjects with low body weight. Furthermore, a fixed dose of 75 mg was expected to fall within the range of exposure obtained at 0.5 mg / kg or 2 mg / kg. Based on these findings, a fixed dose of 50 mg (except 100 mg for subjects with a body weight of over 100 kg) or 75 mg administered once every four weeks was expected to achieve exposure similar to that obtained in the Phase II study.

[0109] Next, modeling and simulation of the pruritus VAS was performed using PK-PD analysis. An indirect turnover model was used for the pruritus VAS portion, and scale conversion was performed. It was confirmed that the model predicted values closely resembled the actual measured values. The calculated model parameters are shown below.

[0110] [Table 4]

[0111] A simulation was performed using the model. The predicted pruritus VAS scores one year after CIM331 administration are shown in Figure 11. It was assumed that when the fixed dose per 4 weeks was 25 mg / body or more, preferably 50 mg / body or more, the pruritus VAS would show similar values to those of 0.5 mg / kg or 2 mg / kg.

[0112] (4-5) Effect of combined administration of CIM331 and topical steroids Part A did not permit the use of any other atopic dermatitis treatment other than moisturizers. However, Part B permitted the use of mild topical steroids (e.g., hydrocortisone, desonide, prednisolone), topical calcineurin inhibitors (e.g., pimecrolimus, tacrolimus), and antihistamines (e.g., fexofenadine). The ranking of topical steroids was based on 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 formulations used only in Japan and the United States. In patients who demonstrated adequate relief of pruritus with CIM331 during Part A but insufficient improvement in dermatitis, concomitant use of topical steroids, such as CIM331 for a short or as-needed period, in Part B demonstrated sustained and significant improvement in dermatitis. In a Phase II repeated-dose study, CIM331 administration suppressed pruritus, thereby breaking the vicious cycle of impaired barrier function due to pruritus, which then led to increased inflammatory responses due to the invasion of foreign antigens, worsening dermatitis, and exacerbating pruritus, resulting in improved dermatitis. Furthermore, for patients who experienced sufficient relief of pruritus with CIM331 but insufficient improvement in dermatitis, continuous improvement of dermatitis was achieved by administering CIM331 in combination with short-term topical steroids. These results suggest that sustained suppression of pruritus with CIM331 combined with suppression of existing inflammatory responses through the concomitant use of topical steroids may prevent further atopic dermatitis exacerbation due to the Itch-Scratch Cycle and result in more effective improvement of dermatitis.

[0113] (4-6) Expected results and beneficial effects Repeated administration of CIM331 every 4 or 8 weeks leads to a steady state in serum CIM331 concentrations, providing a sustained anti-pruritic effect in patients with atopic dermatitis. Furthermore, the maintenance of this anti-pruritic effect, i.e., blocking the Itch-Scratch Cycle, leads to improvement in dermatitis and QOL. The long-term efficacy profile can be confirmed over a total of 64 weeks. Furthermore, given that current systemic treatments for atopic dermatitis require patients to take or apply medication to the affected area several times a day, or in the case of ultraviolet light therapy, may require patients to visit a hospital once or twice a week, a treatment regimen such as repeated administration of CIM331 every four or eight weeks is expected to significantly reduce the burden of medication and hospital visits on patients, further contributing to improving patients' quality of life.

[0114] (4-7) One embodiment of CIM331 after approval Without limitation, CIM331 may be administered to patients with moderate to severe atopic dermatitis who have had an inadequate response to or are intolerant to topical treatments. CIM331 may be repeatedly administered subcutaneously at equal doses and at the same administration intervals, for example, every 2 to 12 weeks, specifically, for example, once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or once every 1, 2, or 3 months. The dose and concentration of CIM331 per body weight may be determined appropriately based on the results of a Phase II repeated-dose study or other studies. For example, if the weight of an atopic dermatitis patient exceeds 120 kg, the investigational drug may be prepared assuming a body weight of 120 kg. Furthermore, if CIM331 is intended to be administered to atopic dermatitis patients on a mg / body basis, the dose of CIM331 may be converted from mg / kg to mg / body based on the results of a Phase II repeated-dose study, and an appropriate and reasonable dose (mg / body) may be selected and administered. In this case, the logic for converting mg / kg to mg / body may be determined appropriately by a person skilled in the art using the following logic, although it is not limited thereto. Assuming that there are minimum effective serum concentrations and maximum tolerated (empirical) serum concentrations of CIM331, we will consider changing the dosage from mg / kg to mg / body based on the results of the Phase II trial so that serum CIM331 concentrations within this range can be achieved regardless of body weight. Furthermore, since mg / body dosing for low-weight children may significantly increase exposure, administration in mg / kg will be considered in such cases. Based on the results of the ongoing Phase II trial, we will determine the minimum effective serum concentration and maximum tolerated serum concentration, and by aligning exposure as described above, conversion to mg / body will be possible. In one non-limiting embodiment, a single dose selected from 0.1 mg to 1000 mg / body, for example, 0.2 mg to 360 mg / body, preferably 10 mg to 200 mg / body, 10 mg to 100 mg / body, 25 mg to 100 mg / body, 50 mg to 100 mg / body, or 50 mg to 75 mg / body may be repeatedly administered subcutaneously at the same dose interval as described above. For the avoidance of doubt, for example, when 0.1mg to 1000mg / body is stated, the ranges are 0.1mg / body, 0.2mg / body, 0.3mg / body, 0.4mg / body, 49.9mg / body, 50mg / body, 50.1mg / body, 50.2mg / body, 99.8mg / body, 99.9mg / body, 100mg / body, 100.1mg / body, 100.2mg / body, 1 It is intended that all doses between 0.1 mg and 1000 mg / body, in increments of 0.1 mg / body, be specifically described, such as 99.9 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, and 1000 mg / body. Therefore, those skilled in the art who read this description will naturally understand directly and unambiguously from the description of 0.1 mg to 1000 mg / body that values such as 55 mg / body and 56.5 mg / body are specifically described in the present examples. Alternatively, in another non-limiting embodiment, a single dose selected from 0.01 mg to 10 mg / kg, for example, 0.1 mg to 3 mg / kg, preferably 0.2 mg to 2 mg / kg, may be repeatedly administered subcutaneously at the same dose interval as described above. For the avoidance of doubt, for example, when 0.01mg-10mg / kg is stated, it is also possible to include 0.01mg / kg, 0.015mg / kg, 0.02mg / kg, 0.025mg / kg, 0.03mg / kg, 0.035mg / kg, 0.04mg / kg, 0.125mg / kg, 0.49mg / kg, 0.495mg / kg, 0.5mg / kg, 0.505mg / kg, 0.51mg / kg, 0.98mg / kg, 0.985mg / kg, 0.99mg / kg, 0.995mg / kg, 1mg / kg, 1.005mg / kg, 1.01mg / kg, 1.49mg / kg, 1.495mg / kg, 1. Any dosage between 0.01 mg and 10 mg / kg inclusive in increments of 0.005 mg / kg is intended to be specifically recited, such as 0.5 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, 10 mg / kg, etc. Therefore, a person skilled in the art who reads this description will naturally understand that, for example, from the description of 0.01 mg to 10 mg / kg, values such as 0.75 mg / kg and 1.245 mg / kg are individually and specifically described in this Example.

[0115] [Reference Example 1] IgG antibody expression and purification Antibody expression was carried out using the following method. Human embryonic kidney cancer cell line HEK293H (Invitrogen) was suspended in DMEM medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen), and 5–6 × 10 5 Ten mL of the medium was seeded into each of 10 adherent cell dishes (10 cm diameter, CORNING) at a cell density of 1000 cells / mL and cultured overnight in a CO2 incubator (37°C, 5% CO2). The medium was then aspirated and 6.9 mL of CHO-S-SFM-II (Invitrogen) medium was added. The prepared plasmid was then introduced into the cells by lipofection. The resulting culture supernatant was collected and centrifuged (approximately 2000 g, 5 minutes, room temperature) to remove cells. The culture supernatant was then sterilized through a 0.22 μm MILLEX®-GV filter (Millipore) to obtain the culture supernatant. The resulting culture supernatant was purified using rProtein A Sepharose™ Fast Flow (Amersham Biosciences) by methods known to those skilled in the art. The concentration of the purified antibody was determined by measuring the absorbance at 280 nm using a spectrophotometer. The antibody concentration was calculated from the obtained value using the extinction coefficient calculated by the method described in Protein Science 1995; 4: 2411-2423.

Claims

[Claim 1] The invention described herein.

Images