TWI871349B - Pharmaceutical composition for the prevention and/or treatment of dialysis pruritus containing IL-31 antagonist as an active ingredient - Google Patents

Abstract

In one non-limiting embodiment, a pharmaceutical composition for preventing and/or treating dialysis pruritus containing an IL-31 antagonist as an active ingredient is provided.

Description

Pharmaceutical composition for the prevention and/or treatment of dialysis pruritus containing IL-31 antagonist as an active ingredient

In a non-limiting aspect, the present disclosure relates to pharmaceutical compositions for the prevention and/or treatment of uremic pruritus, etc., containing an IL-31 antagonist as an active ingredient.

Itch in dialysis patients (also referred to as "dialysis itch" in this manual) is characterized by systemic and intractable itching, and is one of the diseases that causes daily distress to dialysis patients. Generally speaking, patients with a long history of dialysis tend to experience itching frequently (Non-patent Document 1), but the location, frequency, duration, and degree of impact on life vary. Moreover, even in the itchy area, there are almost no obvious skin symptoms (Non-patent Document 2). In a survey conducted in Japan in 2000, 72.8% of hemodialysis patients experienced itching, and about half of them were confirmed to have sleep disorders (Non-patent Document 3). Furthermore, it is reported that the more severe the itching is, the higher the degree of insomnia is (non-patent document 4). In the Dialysis Outcomes and Practice Patterns Study (DOPPS) survey conducted in 12 countries including Japan, it was reported that more than 40% of patients had moderate or above itching and poor sleep quality (non-patent document 5). Furthermore, it is reported that severe itching is a risk factor for the life prognosis of dialysis patients (non-patent document 6). As can be seen from the above content, the improvement of itch in dialysis patients is important for the improvement of QOL or sleep quality, and even more so, the life prognosis of dialysis patients. [Prior art document] [Non-patent document]

[Non-patent document 1] Nakagawa Shigeya, Current status of chronic dialysis therapy in Japan (as of December 31, 1999). Journal of Dialysis Society 2001; 34:1-31 [Non-patent document 2] Danno Kiichiro, Perspectives on itching. A perfect guide to itching treatment in dialysis rooms, Kinhodo. 2008. p.1-16 [Non-patent document 3] Omori Kentaro et al., Actual status of dialysis pruritus - Survey report on 2,474 patients in 41 facilities in Niigata Prefecture -. Dialysis Soc. 2001; 1469-77 [Non-patent literature 4] Narita I et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int. 2006;69:1626-32. [Non-patent literature 5] Pisoni RL et al. Pruritus in haemodialysis patients: International results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2006;21:3495-505. [Non-patent literature 6] Kimata N et al. Pruritus in hemodialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS). Hemodial Int 2014;18:657-67.

[Problems to be solved by the invention]

The mechanism of dialysis pruritus is still not clearly understood, but it has been suggested that it may be related to IL-31 (Gangemi S, Quartuccio S, Casciaro M, Trapani G, Minciullo PL, Imbalzano E. Interleukin 31 and skin diseases: A systematic review. Allergy Asthma Proc. 2017;38(6):401-8.). Regarding IL-31 and pruritus in dialysis patients, it has been reported that in hemodialysis patients in the maintenance period, the serum IL-31 concentration of patients with pruritus is higher than that of patients without pruritus (Ko MJ et al. Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis. J Am Acad Dermatol. 2014;71:1151-9.).

IL-31 (Interleukin-31) is a T cell interleukin. Transgenic mice that overexpress IL-31 are known to develop itchy, dermatitis-like symptoms similar to atopic dermatitis (Nat Immunol (2004) 5, 752-760). In addition, it has been found that the receptor bound by IL-31 is a heterodimer of IL-31RA (Interleukin-31 receptor A) and OSMR (Oncostatin M receptor) (WO2004/003140), and IL-31 transmits signals to cells through this receptor.

To date, IL-31 neutralizing antibodies, IL-31RA neutralizing antibodies, etc. as IL-31 antagonists have been reported (e.g., WO2005/079566; WO2006/063864; WO2006/063865; WO2009/071696; WO2006/088855; WO2006/088955; WO2006/088956; WO2007/133816; WO2007/142325; WO2009/072598; WO2006/122079; WO2007/143231; WO2008/028192; WO2009/072604; WO2010/064697).

However, there are no reports of trial results showing that IL-31 antagonists are effective in preventing and/or treating dialysis pruritus. [Solution]

In a non-limiting embodiment, the present disclosure relates to the following matters: [1] A pharmaceutical composition for the prevention and/or treatment of dialysis pruritus, comprising an IL-31 antagonist as an active ingredient. [2] The pharmaceutical composition as described in [1], wherein the IL-31 antagonist is repeatedly administered to a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus in equal amounts and at the same administration interval 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. [3] The pharmaceutical composition as described in [2], wherein the IL-31 antagonist is administered at a dose of 25 mg to 100 mg/body/4 weeks. [4] The pharmaceutical composition of [2] or [3], wherein the IL-31 antagonist is administered at 50 mg to 100 mg/body/4 weeks. [5] The pharmaceutical composition of any one of [1] to [4], wherein the IL-31 antagonist is administered repeatedly at 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 in equal amounts and at the same administration intervals to a subject suffering from, or at risk of suffering from, dialysis pruritus. [6] The pharmaceutical composition of [5], wherein the IL-31 antagonist is administered at 0.2 mg to 2 mg/kg/4 weeks. [7] A pharmaceutical composition as described in any one of [1] to [6], which is used for administration to a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus whose serum IL-31 concentration is above a predetermined value. [7-2] A pharmaceutical composition as described in any one of [1] to [7], which is used for administering the pharmaceutical composition only to subjects determined to be responsive to prevention and/or treatment with an IL-31 antagonist by a method for predicting the subject's response to prevention and/or treatment with an IL-31 antagonist, wherein the method comprises the following steps: measuring the IL-31 concentration in serum obtained from a subject suffering from or at risk of suffering from dialysis pruritus; and determining the subject whose IL-31 concentration is above a predetermined value as a subject responsive to prevention and/or treatment with an IL-31 antagonist. [7-3] A pharmaceutical composition as described in any one of [1] to [7], for use in a method for predicting a subject's response to prevention and/or treatment with an IL-31 antagonist, wherein the pharmaceutical composition is administered only to subjects determined to be responders to prevention and/or treatment with an IL-31 antagonist, wherein the method comprises the following step: among subjects suffering from dialysis pruritus or at risk of suffering from dialysis pruritus whose serum IL-31 concentration is measured, subjects whose IL-31 concentration is above a predetermined value are determined to be responders to prevention and/or treatment with an IL-31 antagonist. [8] The pharmaceutical composition as described in any one of [1] to [7-3], which is used to improve sleep disorders caused by dialysis pruritus. [9] The pharmaceutical composition as described in [8], which is used to improve the sleep disorder by increasing the time from falling asleep to waking up and/or shortening the sleep latency (the time from going to bed to falling asleep). [10] The pharmaceutical composition as described in any one of [1] to [9], wherein the IL-31 antagonist is an antibody that inhibits IL-31 signaling. [11] The pharmaceutical composition as described in [10], wherein the antibody does not show cross-reactivity to IL-31RA of any of mice, rats, and rabbits. [12] The pharmaceutical composition as described in item [10] or [11], wherein the antibody is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody. [13] The pharmaceutical composition as described in [12], wherein the anti-IL-31RA neutralizing antibody is any one of the following (1) to (3): (1) an anti-IL-31RA antibody comprising: an H chain variable region containing CDR1 recorded in sequence number: 1, CDR2 recorded in sequence number: 2, and CDR3 recorded in sequence number: 3, and an L chain variable region containing CDR1 recorded in sequence number: 4, CDR2 recorded in sequence number: 5, and CDR3 recorded in sequence number: 6; (2) an anti-IL-31RA antibody comprising an H chain variable region recorded in sequence number: 7, and an L chain variable region recorded in sequence number: 8; or (3) an anti-IL-31RA antibody comprising an H chain recorded in sequence number: 9, and an L chain recorded in sequence number: 10. [14] The pharmaceutical composition as described in any one of [1] to [13], wherein the dialysis pruritus is dialysis pruritus that has not been (sufficiently) responded to systemic or local therapy other than nalfurafine hydrochloride. [15] The pharmaceutical composition as described in [14], wherein the systemic therapy is treatment with an antihistamine or antiallergic drug, and the local therapy is treatment with a moisturizer or a steroid. [16] The pharmaceutical composition as described in any one of [1] to [15], wherein the dialysis pruritus is dialysis pruritus caused by IL-31 signaling. [17] A method for preventing and/or treating dialysis pruritus, comprising: administering an IL-31 antagonist to a subject suffering from, or at risk of suffering from, dialysis pruritus. [18] The method described in [17], wherein the IL-31 antagonist is administered repeatedly to a subject suffering from, or at risk of suffering from, dialysis pruritus at an equal dose and at the same administration interval 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. [19] The method as described in [17], wherein the IL-31 antagonist is repeatedly administered to a subject suffering from or at risk of hemodialysis pruritus at an equal dose of 0.01 mg to 10 mg/kg for 2 weeks, 0.01 mg to 10 mg/kg for 4 weeks, or 0.01 mg to 10 mg/kg for 8 weeks. [20] The method as described in any one of [17] to [19], wherein the IL-31 antagonist is administered to a subject suffering from or at risk of hemodialysis pruritus whose serum IL-31 concentration is above a predetermined value. [21] The method described in [20], comprising: measuring the IL-31 concentration in serum obtained from a subject suffering from or at risk of suffering from dialysis pruritus; determining a subject whose IL-31 concentration is above a predetermined value as a responder to prevention and/or treatment with an IL-31 antagonist; and administering the IL-31 antagonist to the subject determined to be a responder. [21-2] The method described in [20], comprising: among subjects suffering from or at risk of suffering from dialysis pruritus whose serum IL-31 concentration is measured, determining the subjects whose IL-31 concentration is above a predetermined value as responders to the prevention and/or treatment with an IL-31 antagonist; and administering the IL-31 antagonist to the subjects determined as responders. [22] A use of an IL-31 antagonist for the manufacture of a drug for the prevention and/or treatment of dialysis pruritus. [23] The use as described in [22], wherein the IL-31 antagonist is administered repeatedly 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 of suffering from, hemodialysis pruritus in equal amounts and at the same dosing interval. [24] The use as described in [22], wherein the IL-31 antagonist is administered repeatedly at 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 to a subject suffering from, or at risk of suffering from, hemodialysis pruritus in equal amounts and at the same dosing interval. [25] The use as described in any one of [22] to [24], wherein the IL-31 antagonist is administered to a subject suffering from or at risk of suffering from dialysis pruritus whose serum IL-31 concentration is above a predetermined value. [26] 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 indicating that the IL-31 antagonist is to be administered repeatedly to a subject suffering from or at risk of dialysis pruritus at an equal dose and at the same administration interval 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; and/or (iv) a document indicating that the IL-31 antagonist is to be administered to a subject suffering from or at risk of dialysis pruritus whose serum IL-31 concentration is above a predetermined value. [27] 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 indicating that the IL-31 antagonist is to be administered repeatedly in equal amounts and at the same dosing intervals to a subject suffering from, or at risk of suffering from, dialysis pruritus 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; and/or (iv) a document indicating that the IL-31 antagonist is to be administered to a subject suffering from, or at risk of suffering from, dialysis pruritus whose serum IL-31 concentration is above a predetermined value. [28] A pharmaceutical composition for the prevention and/or treatment of dialysis pruritus containing an IL-31 antagonist as an active ingredient, and is further used to improve sleep disorders caused by dialysis pruritus. [29] The pharmaceutical composition described in [28] is used to improve the aforementioned sleep disorders in order to increase the time from falling asleep to waking up, and/or shorten the sleep latency (the time from going to bed to falling asleep). [30] An IL-31 antagonist is used for the prevention and/or treatment of dialysis pruritus. [31] The IL-31 antagonist described in [30] is administered repeatedly at 0.1 mg~1000 mg/body/day~12 weeks, 0.1 mg~1000 mg/body/2 weeks, 0.1 mg~1000 mg/body/4 weeks, or 0.1 mg~1000 mg/body/8 weeks in equal doses and at the same dosing intervals to subjects suffering from or at risk of dialysis pruritus. [32] The IL-31 antagonist as described in [30], which is repeatedly administered in equal doses and at the same dosing intervals to a subject suffering from, or at risk of suffering from, hemodialysis pruritus at a dose of 0.01 mg to 10 mg/kg/day to 12 weeks, 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. [33] The IL-31 antagonist as described in any one of [30] to [32], which is administered to a subject suffering from, or at risk of suffering from, hemodialysis pruritus whose serum IL-31 concentration is above a predetermined value. [34] A pharmaceutical composition for the prevention and/or treatment of dialysis pruritus containing an IL-31 antagonist as an active ingredient, wherein the IL-31 antagonist is administered to a subject suffering from, or at risk of suffering from, dialysis pruritus and having a serum IL-31 concentration of at least a predetermined value. [35] The pharmaceutical composition described in [28] or [29], wherein the IL-31 antagonist is administered repeatedly in equal amounts and at the same dosing intervals to a subject suffering from, or at risk of suffering from, dialysis pruritus 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. Any combination of part or all of one or more of the constituent elements listed in any of [1] to [35] above is included in this disclosure as long as it is not technically contradictory based on technical common sense and does not violate the context.

The following describes the preferred non-limiting aspects of the present disclosure.

IL-31 (Interleukin-31) is a T cell interleukin. It is known that transgenic mice that overexpress IL-31 develop dermatitis-like symptoms similar to atopic dermatitis, and itching such as persistent scratching is observed.

The nucleic acid sequence and amino acid sequence of human IL-31 are known as RefSeq Accession No. NM_001014336 and RefSeq Accession No. NP_001014358, respectively.

The receptor for IL-31 is formed by a heterodimer of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) (Nat Immunol (2004) 5, 752-60). IL-31RA is also called NR10, and multiple cleavage variants are known (WO00/075314). The cleavage variants are known to include NR10.1 (652 amino acids), NR10.2 (252 amino acids), NR10.3 (662 amino acids, also called IL-31RAv4), IL-31RAv3 (764 amino acids), etc. Preferred IL-31RAs include NR10.3 (IL-31RAv4) and IL-31RAv3. The nucleic acid sequence and amino acid sequence of human IL-31RA (IL-31RAv4) are also known as RefSeq Accession Number NM_001242638 and RefSeq Accession Number NP_001229567, respectively. The nucleic acid sequence and amino acid sequence of human IL-31RA (IL-31RAv3) are also known as RefSeq Accession Number NM_139017 and RefSeq Accession Number NP_620586, respectively. In addition, the nucleic acid sequence and amino acid sequence of human OSMR are also known as RefSeq Accession Number NM_003999 and RefSeq Accession Number NP_003990, respectively.

In the present disclosure, an IL-31 antagonist, in one aspect, refers to a compound that inhibits or blocks intracellular signaling caused by IL-31. In other words, it can also be said to be a compound that inhibits IL-31 signaling. Such a compound can be a naturally occurring compound or an artificially synthesized compound. Furthermore, it can be a low molecular weight compound or a high molecular weight compound such as a protein.

It is known that IL-31 present outside the cell will cause intracellular signal transduction through 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 the IL-31 binding domain. If IL-31 binds to this, the stereostructure of the IL-31 receptor will change, and the intracellular signal transduction will start from the intracellular domain of the IL-31 receptor.

As a method for confirming whether a certain compound inhibits IL-31 signaling, it can be confirmed by examining whether the compound inhibits the binding of IL-31 to the IL-31 receptor. As methods for performing such determinations, there are ELISA, flow cytometric analysis, surface plasmon resonance analysis, etc. For example, in the case of ELISA, a system is prepared in which the IL-31 receptor (or IL-31RA) protein is fixed on a plate, and the amount of the bound IL-31 protein can be detected using a secondary antibody such as an enzyme-labeled anti-IL-31 antibody. By measuring whether the amount of the detected IL-31 protein decreases when the compound is added, it is possible to evaluate whether the compound inhibits the binding of IL-31 to the IL-31 receptor. In addition, as another method, whether a certain compound inhibits IL-31 signaling can also be confirmed by examining whether the physiological activity caused by the action of IL-31 on cells is inhibited by the compound. The aforementioned physiological activity is not particularly limited as long as it can be quantitatively or qualitatively measured using a certain method, and examples thereof include cell proliferation activity, protein phosphorylation activity, gene/protein expression induction activity, etc. For example, cells that express IL-31 receptors on the surface and induce proliferation activity in response to IL-31 stimulation from the outside are prepared, and by measuring whether the cell proliferation activity induced by IL-31 is reduced when a compound is added thereto, it is possible to evaluate whether the compound inhibits IL-31 signaling. As such cells, natural cells that naturally express IL-31 receptors can be used, and genetic recombinant cells that artificially express IL-31 receptors can also be used. A good example of genetically recombinant cells is Ba/F3 cells that express IL-31 receptors. Alternatively, the method described in the literature by Dillon et al. (Nat Immunol (2004) 5, 752-760) can be used.

In the present disclosure, the degree to which the IL-31 antagonist inhibits IL-31 signaling 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, 90% or more, 95% or more, or 98% or more.

In the present disclosure, the preferred embodiment of the compound that inhibits IL-31 signaling includes proteins that inhibit IL-31 signaling. The protein herein is not particularly limited as long as it has the property of specifically binding to IL-31 or 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 various antibodies such as monoclonal antibodies (e.g., IgG, IgM, IgE, IgA, IgD, etc.), polyclonal antibodies, modified antibodies (e.g., chimeric antibodies, humanized antibodies, sugar chain modified antibodies (WO99/54342, WO00/61739)), antibody fragments (e.g., Fab, F(ab')2, Fv, CDR, etc.), multispecific antibodies (e.g., bispecific antibodies, etc.), conjugated antibodies (e.g., antibodies to which polyethylene glycol (PEG), radioisotopes, or drugs are attached). On the other hand, examples of antibody-like molecules include DARPin (WO2002/020565), Affibody (WO1995/001937), Avimer (WO2004/044011), Adnectin (WO2002/032925), etc. More preferred are antibodies that inhibit IL-31 signals. Another preferred example of proteins that inhibit IL-31 signals includes proteins that include the extracellular domain of IL-31RA or proteins that include each extracellular domain of IL-31 receptor (heterodimer of IL-31RA and OSMR).

In the present disclosure, preferred aspects of antibodies that inhibit IL-31 signals include antibodies that inhibit IL-31 signals by binding to IL-31 (anti-IL-31 neutralizing antibodies), or antibodies that inhibit IL-31 signals by binding to IL-31 receptors (anti-IL-31 receptor neutralizing antibodies). Anti-IL-31 receptor neutralizing antibodies include antibodies that inhibit IL-31 signals by binding to IL-31RA (anti-IL-31RA neutralizing antibodies), antibodies that inhibit IL-31 signals by binding to OSMR (anti-OSMR neutralizing antibodies), or antibodies that inhibit IL-31 signals by binding to heterodimers of IL-31RA and OSMR (anti-IL-31RA/OSMR heterodimer neutralizing antibodies), etc. Among the 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.

Although the antibodies that inhibit IL-31 signaling disclosed herein in one or another embodiment may be cross-reactive to human and cynomolgus macaque IL-31RA, it is preferred that they do not (substantially) show cross-reactivity to mouse, rat, and rabbit IL-31RA.

Methods for preparing antibodies are well known to those skilled in the art, and can be prepared, for example, using the hybridoma method (Nature (1975) 256, 495) and the phage antibody library method (Nature (1991) 352, 624-628, J Mol Biol (1991) 222, 581-597). If IL-31 protein, IL-31 receptor protein, etc. are used as immunogens, a large number of anti-IL-31 antibodies and anti-IL-31 receptor antibodies can be obtained according to these methods. Furthermore, from among these antibodies, if screening is performed using the above-mentioned method for detecting compounds that inhibit IL-31 signals, anti-IL-31 neutralizing antibodies and anti-IL-31 receptor neutralizing antibodies can be obtained. Proteins such as IL-31 and IL-31 receptor can also be prepared by genetic engineering methods known to those skilled in the art. Specifically, a gene encoding a desired protein can be inserted into an expression vector, which is introduced into a suitable host cell, and the target protein expressed in the host cell or in the culture supernatant of the host cell can be purified to prepare the protein.

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

Although not limited, preferred examples of anti-IL-31RA neutralizing antibodies include anti-IL-31RA (NR10) antibodies described in WO2007/142325, anti-IL-31RA (NR10) antibodies described in WO2009/072604, and anti-IL-31RA (NR10) antibodies described in WO2010/064697. In addition, other preferred examples include anti-human IL-31RA (neutralizing) antibodies, and specifically, anti-IL-31RA (neutralizing) antibodies that recognize domain 1 and/or domain 2 of human IL-31RA. Here, domain 1 of human IL-31RA refers to the region from amino acids 53 to 152 of the amino acid sequence described in sequence number: 11 (LPAKP~LENIA). In addition, domain 2 refers to the region from amino acid 153 to amino acid 259 of the amino acid sequence recorded in sequence number: 11 (KTEPP~EEEAP). Although not limited, among the anti-IL-31RA neutralizing antibodies, preferably, an anti-IL-31RA antibody comprises an H chain (heavy chain) variable region containing CDR1 recorded in sequence number: 1, CDR2 recorded in sequence number: 2, and CDR3 recorded in sequence number: 3, and an L chain (light chain) variable region containing CDR1 recorded in sequence number: 4, CDR2 recorded in sequence number: 5, and CDR3 recorded in sequence number: 6; more preferably, an anti-IL-31RA antibody comprises an H chain variable region recorded in sequence number: 7, and an L chain variable region recorded in sequence number: 8; and particularly preferably, an anti-IL-31RA antibody comprises an H chain recorded in sequence number: 9, and an L chain recorded in sequence number: 10.

Therefore, in a non-limiting embodiment, a pharmaceutical composition may contain any of the following as an active ingredient: (1) an anti-IL-31RA antibody, comprising: an H chain variable region containing CDR1 recorded in sequence number: 1, CDR2 recorded in sequence number: 2, and CDR3 recorded in sequence number: 3, and an L chain variable region containing CDR1 recorded in sequence number: 4, CDR2 recorded in sequence number: 5, and CDR3 recorded in sequence number: 6; (2) an anti-IL-31RA antibody, comprising an H chain variable region recorded in sequence number: 7, and an L chain variable region recorded in sequence number: 8; (3) an anti-IL-31RA antibody, comprising an H chain recorded in sequence number: 9, and an L chain recorded in sequence number: 10; or (4) Nemolizumab, For subjects suffering from or at risk of dialysis pruritus (e.g., human patients), is administered in the following manner: (A) 0.1mg-1000mg/body/2 weeks, 0.1mg-1000mg/body/4 weeks, 0.1mg-1000mg/body/8 weeks, 25mg-100mg/body/4 weeks, 50mg-100mg/body/4 weeks, 5mg-75mg/body/4 weeks, 5mg-50mg/body/4 weeks, 5mg-25mg/body/4 weeks, 5mg-20mg/body y/4 weeks, 5mg/body/4 weeks, 10mg/body/4 weeks, 15mg/body/4 weeks, 20mg/body/4 weeks, 25mg/body/4 weeks, 30mg/body/4 weeks (in this case, for example, the initial dose is 60mg/body, the interval between the initial dose and the first continued dose is 4 weeks, and the continued dose may be 30mg/body/4 weeks), or 60mg/body/4 weeks; or (B) 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/8 weeks, 0.125 to 2.0 mg/kg/4 weeks, 0.125 to 0.5 mg/kg/4 weeks, 0.5 mg to 2.0 mg/kg/4 weeks, or 0.5 mg/kg/4 weeks. In this case, the IL-31 concentration in the subject's serum may be above a predetermined value (e.g., when measured using ultra-high sensitivity enzyme-linked immunosorbent assay (ELISA; SiMoATM, Quanterix, Billerica, MA, USA), for example, 0.15 pg/mL or more, 0.2 pg/mL or more, 0.3 pg/mL or more, 0.4 pg/mL or more, 0.5 pg/mL or more, 0.6 pg/mL or more, 0.7 pg/mL or more, 0.8 pg/mL or more, 0.86 pg/mL or more, 0.9 pg/mL or more, 1.0 pg/mL or more, 1.1 pg/mL or more, 1.25 pg/mL or more, 1.5 pg/mL or more, 1.75 pg/mL or more, 2 pg/mL or more, 2.25 pg/mL or more, or 2.5 pg/mL or more).

In addition, the 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 the method based on the contact region of antigen-antibody (J Mol Biol (1996) 262, 732-745). Specifically, the CDRs measured by 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

In the present disclosure, preferred examples of anti-IL-31RA neutralizing antibodies include anti-IL-31RA antibodies comprising: CDR1, CDR2, and CDR3 contained in the H chain variable region of SEQ ID NO: 7, and CDR1, CDR2, and CDR3 contained in the L chain variable region of SEQ ID NO: 8, as H chain CDR1, CDR2, and CDR3, and L chain CDR1, CDR2, and CDR3, respectively. In such antibodies, the method for defining CDRs may be based on any of the methods of Kabat et al., Chothia et al., and methods based on antigen-antibody contact regions, or may be based on a combination of these methods.

Anti-IL-31RA antibodies that bind to the same epitope as the anti-IL-31RA antibodies specified by the above-mentioned H chain and L chain CDR sequences, H chain variable region sequences and L chain variable region sequences, and H chain and L chain full-length sequences are also suitable as anti-IL-31RA neutralizing antibodies. The epitope refers to the specific structural unit of the antigen that the antibody recognizes and binds to. When the antigen is a polypeptide, it is usually composed of about 6 to 10 amino acids. The identification of antigenic determinants can be carried out by methods known to those skilled in the art, such as methods for synthesizing peptides obtained by fragmenting antigens, methods for introducing mutations specifically into antigen entry sites (e.g., arginine/glutamine scanning, J Biol Chem (1995) 270, 21619-21625, J Biol Chem (2006) 281, 20464-20473), and methods for crystallizing antigen-antibody complexes (Using Antibodies: A Laboratory Manual (1999), Cold Spring Harbor Laboratory Press, New York). In the present disclosure, "binding to the same antigenic determinant" means that the antigenic determinant to which the two antibodies bind is at least partially overlapped. The degree of repetition is not limited, but is at least 10%, preferably 20%, 30%, 40%, 50%, 60%, 70%, 80%, more preferably 90%, and most preferably 100%.

Furthermore, anti-IL-31RA antibodies that compete with the anti-IL-31RA antibodies specified by the above-mentioned H chain and L chain CDR sequences, H chain variable region and L chain variable region sequences, and H chain and L chain full-length sequences for binding to IL-31RA are also suitable as anti-IL-31RA neutralizing antibodies. Whether two antibodies compete with each other can be evaluated by competitive binding analysis such as ELISA. Specifically, one of the two antibodies is labeled with fluorescence or the like in advance, and a system is prepared to detect the binding of this antibody (labeled antibody) to the antigen. The situation where the other unlabeled antibody (test antibody) coexists with the situation where it does not coexist is compared. If the amount of binding of the labeled antibody to the antigen decreases when the test antibody coexists, 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, and 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, 98% or more (that is, the amount of binding of the other antibody is reduced).

The base sequence, amino acid sequence, etc. encoding the antibody that inhibits IL-31 signaling disclosed herein (e.g., anti-IL-31 neutralizing antibody or anti-IL-31RA neutralizing antibody) can be obtained according to methods known to those skilled in the art. The amino acids contained in the amino acid sequence of the antibody disclosed herein may be modified post-translationally (e.g., modification to pyroglutamine by pyroglutamylation of N-terminal glutamic acid is a modification known to those skilled in the art). Thus, the amino acid sequence disclosed herein is also included in the case where the amino acid is modified post-translationally.

In the present disclosure, although the dialysis itch is not limited, it is preferably caused by IL-31 signaling, or it may be dialysis itch caused by IL-31, and it may also be dialysis itch that is responsive to prevention and/or treatment using an IL-31 antagonist. Such dialysis itch may be dialysis itch in patients whose IL-31 concentration in the serum before the start of IL-31 antagonist administration is above a predetermined value. In this case, by administering an IL-31 antagonist, a higher itch improvement effect can be expected. Thus, the predetermined IL-31 concentration in the serum that is a benchmark for expecting a high itch improvement effect can be, for example, 0.86 pg/mL. In one non-limiting embodiment, the inventors unexpectedly observed that the group of patients with dialysis pruritus whose itch was significantly suppressed by the administration of IL-31 antagonists showed higher IL-31 concentrations in serum than the group of patients without dialysis pruritus. Therefore, it is shown that the serum IL-31 concentration can be used as an indicator to predict the effectiveness of the treatment or prevention of dialysis pruritus and/or its itch caused by IL-31 antagonists (e.g., nemolizumab). In a non-limiting embodiment, the predetermined IL-31 concentration in the serum is measured using an ultra-high sensitivity enzyme-linked immunosorbent assay (ELISA; SiMoATM, Quanterix, Billerica, MA, USA), for example, 0.15 pg/mL or more, 0.2 pg/mL or more, 0.3 pg/mL or more, 0.4 pg/mL or more, 0.5 pg/mL or more, 0.6 pg/mL or more, 0.7 pg/mL or more, 0.8 pg/mL or more, 0.86 pg/mL or more, 0.9 pg/mL or more, 1.0 pg/mL or more, 1.1 pg/mL or more, 1.25 pg/mL or more, 1.5 pg/mL or more, 1.75 pg/mL or more, 2 pg/mL or more, 2.25 pg/mL or more, or 2.5 pg/mL or more.

The dialysis pruritus disclosed herein is not limited, but may be dialysis pruritus for which systemic therapy (antihistamine or antiallergic drug, etc.) or local therapy (moisturizer, steroid, etc.) other than nalfurafine hydrochloride is performed, and dialysis pruritus is not sufficiently responded to these treatments.

As the causes of pruritus in dialysis patients, various factors are considered, such as accumulation of uremic substances, abnormal calcium-phosphorus metabolism, secondary hyperparathyroidism, activation of toxins due to dialysis membranes or the effects of heparin, dry skin, involvement of itch mediators such as amines (histamine, serotonin, etc.) or neuropeptides (substance P, etc.), abnormalities of the immune system, and abnormalities of endogenous opioids. However, its pathogenesis is still unclear. Therefore, there is no unified policy for the treatment of pruritus in dialysis patients. Although the use of highly biocompatible dialysis membranes or changes in dialysis conditions, adjustment of calcium-phosphorus concentrations, treatment of secondary hyperparathyroidism, application of moisturizers or steroids, oral administration of antiallergic drugs or antihistamines, or ultraviolet therapy are used, many of these treatments are ineffective. Since Japan launched nalfurapine hydrochloride in 2009, which is effective in "improving pruritus in hemodialysis patients (only when existing treatment is insufficient)", the degree of improvement of pruritus by nalfurapine hydrochloride varies from patient to patient (Yamada Naoki et al., Actuality of pruritus in hemodialysis patients and clinical effect of nalfurapine hydrochloride - Questionnaire survey of 1,936 patients in 17 facilities in the Tokai region - Journal of Dialysis 2012; 45:1133-40.), or 15.8% of patients think it has a side effect of insomnia (Remitch (registered trademark) capsule 2.5μg drug summary (Interview Form) (Revised in June 2013 (8th edition)), but it is considered that treatment satisfaction is still insufficient. Therefore, a treatment method with sufficient effectiveness and high safety is needed. (1)  Nalfurafine hydrochloride for oral administration (product name: Remitch capsule) Generally, for adults, nalfurafine hydrochloride is orally administered at a dose of 2.5 μg once a day after dinner or before bedtime. In addition, the dose can be increased according to the symptoms, but it is limited to 5 μg once a day.

The severity of dialysis pruritus (mild, moderate, severe, etc.) can be classified based on, for example, the severity standard obtained by dialysis, the Visual Analogue Scale (VAS), the Verbal Rating Scale (VRS), and other classification methods that score the degree of itching felt by the subject and are known to those skilled in the art. For example, in one embodiment, a subject whose itching intensity is measured as 50 mm or more by VAS can be identified as suffering from dialysis pruritus. However, if the subject is dialysis pruritus for which systemic therapy (antihistamine or antiallergic drug, etc.) or local therapy (moisturizer, steroid, etc.) other than nalfurafine hydrochloride is performed and the treatment is not sufficiently effective, then the subject is not particularly limited.

In this specification, "subject" is not limited, and is preferably an animal, more preferably a mammal (mice, rats, rabbits, dogs, monkeys (e.g., crab-eating macaques), etc.), and particularly preferably a human. The human may be an adult (over 18 years old) or a child (0 to under 18 years old, e.g., 6 months to under 18 years old, etc.).

In one aspect, the present disclosure relates to a preventive and/or therapeutic pharmaceutical composition for dialysis pruritus containing an IL-31 antagonist as an active ingredient (also, "preventive and/or therapeutic pharmaceutical composition" may also be referred to as "preventive and/or therapeutic agent"). In this case, it is intended that the IL-31 antagonist is repeatedly administered at a predetermined dosage (dosage) equal to the predetermined administration interval as described below and at the same administration interval.

In one embodiment, the pharmaceutical composition disclosed herein can be used for the prevention and/or treatment of dialysis pruritus. In a specific embodiment, the pharmaceutical composition disclosed herein can be used for the prevention and/or treatment of dialysis pruritus in patients whose serum IL-31 concentration before the start of IL-31 antagonist administration is above a predetermined value. In an exemplary embodiment, the pharmaceutical composition of the present disclosure can be administered only to subjects determined to be responsive to prevention and/or treatment with an IL-31 antagonist by a method for predicting whether the subject is responsive to prevention and/or treatment with an IL-31 antagonist, wherein the method comprises the following steps: (1) measuring the IL-31 concentration in serum obtained from a subject suffering from or at risk of suffering from dialysis pruritus; and (2) determining a subject having an IL-31 concentration of a predetermined value or above as a responsive subject to prevention and/or treatment with an IL-31 antagonist. In this case, a higher itch improvement effect can be expected by administering the pharmaceutical composition of the present disclosure. Thus, the predetermined IL-31 concentration in serum that is expected to exert a high itch improvement effect can be, for example, 0.86 pg/mL. The IL-31 concentration in the serum obtained from the patient can be measured by any means known to those of ordinary skill in the art. In a preferred non-limiting embodiment, the predetermined IL-31 concentration in the serum can be measured using an ultra-high sensitivity enzyme-linked immunosorbent assay (ELISA; SiMoATM, Quanterix, Billerica, MA, USA).

In another embodiment or another embodiment, the pharmaceutical composition disclosed herein can be used to improve sleep disorders caused by dialysis pruritus. The improvement of the sleep disorder can be characterized by, for example, an increase in the time from falling asleep to waking up, and/or a shortening of sleep latency (the time from going to bed to falling asleep).

In one embodiment of the present disclosure, the prevention and/or treatment of dialysis pruritus is not limited to administering a drug or the like to a subject exhibiting pruritus to suppress such symptoms, and/or administering a drug or the like to a subject exhibiting pruritus to prevent the manifestation of such symptoms in advance or reduce the manifestation rate. By improving pruritus, it is expected that the QOL or sleep quality or life prognosis of dialysis patients will be improved.

Although not limited to this, a subject at risk of developing dialysis pruritus may be a subject who has suffered from dialysis pruritus in the past and is at risk of recurring symptoms, or a subject who is suspected of having dialysis pruritus before being diagnosed or determined by a physician or the like to have developed dialysis pruritus. In one embodiment, prevention and treatment of dialysis pruritus are sometimes interpreted with the same meaning.

In this embodiment, in a single subcutaneous administration trial of an IL-31 antagonist in patients with atopic dermatitis, it is believed that the sleep efficiency of the group administered with the IL-31 antagonist is improved. The improvement of dialysis pruritus as described above is believed to be important for improving the patient's QOL, sleep quality, or life prognosis. Therefore, in another non-limiting embodiment, the present disclosure is related to a pharmaceutical composition, which is a preventive and/or therapeutic pharmaceutical composition for dialysis pruritus containing an IL-31 antagonist as an active ingredient, and is further used to improve sleep disorders caused by dialysis pruritus. The characteristics of the improvement of the sleep disorder can be, for example, an increase in the time from falling asleep to waking up, and/or a shortening of sleep latency (the time from going to bed to falling asleep). Alternatively, in another non-limiting aspect or another non-limiting aspect, the present disclosure is about a pharmaceutical composition for improving QOL caused by dialysis pruritus. Alternatively, in another non-limiting aspect or another non-limiting aspect, the present disclosure is about a pharmaceutical composition for improving life prognosis caused by dialysis pruritus.

In this specification, repeated administration of equal amounts and the same administration interval may mean that the dosage (initial dosage) of the IL-31 antagonist disclosed herein administered to a subject for the first time and the subsequent dosage (i.e., the dosage of the subsequent dosage after the initial dosage) are equal, and may mean administration at the same administration interval (interval between each administration). That is, for example, the interval between the administration of the initial dosage and the administration of the first subsequent dosage, the interval between the administration of the nth (n is an integer greater than 1) subsequent dosage and the administration of the n+1th subsequent dosage are completely equal and the dosage is equal. In the determined administration interval (for example, once every 4 weeks when the administration interval is determined to be once every 4 weeks), a person skilled in the art will of course understand that each administration interval may be accompanied by a "tolerable range", and a person skilled in the art can appropriately determine the tolerable range.

In one embodiment, in the present disclosure, the number of repeated administrations, for example, the administration of a subsequent dose following the initial dose, is not limited to, for example, 1 to 10,000 times or more, and more specifically, for example, 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, ... 15 times, ... 20 times, ... 25 times, ... 35 times, ... 40 times, ... 50 times, ... 60 times, ... 70 times, ... 80 times, ... 90 times, ... 100 times, ... 500 times, ... 1000 times, ... 10,000 times, ...

In one embodiment, the administration interval of the pharmaceutical composition or IL-31 antagonist disclosed herein is intended to mean a minimum period of more than 1 day to a maximum period of less than 12 weeks, specifically, 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. In addition, the administration interval can be expressed in another way, for example, it can also be recorded as once a day to once every 12 weeks, or it can also be recorded as once every day to once every 12 weeks.

In the present disclosure, the dosage (dosage) may be expressed in terms of mg/kg, for example, a fixed dosage (mg/body) equivalent to a dosage converted by body weight, or a dosage converted by body surface area (mg/m ² ). For example, when the IL-31 antagonist of the present disclosure is administered to a subject suffering from or at risk of dialysis pruritus at a fixed dosage (mg/body), the dosage of the IL-31 antagonist of the present disclosure may be converted from mg/kg to mg/body, and an appropriate dosage (mg/body) may be set and administered to the subject. In this case, the conversion logic from mg/kg to mg/body is not limited, but may be appropriately determined using logic known to a person skilled in the art. As an example of such logic, the following can be considered: It can also be assumed that the IL-31 antagonist disclosed in the present invention has a minimum effective serum concentration and a maximum tolerable (empirical) serum concentration, and the change from the mg/kg dosage to the mg/body dosage can be discussed in a manner that the serum IL-31 antagonist concentration can be obtained regardless of body weight within this concentration range. Such a subject can be, for example, a subject weighing less than 100 kg or less than 120 kg. Although not limited, for subjects with a heavier weight (for example, a weight exceeding 100 kg or exceeding 120 kg), the mg/body dosage can be increased depending on the situation. In addition, if the exposure of children with a lighter weight may be significantly increased when the dosage is mg/body, the mg/kg dosage can be discussed. Alternatively, the weight of a general dialysis pruritus patient may be assumed based on statistical data, and based on the assumed weight, the dosage per unit weight (mg/kg) may be converted into a fixed dosage (mg/body) by the calculation formula "dosage per unit weight x assumed weight = fixed dosage". For example, if the assumed weight of each adult is 60 kg, the fixed dosage can be calculated as 30 mg/body from the dosage per unit weight (0.5 mg/kg). Similarly, if the assumed weight of each child is 30 kg, the fixed dosage can be calculated as 15 mg/body from the dosage per unit weight (0.5 mg/kg).

In a non-limiting embodiment, for subjects suffering from hemodialysis pruritus or at risk of suffering from the same, such as human adults and/or children, the dosage may be from 0.1 mg to 1000 mg/body, such as 0.2 mg to 360 mg/body, preferably 5 mg to 100 mg/body, 5 mg to 75 mg/body, 5 mg to 50 mg/body, 5 mg to 25 mg/body, 5 mg to 20 mg/body, 10 mg to 100 mg/body, 10 mg to 75 mg/body, 10 mg ~50mg/body, 10mg~40mg/body, 10mg~39.5mg/body, 10mg~39mg/body, 10mg~38.5mg/body, 10mg~38mg/body, 10mg~3 7.5mg/body, 15mg~100mg/body, 15mg~75mg/body, 15mg~50mg/body, 15mg~40mg/body, 15mg~39.5mg/body, 15mg~39m g/body, 15mg~38.5mg/body, 15mg~38mg/body, 15mg~37.5mg/body, 17.5mg~100mg/body, 17.5mg~75mg/body, 17.5m g~50mg/body, 17.5mg~40mg/body, 17.5mg~39.5mg/body, 17.5mg~39mg/body, 17.5mg~38.5mg/body, 17.5mg~38mg/b ody, 17.5mg~37.5mg/body, 20mg~100mg/body, 20mg~75mg/body, 20mg~50mg/body, 20mg~40mg/body, 20mg~39.5mg/b ody, 20mg~39mg/body, 20mg~38.5mg/body, 20mg~38mg/body, 20mg~37.5mg/body, 22.5mg~100mg/body, 22.5mg~75mg /body, 22.5mg~50mg/body, 22.5mg~40mg/body, 22.5mg~39.5mg/body, 22.5mg~39mg/body, 22.5mg~38.5mg/body, 2 2.5mg~38mg/body, 22.5mg~37.5mg/body, 25mg~500mg/body, 25mg~200mg/body, 25mg~120mg/body, 25mg~110mg/bod y, 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/b ody, 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/b ody, 40mg~90mg/body, 40mg~100mg/body, 40mg~110mg/body, 40mg~120mg/body, 42.5mg~70mg/body, 42.5mg~71mg/b ody, 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, 4 2.5mg~110mg/body, 42.5mg~120mg/body, 45mg~70mg/body, 45mg~71mg/body, 45mg~72mg/body, 45mg~73mg/body, 45 mg~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~71m g/body, 47.5mg~72mg/body, 47.5mg~73mg/body, 47.5mg~74mg/body, 47.5mg~75mg/body, 47.5mg~76mg/body, 47.5m g~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~8 0mg/body, 50mg~90mg/body, 50mg~100mg/body, 50mg~110mg/body, 50mg~120mg/body, 50mg~150mg/body, 50mg~200m g/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, 52.5mg~100mg/body, 52.5mg~110mg/body, 52.5mg~120m g/body, 75mg~100mg/body, 75mg~150mg/body, 75mg~200mg/body, 75mg~250mg/body, 75mg~300mg/body, 100mg~150m g/body, 100mg~200mg/body, 100mg~250mg/body, 100mg~300mg/body, 150mg~200mg/body, 150mg~250mg/body, 150mg~300mg/body, 200mg~250mg/body, 200mg~300mg/body, etc. as the dosage of the IL-31 antagonist disclosed herein, and the above-mentioned dosage is repeated in equal amounts and at the same dosage interval. In order to avoid ambiguity, for example, when the dosage range is 50 to 200 mg/body, a person skilled in the art can directly and unambiguously understand that, 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, 60 mg/body, 61 mg/body, 61.5 mg/body, 62 mg/body, 62.5 mg/body, 63 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 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 Numerical values such as 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, 200 mg/body, etc. can be described individually and specifically.

Alternatively, in another non-limiting embodiment, for subjects suffering from dialysis pruritus or at risk of suffering from the pruritus, such as human adults and/or children, the dosage can be selected from 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, 0.125 mg to 0.25 mg/kg, 0.125 mg to 0.3 mg/kg g, 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/k g, 1 mg ~ 3 mg / kg, 1.5 mg ~ 2 mg / kg, 1.5 mg ~ 3 mg / kg, 2 mg ~ 3 mg / kg, 0.15 mg ~ 2.9 mg / kg, 0.2 mg ~ 2.8 mg / kg, 0.25 mg ~ 2.7 mg / kg, 0.3 mg ~ 2.6 mg / kg, 0.35 mg ~ 2.5 mg / kg, 0.4 mg ~ 2.4 mg / kg, 0.425 mg ~ 2.3 mg / kg, 0.45 mg ~ 2.2 mg / kg, 0.475 mg ~ 2.1 mg / kg, 0.5 mg ~ 2 mg / kg, or 0.5 mg ~ 1.5 mg / kg as the dosage of the IL-31 antagonist of the present disclosure, and the above-mentioned dosage interval is repeated in equal amounts and at the same dosage interval. In order to avoid ambiguity, it is indicated that, for example, a person with ordinary knowledge in the art who mentions 0.1 mg to 3 mg/kg can of course directly and unambiguously understand that, 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, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 1 ... 21mg/kg, 0.22mg/kg, 0.23mg/kg, 0.24mg/kg, 0.25mg/kg, 0.26mg/kg, 0.27mg/kg, 0.28mg/kg, 0.29mg/kg, 0.3m g/kg, 0.31mg/kg, 0.32mg/kg, 0.33mg/kg, 0.34mg/kg, 0.35mg/kg, 0.36mg/kg, 0.37mg/kg, 0.38mg/kg, 0.39mg/k g, 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, 0.58m g/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/k g, 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, 0.86m g/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, 1.05 mg/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/k g, 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, 1.33m g/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/k g, 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, 1.61m g/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, 1.89m g/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/k g, 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, 2.08 mg/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, 2.36 mg/kg, 2.37mg/kg, 2.38mg/kg, 2.39mg/kg, 2.4mg/kg, 2.41mg/kg, 2.42mg/kg, 2.43mg/kg, 2.44mg/kg, 2.45mg/k g, 2.46mg/kg, 2.47mg/kg, 2.48mg/kg, 2.49mg/kg, 2.5mg/kg, 2.51mg/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, 2.64m g/kg, 2.65mg/kg, 2.66mg/kg, 2.67mg/kg, 2.68mg/kg, 2.69mg/kg, 2.7mg/kg, 2.71mg/kg, 2.72mg/kg, 2.73mg/k g, 2.74mg/kg, 2.75mg/kg, 2.76mg/kg, 2.77mg/kg, 2.78mg/kg, 2.79mg/kg, 2.8mg/kg, 2.81mg/kg, 2.82mg/kg, 2. The values may be specifically described individually or in detail.

Thus, the IL-31 antagonist disclosed herein can be administered repeatedly at a predetermined administration interval and a predetermined dosage (administration amount) in equal amounts and at the same administration interval, and can be administered as "0.1 mg to 1000 mg/body/1 day to 12 weeks". Here, in this specification, for example, "0.1 mg to 1000 mg/body/1 day to 12 weeks" means that an administration amount selected from 0.1 mg to 1000 mg is used as the administration amount of the IL-31 antagonist disclosed herein (e.g., 100 mg/body), and an administration interval selected from 1 day to 12 weeks is used as the administration interval of the IL-31 antagonist disclosed herein (e.g., 4 weeks), and the same amount and the same administration interval are repeatedly administered to the subject. For example, "100 mg/body/4 weeks" means that 100 mg/body of the IL-31 antagonist disclosed herein is repeatedly administered to a subject in equal amounts and at the same administration interval every 4 weeks. Although not limited thereto, the IL-31 antagonist disclosed herein is repeatedly administered in equal amounts and at the same administration interval at a predetermined administration interval and a predetermined dosage (administration amount), preferably in the range of 0.1 mg to 1000 mg/body/2 weeks to 8 weeks, 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, 0.2 mg to 360 mg/body/2 weeks to 8 weeks is more preferred, such as 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 0.2 mg to 360 mg/body/8 weeks. Alternatively, as an example, 10 mg to 200 mg/body/2 weeks to 8 weeks is more preferred, such as 10 mg to 200 mg/body/2 weeks, 10 mg to 200 mg/body/4 weeks, 10 mg to 200 mg/body/6 weeks, or 10 mg to 200 mg/body/8 weeks. Alternatively, as an example, 10 mg to 100 mg/body/2 weeks to 8 weeks is more preferred, such as 10 mg to 100 mg/body/2 weeks, 10 mg to 100 mg/body/4 weeks, 10 mg to 100 mg/body/6 weeks, or 10 mg to 100 mg/body/8 weeks. Alternatively, as an example, 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 a non-limiting embodiment, it can be, for example, 5 mg/body/4 weeks, 10 mg/body/4 weeks, 15 mg/body/4 weeks, 20 mg/body/4 weeks, 25 mg/body/4 weeks, 30 mg/body/4 weeks, 50 mg/body/4 weeks, 50.5 mg/body/4 weeks, 51 mg/body/4 weeks, 51.5 mg/body/4 weeks, 52 mg/body/4 weeks, 52.5 mg/body/4 weeks, 53 mg/body/4 weeks, 53.5 mg/body/4 weeks, 54 mg/body/4 weeks, 54.5 mg/body/4 weeks, 55 mg/body/4 weeks, 55.5 mg/body/4 weeks, 56 mg/body/4 weeks, 56.5 mg/body/4 weeks. body/4 weeks, 57mg/body/4 weeks, 57.5mg/body/4 weeks, 58mg/body/4 weeks, 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 dy/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 week, 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/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, 119mg/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, 1 30mg/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/4 weeks, 144mg/body/4 weeks g/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, 152mg/body/4 weeks, 152.5mg/body/4 weeks, 153mg/body/4 weeks, 154mg/body/4 weeks 3.5mg/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 week, 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 y/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, 184mg/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, 191 mg/body/4 weeks, 191.5mg/body/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, 199.5mg/body/4 weeks, 200mg/body/4 weeks, etc. Alternatively, in a non-limiting embodiment, it can 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 dy/6 weeks, 59.5mg/body/6 weeks, 60mg/body/6 weeks, 60.5mg/body/6 weeks, 61mg/body/6 weeks, 61.5mg/body/6 weeks, 62mg/body/6 weeks, 62.5mg/body/6 weeks, 63mg/body/6 weeks, 63.5mg/body/6 weeks, 64mg/body/6 weeks, 64.5mg/body/6 weeks, 65mg/body/6 weeks, 65.5mg/body/6 weeks, 66mg/body/6 weeks, 66.5mg/body/6 weeks, 67mg/body/6 weeks, 67.5mg/body/6 weeks, 68mg/body/6 weeks, 68.5mg/body/6 weeks, 69mg /body/6 weeks, 69.5mg/body/6 weeks, 70mg/body/6 weeks, 70.5mg/body/6 weeks, 71mg/body/6 weeks, 71.5mg/body/6 weeks, 72mg/body/6 weeks, 72.5mg/body/6 weeks, 73mg/body/6 weeks, 73.5mg/body/6 weeks, 74mg/body/6 weeks, 74.5mg/body/6 weeks, 75mg/body/6 weeks, 75.5mg/body/6 weeks, 76mg/body/6 weeks, 76.5mg/body/6 weeks, 77mg/body/6 weeks, 77.5mg/body/6 weeks, 78mg/body/6 weeks, 78.5mg/body/6 weeks, 7 9mg/body/6 weeks, 79.5mg/body/6 weeks, 80mg/body/6 weeks, 80.5mg/body/6 weeks, 81mg/body/6 weeks, 81.5mg/body/6 weeks, 82mg/body/6 weeks, 82.5mg/body/6 weeks, 83mg/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 week, 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, 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 y/6 weeks, 99mg/body/6 weeks, 99.5mg/body/6 weeks, 100mg/body/6 weeks, 100.5mg/body/6 weeks, 101mg/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, 108m g/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, 133mg/body/6 weeks, 133.5mg/body/6 weeks, 134mg/body/6 weeks, 134.5mg/body/6 weeks, 135mg/body/6 weeks, 135.5mg/body y/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/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, 145.5mg/body/6 weeks, 146mg/body/6 weeks 5mg/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, 148.5mg/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 y/6 weeks, 154.5mg/body/6 weeks, 155mg/body/6 weeks, 155.5mg/body/6 weeks, 156mg/body/6 weeks, 156.5mg/body/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, 164mg/body/6 weeks 3.5mg/body/6 weeks, 164mg/body/6 weeks, 164.5mg/body/6 weeks, 165mg/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 ody/6 weeks, 173mg/body/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, 181.5mg/body/6 weeks, 182mg/body/6 weeks, 182.5mg/body/6 weeks, 183mg/body/6 weeks, 183.5mg/body/6 weeks, 184mg/body/6 weeks, 184.5mg/body/6 weeks, 185mg/body/6 weeks, 185.5mg/body/6 weeks, 186mg/body/6 weeks, 186.5mg/body/6 weeks, 187mg/body/6 weeks, 187.5mg/body/6 weeks, 188mg/body/6 weeks, 188.5mg/body/6 weeks, 189mg/body/6 weeks, 189.5mg/body/6 weeks, 190mg/body/6 weeks, 190.5mg/body/6 weeks, 191mg/body ody/6 weeks, 191.5mg/body/6 weeks, 192mg/body/6 weeks, 192.5mg/body/6 weeks, 193mg/body/6 weeks, 193.5mg/body/6 weeks, 194mg/body/6 weeks, 194.5mg/body/6 weeks, 195mg/body/6 weeks, 195.5mg/body/6 weeks, 196mg/body/6 weeks, 196.5mg/body/6 weeks, 197mg/body/6 weeks, 197.5mg/body/6 weeks, 198mg/body/6 weeks, 198.5mg/body/6 weeks, 199mg/body/6 weeks, 199.5mg/body/6 weeks, 200mg/body/6 weeks, etc. Alternatively, in a non-limiting embodiment, it can 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. ody/8 weeks, 59.5mg/body/8 weeks, 60mg/body/8 weeks, 60.5mg/body/8 weeks, 61mg/body/8 weeks, 61.5mg/body/8 weeks, 62mg/body/8 weeks, 62.5mg/body/8 weeks, 63mg/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 g/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, 81mg/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/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 dy/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, 108 mg/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, 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 y/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/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, 145.5mg/body/8 weeks, 146mg/body/8 weeks 5mg/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、148mg/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 y/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, 164mg/body/8 weeks 3.5mg/body/8weeks、164mg/body/8weeks、164.5mg/body/8weeks、165mg/body/8weeks、165.5mg/body/8weeks、166mg/body/8weeks、166.5mg/body/8weeks、167mg/body/8weeks、167.5mg/body/8weeks、168mg/body/8weeks、168.5mg/body/8weeks、169mg/body/8weeks、169.5mg/body/8weeks、170mg/body/8weeks、170.5mg/body/8weeks、171mg/body/8weeks、171.5mg/body/8weeks、172mg/body/8weeks、172.5mg/body ody/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, 181mg/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 ody/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, 197.5mg/body/8 weeks, 198mg/body/8 weeks, 198.5mg/body/8 weeks, 199mg/body/8 weeks, 199.5mg/body/8 weeks, 200mg/body/8 weeks, etc. Alternatively, in a non-limiting embodiment, it can 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, 54.5mg/body/10 weeks, 55mg/body/10 weeks, 55.5mg/body/10 weeks, 56mg/body/10 weeks, 56.5mg/body/10 weeks, 57mg/body/10 weeks, 57.5mg/body/10 weeks, 58mg/body/10 weeks, 58.5mg/body/10 weeks, 59mg/body dy/10 weeks, 59.5mg/body/10 weeks, 60mg/body/10 weeks, 60.5mg/body/10 weeks, 61mg/body/10 weeks, 61.5mg/body/10 weeks, 62mg/body/10 weeks, 62.5mg/body/10 weeks, 63mg/body/10 weeks, 63.5mg/body/10 weeks, 64mg/ body/10 weeks, 64.5mg/body/10 weeks, 65mg/body/10 weeks, 65.5mg/body/10 weeks, 66mg/body/10 weeks, 66.5mg/body/10 weeks, 67mg/body/10 weeks, 67.5mg/body/10 weeks, 68mg/body/10 weeks, 68.5mg/body/10 weeks, 69mg/body/10 weeks g/body/10 weeks, 69.5mg/body/10 weeks, 70mg/body/10 weeks, 70.5mg/body/10 weeks, 71mg/body/10 weeks, 71.5mg/body/10 weeks, 72mg/body/10 weeks, 72.5mg/body/10 weeks, 73mg/body/10 weeks, 73.5mg/body/10 weeks, 7 4mg/body/10 weeks, 74.5mg/body/10 weeks, 75mg/body/10 weeks, 75.5mg/body/10 weeks, 76mg/body/10 weeks, 76.5mg/body/10 weeks, 77mg/body/10 weeks, 77.5mg/body/10 weeks, 78mg/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/1 0 weeks, 84 mg/body/10 weeks, 84.5 mg/body/10 weeks, 85 mg/body/10 weeks, 85.5 mg/body/10 weeks, 86 mg/body/10 weeks, 86.5 mg/body/10 weeks, 87 mg/body/10 weeks, 87.5 mg/body/10 weeks, 88 mg/body/10 weeks, 88.5 mg/body /10 weeks, 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 dy/10 weeks, 94mg/body/10 weeks, 94.5mg/body/10 weeks, 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/10 weeks, 103mg/body/10 weeks week, 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, 1 08mg/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 g/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 y/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/1 0 weeks, 122 mg/body/10 weeks, 122.5 mg/body/10 weeks, 123 mg/body/10 weeks, 123.5 mg/body/10 weeks, 124 mg/body/10 weeks, 124.5 mg/body/10 weeks, 125 mg/body/10 weeks, 125.5 mg/body/10 weeks, 126 mg/body/10 weeks, 12 6.5mg/body/10 weeks, 127mg/body/10 weeks, 127.5mg/body/10 weeks, 128mg/body/10 weeks, 128.5mg/body/10 weeks, 129mg/body/10 weeks, 129.5mg/body/10 weeks, 130mg/body/10 weeks, 130.5mg/body/10 weeks, 131mg/body/10 weeks g/body/10 weeks, 131.5mg/body/10 weeks, 132mg/body/10 weeks, 132.5mg/body/10 weeks, 133mg/body/10 weeks, 133.5mg/body/10 weeks, 134mg/body/10 weeks, 134.5mg/body/10 weeks, 135mg/body/10 weeks, 135.5mg/b ody/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 0 weeks, 140.5 mg/body/10 weeks, 141 mg/body/10 weeks, 141.5 mg/body/10 weeks, 142 mg/body/10 weeks, 142.5 mg/body/10 weeks, 143 mg/body/10 weeks, 143.5 mg/body/10 weeks, 144 mg/body/10 weeks, 144.5 mg/body/10 weeks, 145mg/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, 149.5 mg/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 dy/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, 1 63.5mg/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 weeks, 168mg/body/10 weeks g/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/b ody/10 weeks, 173mg/body/10 weeks, 173.5mg/body/10 weeks, 174mg/body/10 weeks, 174.5mg/body/10 weeks, 175mg/body/10 weeks, 175.5mg/body/10 weeks, 176mg/body/10 weeks, 176.5mg/body/10 weeks, 177mg/body/1 0 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, 182mg/body/10 weeks, 182.5mg/body/10 weeks, 183mg/body/10 weeks, 183.5mg/body/10 weeks, 184mg/body/10 weeks, 184.5mg/body/10 weeks, 185mg/body/10 weeks, 185.5mg/body/10 weeks, 186mg/body/10 weeks, 186.5 mg/body/10 weeks, 187mg/body/10 weeks, 187.5mg/body/10 weeks, 188mg/body/10 weeks, 188.5mg/body/10 weeks, 189mg/body/10 weeks, 189.5mg/body/10 weeks, 190mg/body/10 weeks, 190.5mg/body/10 weeks, 191mg/body dy/10 weeks, 191.5mg/body/10 weeks, 192mg/body/10 weeks, 192.5mg/body/10 weeks, 193mg/body/10 weeks, 193.5mg/body/10 weeks, 194mg/body/10 weeks, 194.5mg/body/10 weeks, 195mg/body/10 weeks, 195.5mg/body/ 10 weeks, 196mg/body/10 weeks, 196.5mg/body/10 weeks, 197mg/body/10 weeks, 197.5mg/body/10 weeks, 198mg/body/10 weeks, 198.5mg/body/10 weeks, 199mg/body/10 weeks, 199.5mg/body/10 weeks, 200mg/body/10 weeks, etc. Alternatively, in a non-limiting embodiment, it can be, 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, 54.5mg/body/12 weeks, 55mg/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 dy/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/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 g/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, 72mg/body/12 weeks, 72.5mg/body/12 weeks, 73mg/body/12 weeks, 73.5mg/body/12 weeks, 7 4mg/body/12 weeks, 74.5mg/body/12 weeks, 75mg/body/12 weeks, 75.5mg/body/12 weeks, 76mg/body/12 weeks, 76.5mg/body/12 weeks, 77mg/body/12 weeks, 77.5mg/body/12 weeks, 78mg/body/12 weeks, 78.5mg/body/12 weeks , 79mg/body/12 weeks, 79.5mg/body/12 weeks, 80mg/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/1 2 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 dy/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, 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 week, 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, 1 08mg/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 g/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 y/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/1 2 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, 12 6.5mg/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 g/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, 135mg/body/12 weeks, 135.5mg/body ody/12 weeks, 136mg/body/12 weeks, 136.5mg/body/12 weeks, 137mg/body/12 weeks, 137.5mg/body/12 weeks, 138mg/body/12 weeks, 138.5mg/body/12 weeks, 139mg/body/12 weeks, 139.5mg/body/12 weeks, 140mg/body/1 2 weeks, 140.5mg/body/12 weeks, 141mg/body/12 weeks, 141.5mg/body/12 weeks, 142mg/body/12 weeks, 142.5mg/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, 149.5 mg/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 dy/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, 1 63.5mg/body/12 weeks, 164mg/body/12 weeks, 164.5mg/body/12 weeks, 165mg/body/12 weeks, 165.5mg/body/12 weeks, 166mg/body/12 weeks, 166.5mg/body/12 weeks, 167mg/body/12 weeks, 167.5mg/body/12 weeks, 168mg/body/12 weeks g/body/12 weeks, 168.5mg/body/12 weeks, 169mg/body/12 weeks, 169.5mg/body/12 weeks, 170mg/body/12 weeks, 170.5mg/body/12 weeks, 171mg/body/12 weeks, 171.5mg/body/12 weeks, 172mg/body/12 weeks, 172.5mg/b ody/12 weeks, 173mg/body/12 weeks, 173.5mg/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/1 2 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, 186.5 mg/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 dy/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/ In one non-limiting embodiment, the dosage may be 25 mg to 100 mg/body/4 weeks, 50 mg to 100 mg/body/4 weeks, or 50 mg to 75 mg/body/4 weeks. In another non-limiting embodiment, the dosage may be 10 mg to 50 mg/body/2 weeks or 20 mg to 40 mg/body/2 weeks.

In addition, as an aspect of the IL-31 antagonist disclosed herein, the IL-31 antagonist is repeatedly administered at a predetermined administration interval and a predetermined dosage (administration amount) in equal amounts and at the same administration interval, it is also possible to administer a subsequent dosage (i.e., a subsequent dosage after the initial dosage) after the first administration of the IL-31 antagonist disclosed herein to the subject. In a non-limiting aspect, the initial dosage may be a multiple of the subsequent dosage. For example, the initial dosage may be 60 mg/body, the interval between the initial dosage and the first subsequent dosage is 4 weeks, and the subsequent dosage is 30 mg/body/4 weeks.

Alternatively, the IL-31 antagonist disclosed herein can be administered repeatedly at a predetermined administration interval and a predetermined dosage (administration amount) in equal amounts and at the same administration interval as "0.01 mg ~ 10 mg / kg / 1 day ~ 12 weeks". Here, in this specification, for example, "0.01 mg ~ 10 mg / kg / 1 day ~ 12 weeks" means that the administration amount of the IL-31 antagonist disclosed herein is selected from 0.01 mg ~ 10 mg, and the administration interval of the IL-31 antagonist disclosed herein is selected from 1 day to 12 weeks as the administration interval (for example, 4 weeks), and the same amount and the same administration interval are administered to the subject repeatedly. Although not limited, the IL-31 antagonist disclosed herein is preferably administered at a predetermined administration interval and a predetermined dosage (administration amount) in an equal amount and repeated administration at the same administration interval, preferably 0.01 mg ~ 10 mg / kg / 2 weeks to 8 weeks, for example, 0.01 mg ~ 10 mg / kg / 2 weeks, 0.01 mg ~ 10 mg / kg / 4 weeks, 0.01 mg ~ 10 mg / kg / 6 weeks, or 0.01 mg ~ 10 mg / kg / 8 weeks. Alternatively, 0.1 mg ~ 3 mg / kg / 2 weeks to 8 weeks is more preferred, which can be, for example, 0.1 mg ~ 3 mg / kg / 2 weeks, 0.1 mg ~ 3 mg / kg / 4 weeks, 0.1 mg ~ 3 mg / kg / 6 weeks, or 0.1 mg ~ 3 mg / kg / 8 weeks. Alternatively, as an example, 0.2 mg to 2 mg/kg/2 weeks to 8 weeks is more preferred, such as 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, 0.5 mg to 1.5 mg/kg/4 weeks to 8 weeks is more preferred, such as 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 a non-limiting embodiment, it can be, for example, 0.1 mg/kg/4 week, 0.11 mg/kg/4 week, 0.12 mg/kg/4 week, 0.125 mg/kg/4 week, 0.13 mg/kg/4 week, 0.14 mg/kg/4 week, 0.15 mg/kg/4 week, 0.16 mg/kg/4 week, 0.17 mg/kg/4 week, 0.18 mg/kg/4 week, 0.19 mg/kg/4 week, 0.2 mg/kg/4 week, 0.21 mg/kg/4 week, 0.22 mg/kg/4 week, 0.23 mg/kg/4 week, 0.24 mg/kg/4 week, 0.25 mg/kg/4 week, 0. 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, 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 g/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/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, 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, 0.9 9mg/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, 1.54 mg/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 g/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, 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, 2.09 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 g/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, 2.56mg/kg/4 weeks, 2.57mg/kg/4 weeks, 2.58mg/kg/4 weeks, 2.59mg/kg/4 weeks, 2.6mg/kg/4 weeks, 2.61mg/kg/4 weeks, 2.62mg/kg/4 weeks, 2.63mg/kg/4 weeks, 2.6 4mg/kg/4 weeks, 2.65mg/kg/4 weeks, 2.66mg/kg/4 weeks, 2.67mg/kg/4 weeks, 2.68mg/kg/4 weeks, 2.69mg/kg/4 weeks, 2.7mg/kg/4 weeks, 2.71mg/kg/4 weeks, 2.72mg/kg/4 weeks, 2.73mg/kg/4 weeks, 2.74mg/kg/4 weeks, 2.75mg/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, 2.82mg/ kg/4 weeks, 2.83mg/kg/4 weeks, 2.84mg/kg/4 weeks, 2.85mg/kg/4 weeks, 2.86mg/kg/4 weeks, 2.87mg/kg/4 weeks, 2.88mg/kg/4 weeks, 2.89mg/kg/4 weeks, 2.9mg/kg/4 weeks, 2.91mg/kg/4 weeks, 2.92mg/kg/4 weeks, 2.93mg/kg/4 weeks, 2.94mg/kg/4 weeks, 2.95mg/kg/4 weeks, 2.96mg/kg/4 weeks, 2.97mg/kg/4 weeks, 2.98mg/kg/4 weeks, 2.99mg/kg/4 weeks, 3mg/kg/4 weeks, etc. Alternatively, in a non-limiting embodiment, it can be, for example, 0.1 mg/kg/6 week, 0.11 mg/kg/6 week, 0.12 mg/kg/6 week, 0.125 mg/kg/6 week, 0.13 mg/kg/6 week, 0.14 mg/kg/6 week, 0.15 mg/kg/6 week, 0.16 mg/kg/6 week, 0.17 mg/kg/6 week, 0.18 mg/kg/6 week, 0.19 mg/kg/6 week, 0.2 mg/kg/6 week, 0.21 mg/kg/6 week, 0.22 mg/kg/6 week, 0.23 mg/kg/6 week, 0.24 mg/kg/6 week, 0.25 mg/kg/6 week. week, 0.26mg/kg/6 weeks, 0.27mg/kg/6 weeks, 0.28mg/kg/6 weeks, 0.29mg/kg/6 weeks, 0.3mg/kg/6 weeks, 0.31mg/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, 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/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 week, 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, 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 week, 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/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, 1.5 4mg/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, 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, 1.90mg/kg/6 weeks week, 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, 2.0 9mg/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 g/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, 2.6 4mg/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, 2.73mg/kg/6 weeks, 2.74mg/kg/6 weeks, 2.75mg/kg/6 weeks, 2.76mg/kg/6 weeks, 2.77mg/kg/6 weeks, 2.78mg/kg/6 weeks, 2.79mg/kg/6 weeks, 2.8mg/kg/6 weeks, 2.81mg/kg/6 weeks, 2.82mg/ kg/6 weeks, 2.83mg/kg/6 weeks, 2.84mg/kg/6 weeks, 2.85mg/kg/6 weeks, 2.86mg/kg/6 weeks, 2.87mg/kg/6 weeks, 2.88mg/kg/6 weeks, 2.89mg/kg/6 weeks, 2.9mg/kg/6 weeks, 2.91mg/kg/6 weeks, 2.92mg/kg/6 weeks, 2.93mg/kg/6 weeks, 2.94mg/kg/6 weeks, 2.95mg/kg/6 weeks, 2.96mg/kg/6 weeks, 2.97mg/kg/6 weeks, 2.98mg/kg/6 weeks, 2.99mg/kg/6 weeks, 3mg/kg/6 weeks, etc. Alternatively, in a non-limiting embodiment, it can be, for example, 0.1 mg/kg/8 weeks, 0.11 mg/kg/8 weeks, 0.12 mg/kg/8 weeks, 0.125 mg/kg/8 weeks, 0.13 mg/kg/8 weeks, 0.14 mg/kg/8 weeks, 0.15 mg/kg/8 weeks, 0.16 mg/kg/8 weeks, 0.17 mg/kg/8 weeks, 0.18 mg/kg/8 weeks, 0.19 mg/kg/8 weeks, 0.2 mg/kg/8 weeks, 0.21 mg/kg/8 weeks, 0.22 mg/kg/8 weeks, 0.23 mg/kg/8 weeks, 0.24 mg/kg/8 weeks, 0.25 mg/kg/8 weeks. week, 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, 0.38mg/kg/8 weeks, 0.39mg/kg/8 weeks, 0.4mg/kg/8 weeks, 0.41mg/kg/8 weeks, 0.42mg/kg/8 weeks, 0.43mg/kg/8 weeks, 0. 44mg/kg/8 weeks, 0.45mg/kg/8 weeks, 0.46mg/kg/8 weeks, 0.47mg/kg/8 weeks, 0.48mg/kg/8 weeks, 0.49mg/kg/8 weeks, 0.5mg/kg/8 weeks, 0.51mg/kg/8 weeks, 0.52mg/kg/8 weeks, 0.53mg/kg/8 weeks, 0.54mg/kg/8 weeks, 0.55mg/kg/8 weeks, 0.56mg/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, 0.67mg/kg/8 weeks, 0.68mg/kg/8 weeks, 0.69mg/kg/8 weeks, 0.7mg/kg/8 weeks, 0.71mg/kg/8 weeks, 0.72mg/kg/8 weeks, 0.73mg/kg/8 weeks, 0.74mg/kg/8 weeks, 0.75mg/kg/8 weeks, 0.76mg/kg/8 weeks, 0.77mg/kg/8 weeks, 0.78mg/kg/8 weeks, 0.79mg/kg/8 weeks, 0.8mg/kg/8 week, 0.81mg/kg/8 weeks, 0.82mg/kg/8 weeks, 0.83mg/kg/8 weeks, 0.84mg/kg/8 weeks, 0.85mg/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 week, 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, 1.5 4mg/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, 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, 1.90mg/kg/8 week, 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, 2.0 9mg/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 g/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, 2.48mg/kg/8 weeks, 2.49mg/kg/8 weeks, 2.5mg/kg/8 weeks, 2.51mg/kg/8 weeks, 2.52mg/kg/8 weeks, 2.53mg/kg/8 weeks, 2.54mg/kg/8 weeks, 2.55mg/kg/8 weeks, 2.56mg/kg/8 weeks, 2.57mg/kg/8 weeks, 2.58mg/kg/8 weeks, 2.59mg/kg/8 weeks, 2.6mg/kg/8 weeks, 2.61mg/kg/8 weeks, 2.62mg/kg/8 weeks, 2.63mg/kg/8 weeks, 2.6 4mg/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, 2.71mg/kg/8 weeks, 2.72mg/kg/8 weeks, 2.73mg/kg/8 weeks, 2.74mg/kg/8 weeks, 2.75mg/kg/8 weeks, 2.76mg/kg/8 weeks, 2.77mg/kg/8 weeks, 2.78mg/kg/8 weeks, 2.79mg/kg/8 weeks, 2.8mg/kg/8 weeks, 2.81mg/kg/8 weeks, 2.82mg/ kg/8 weeks, 2.83mg/kg/8 weeks, 2.84mg/kg/8 weeks, 2.85mg/kg/8 weeks, 2.86mg/kg/8 weeks, 2.87mg/kg/8 weeks, 2.88mg/kg/8 weeks, 2.89mg/kg/8 weeks, 2.9mg/kg/8 weeks, 2.91mg/kg/8 weeks, 2.92mg/kg/8 weeks, 2.93mg/kg/8 weeks, 2.94mg/kg/8 weeks, 2.95mg/kg/8 weeks, 2.96mg/kg/8 weeks, 2.97mg/kg/8 weeks, 2.98mg/kg/8 weeks, 2.99mg/kg/8 weeks, 3mg/kg/8 weeks, etc. Alternatively, in a non-limiting embodiment, it can 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/1 0 weeks, 0.17 mg/kg/10 weeks, 0.18 mg/kg/10 weeks, 0.19 mg/kg/10 weeks, 0.2 mg/kg/10 weeks, 0.21 mg/kg/10 weeks, 0.22 mg/kg/10 weeks, 0.23 mg/kg/10 weeks, 0.24 mg/kg/10 weeks, 0.25 mg/kg/10 weeks , 0.26mg/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 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, 0.4mg/kg/10 weeks, 0.41mg/kg/10 weeks, 0.42mg/kg/10 weeks, 0.43mg/kg/10 weeks, 0.44 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, 0.58mg/kg/10 weeks, 0.59mg/kg/10 weeks, 0.6mg/kg/10 weeks, 0.61mg/kg/10 weeks, 0.62mg/kg g/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, 1.12mg/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/1 0 weeks, 1.27 mg/kg/10 weeks, 1.28 mg/kg/10 weeks, 1.29 mg/kg/10 weeks, 1.3 mg/kg/10 weeks, 1.31 mg/kg/10 weeks, 1.32 mg/kg/10 weeks, 1.33 mg/kg/10 weeks, 1.34 mg/kg/10 weeks, 1.35 mg/kg/10 weeks , 1.36mg/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, 1.54 mg/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 g/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, 2mg/kg/10 weeks, 2.01mg/kg/10 weeks, 2.02mg/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, 2.09 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/1 0 weeks, 2.37 mg/kg/10 weeks, 2.38 mg/kg/10 weeks, 2.39 mg/kg/10 weeks, 2.4 mg/kg/10 weeks, 2.41 mg/kg/10 weeks, 2.42 mg/kg/10 weeks, 2.43 mg/kg/10 weeks, 2.44 mg/kg/10 weeks, 2.45 mg/kg/10 weeks , 2.46mg/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 weeks, 2.62mg/kg/10 weeks, 2.63mg/kg/10 weeks, 2.64 mg/kg/10 weeks, 2.65mg/kg/10 weeks, 2.66mg/kg/10 weeks, 2.67mg/kg/10 weeks, 2.68mg/kg/10 weeks, 2.69mg/kg/10 weeks, 2.7mg/kg/10 weeks, 2.71mg/kg/10 weeks, 2.72mg/kg/10 weeks, 2.73mg /kg/10 weeks, 2.74mg/kg/10 weeks, 2.75mg/kg/10 weeks, 2.76mg/kg/10 weeks, 2.77mg/kg/10 weeks, 2.78mg/kg/10 weeks, 2.79mg/kg/10 weeks, 2.8mg/kg/10 weeks, 2.81mg/kg/10 weeks, 2.82mg/kg g/10 weeks, 2.83mg/kg/10 weeks, 2.84mg/kg/10 weeks, 2.85mg/kg/10 weeks, 2.86mg/kg/10 weeks, 2.87mg/kg/10 weeks, 2.88mg/kg/10 weeks, 2.89mg/kg/10 weeks, 2.9mg/kg/10 weeks, 2.91mg/kg/ 10 weeks, 2.92mg/kg/10 weeks, 2.93mg/kg/10 weeks, 2.94mg/kg/10 weeks, 2.95mg/kg/10 weeks, 2.96mg/kg/10 weeks, 2.97mg/kg/10 weeks, 2.98mg/kg/10 weeks, 2.99mg/kg/10 weeks, 3mg/kg/10 weeks, etc. Alternatively, in a non-limiting embodiment, it can 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, 0.15 mg/kg/12 weeks, 0.16 mg/kg/1 2 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, 0.31mg/kg/12 weeks, 0.32mg/kg/12 weeks, 0.33mg/kg/12 weeks, 0.34mg/kg/12 weeks, 0 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, 0.44 mg/kg/12 weeks, 0.45mg/kg/12 weeks, 0.46mg/kg/12 weeks, 0.47mg/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 g/12 weeks, 0.63mg/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, 0.79mg/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, 1.15mg/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/1 2 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, 1.54 mg/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 g/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, 2.09 mg/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/1 2 weeks, 2.37mg/kg/12 weeks, 2.38mg/kg/12 weeks, 2.39mg/kg/12 weeks, 2.4mg/kg/12 weeks, 2.41mg/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, 2.64 mg/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 g/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, 2.95mg/kg/12 weeks, 2.96mg/kg/12 weeks, 2.97mg/kg/12 weeks, 2.98mg/kg/12 weeks, 2.99mg/kg/12 weeks, 3mg/kg/12 weeks, etc.

The IL-31 antagonist disclosed herein can be repeatedly administered to subjects suffering from or at risk of dialysis pruritus in equal amounts and at the same administration intervals at the above-mentioned predetermined administration intervals and predetermined dosages (administration doses), and can continuously suppress or improve dialysis pruritus and various symptoms associated therewith (e.g., reduced QOL, reduced sleep quality, reduced life prognosis, etc.). The dosage administered in equal amounts and the same administration intervals can be determined in consideration of, for example, efficacy and safety.

In one embodiment, the method of administration of the pharmaceutical composition disclosed herein to a subject can be oral administration or parenteral administration. Although not limited, typically, when the active ingredient is a low molecular weight compound, it can be administered orally or parenterally, and when it is a high molecular weight compound, parenteral administration is preferred. Examples of parenteral administration include injection, nasal administration, transpulmonary administration, transdermal administration, etc., and examples of injection include intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc. Using these administration methods, the pharmaceutical composition disclosed herein can be administered systemically or locally.

In one embodiment, the pharmaceutical composition disclosed herein can be formulated by combining the IL-31 antagonist as an active ingredient with a pharmaceutically acceptable carrier. For example, the IL-31 antagonist and a pharmaceutically acceptable carrier or medium, such as sterile water or physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc. can be appropriately combined and formulated. Examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylamino acetate, polyvinyl pyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hardened castor oil 60, white sugar, carboxymethyl cellulose, corn starch, inorganic salts, etc. The amount of the active ingredient in these preparations can be appropriately set within the indicated dosage range.

In another embodiment, the present disclosure is related to a method for preventing and/or treating dialysis pruritus, including the step of administering an IL-31 antagonist to a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus. In this case, the aforementioned IL-31 antagonist can be administered to a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus at 0.1 mg~1000 mg/body/1 day~12 weeks, preferably 0.1 mg~1000 mg/body/2 weeks, 0.1 mg~1000 mg/body/4 weeks, or 0.1 mg~1000 mg/body/8 weeks, in equal amounts and at the same administration interval. Alternatively, the aforementioned IL-31 antagonist can be administered repeatedly at 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 to subjects suffering from dialysis pruritus or at risk of suffering from dialysis pruritus. Furthermore, the aforementioned IL-31 antagonist can be administered to subjects suffering from dialysis pruritus or at risk of suffering from dialysis pruritus whose serum IL-31 concentration is above a predetermined value. In a specific embodiment, the prevention and/or treatment method of the present disclosure further includes: before administering the IL-31 antagonist, selecting a subject whose IL-31 concentration in the serum obtained from the subject is greater than a predetermined value as a subject for prevention and/or treatment. That is, the present disclosure provides a method for preventing and/or treating dialysis pruritus, including: selecting a subject whose IL-31 concentration in the serum obtained from the subject is greater than a predetermined value; and administering the IL-31 antagonist to the selected subject. This embodiment of the present disclosure may further include: before performing the aforementioned selection, measuring the IL-31 concentration in the serum obtained from a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus. Alternatively, the present disclosure may provide a method for preventing and/or treating dialysis pruritus, comprising: measuring the IL-31 concentration in serum obtained from a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus; determining a subject whose IL-31 concentration is above a predetermined value as a responder to the prevention and/or treatment caused by an IL-31 antagonist; and administering an IL-31 antagonist to the subject determined as a responder. Alternatively, in the aforementioned implementation, the IL-31 concentration in serum of a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus, whose IL-31 concentration is above a predetermined value, may be determined as a responder to the prevention and/or treatment caused by an IL-31 antagonist.

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 aforementioned container containing an IL-31 antagonist as an active ingredient; and (iii) instructions for repeatedly administering the aforementioned IL-31 antagonist to a subject suffering from, or at risk of suffering from, dialysis pruritus at 0.1 mg to 1000 mg/body/day to 12 weeks, or 0.01 mg to 10 mg/kg/day to 12 weeks in equal amounts and at the same dosing interval. Labels, syringes, injection needles, pharmaceutically acceptable media, alcohol sponges, bandages, etc. may also be appropriately packaged in the product. The container is, for example, a bottle, a glass bottle, or a syringe, and can be made of various materials such as glass or plastic. The container contains the pharmaceutical composition, and the inlet and outlet are sealed with a rubber cap, for example. The container may be provided with a label, for example, indicating that the pharmaceutical composition is used for the prevention and treatment of the selected disease condition.

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

In this specification, the term "and/or" means the combination of the terms before and after the term "and/or", and is understood to include various combinations of "and" and "or" as appropriate.

The terms used in this specification are intended to describe specific implementations and are not to be construed as limiting the invention. Unless otherwise explicitly defined, the terms used in this specification (including technical terms and scientific terms) have the same meanings as those widely understood by those with ordinary knowledge in the technical field to which the present disclosure belongs, and should not be interpreted in an idealized or excessive manner.

The term "comprising" used in this specification, unless the context clearly indicates otherwise, means the existence of the described matters (steps, elements, numbers, etc.) and does not exclude the existence of other matters (steps, elements, numbers, etc.).

The embodiments of the present disclosure are described with reference to schematic diagrams, but for the sake of clarity, some of the diagrams may be exaggerated.

The numerical values recorded in this specification can be understood as values with a certain range according to the technical common sense of a person with ordinary knowledge in the technical field, as long as they do not conflict with the context. For example, the description of "1 mg" is understood as the description of "about 1 mg", which is understood to include a certain amount of variation based on the description of this specification and the technical common sense of a person with ordinary knowledge in the technical field. In addition, in this specification, for example, when it is recorded as "1 to 5 times", as long as it does not conflict with the context, it can be understood that each value of "1 time, 2 times, 3 times, 4 times, 5 times" is recorded individually and specifically. In this specification, for example, when "20 times, ... 25 times" is described, it can be understood that each value of "20 times, 21 times, 22 times, 23 times, 24 times, 25 times" is specifically described individually unless it conflicts with the context. In the present specification, for example, when “1 to 5000 pg/mL” is described, as long as it does not conflict with the context, although not limiting, it can be understood that, for example: “1 pg/mL, 2 pg/mL, 3 pg/mL, 4 pg/mL, 5 pg/mL, 6 pg/mL, 7 pg/mL, 8 pg/mL, 9 pg/mL, 10 pg/mL, ... 15 pg/mL, ... 20 pg/mL, ... 25 pg/mL, ... 30 pg/mL, ... 35 pg/mL, ... 40 pg/mL, ... 45 pg/mL, ... 50 pg/mL, ... 55 pg/mL, ... 60 pg/mL, ... 65 pg/mL, ... 70 pg/mL, ... 75 pg/mL, ... 80 pg/mL,・・・85 pg/mL,・・・90 pg/mL,・・・95 pg/mL,・・・100 pg/mL,・・・150 pg/mL,・・・200 pg/mL,・・・250 pg/mL,・・・300 pg/mL,・・・350 pg/mL,・・・400 pg/mL,・・・450 pg/mL,・・・500 pg/mL,・・・600 pg/mL,・・・700 pg/mL,・・・800 pg/mL,・・・900 pg/mL,・・・1000 pg/mL,・・・2000 pg/mL,・・・3000 pg/mL,・・・4000 pg/mL,・・・5000 pg/mL”. Moreover, for example, when "10 pg/mL, ... 15 pg/mL" is recorded, as long as it does not conflict with the context, it can be understood that "10 pg/mL, 11 pg/mL, 12 pg/mL, 13 pg/mL, 14 pg/mL, 15 pg/mL" are each value specifically recorded individually. Therefore, a person with ordinary knowledge in the technical field can directly and unambiguously understand that, for example, "1~5000 pg/mL" is recorded as, for example, 100 pg/mL, 224 pg/ml, 1500 pg/mL, etc. The numerical values recorded in this specification can be appropriately interpreted in the same way as long as it does not conflict with the context. Similarly, a person with ordinary knowledge in the technical field can directly and unambiguously understand that each value is recorded individually and specifically. [Implementation example]

The present disclosure is described in more detail below with respect to embodiments, but the present disclosure is not limited to these embodiments.

[Example 1] Preparation of anti-human IL-31RA antibody According to the description of the aforementioned patent document, the anti-human IL-31RA antibody CIM331 (nemolizumab) (specifically, the amino acid sequence of the sequence number of the H chain: 9; the sequence number of the L chain: 10) was prepared by a method known to those skilled in the art. As also described in WO2010/064697, CIM331 has neutralizing activity against human IL-31RA and cynomolgus macaque IL-31RA.

[Example 2] In the non-clinical trials before the clinical trials of CIM331, a significant fact worth recording was discovered. That is, using a method known to those skilled in the art, the antigen-antibody interaction between CIM331 and each IL-31RA of mice, rats, and rabbits was evaluated by Biacore (Biacore T100 (GE Healthcare)). The results showed that CIM331 did not show cross-reactivity with IL-31RA of mice, rats, and rabbits (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, regarding the effects of CIM331 on human dosage and dosage interval, even those with general knowledge in the field still need to confirm the effects by actually administering CIM331 to humans, or administering it to human models that show cross-reactivity (e.g., cynomolgus macaques) and then extrapolating the results to humans to predict the effects.

[Example 3A] The inhibitory effect of subcutaneous administration of CIM331 on IL-31-induced itching in cynomolgus macaques The effect of subcutaneous administration of CIM331 on itching induced by intravenous administration of cynomolgus macaque IL-31 in cynomolgus macaques was investigated. The number of itching movements was measured as an indicator of responsiveness to itching. The number of itching movements was measured by visually observing the movements of the monkeys recorded by a camera (2 hours), and the movement of scratching a part of the body with the forelimbs or hindlimbs was counted as one itching movement. However, itching movements that ended with one or two times were considered to be sporadic and were excluded from the number of itching movements. First, the individual movements of cynomolgus macaques were filmed with a camera (2 hours) before CIM331 administration when IL-31 was not administered. The video was then replayed and the number of scratching movements of cynomolgus macaques when IL-31 was not administered was measured using the above method. CIM331 0.2 or 1 mg/kg was administered subcutaneously to cynomolgus macaques once, and the number of scratching movements of cynomolgus macaques after IL-31 administration was measured in the following manner to evaluate the effect of subcutaneous administration of CIM331. 0.2 mg/kg of CIM331 was subcutaneously administered to cynomolgus macaques once, and 1 μg/kg of cynomolgus macaque IL-31 was intravenously administered before and 3, 15, 28, 42, 56, and 93 days after subcutaneous administration of CIM331. After IL-31 administration to cynomolgus macaques, individual movements were recorded with a camera (2 hours). Similarly, 1 mg/kg of CIM331 was subcutaneously administered to cynomolgus macaques once, and 1 μg/kg of cynomolgus macaque IL-31 was intravenously administered before and 28, 42, 56, 77, 79, 81, 84, and 93 days after subcutaneous administration of CIM331. After IL-31 administration to cynomolgus macaques, individual movements were recorded with a camera (2 hours). The video was then replayed and the number of scratching movements after IL-31 administration to cynomolgus macaques was measured using the aforementioned method.

By administering IL-31 to cynomolgus macaques before CIM331 administration, the number of scratching movements increased compared to before IL-31 administration, confirming that itching is induced. In addition, by administering CIM331 subcutaneously to cynomolgus macaques once, it was confirmed that the number of scratching movements decreased after IL-31 administration. By administering a single subcutaneous dose of 0.2 mg/kg CIM331 to cynomolgus macaques, the average number of scratching movements of cynomolgus macaques after IL-31 administration was found to be reduced 3 days after CIM331 administration, and 42 days after CIM331 administration (Figure 6). In addition, by administering a single subcutaneous dose of 1 mg/kg CIM331, the average number of scratching movements of cynomolgus macaques after IL-31 administration was found to be reduced 77 days after CIM331 administration (Figure 7).

When setting the dosage for humans, the effective plasma concentration of CIM331 was determined using the results of the in vivo cynomolgus macaque IL-31-induced itch model, in which cynomolgus macaque IL-31 was administered to induce systemic itch. In this experiment, CIM331 was intravenously administered to the same cynomolgus macaque, and the plasma concentration was increased by increasing the dosage from 3 μg/kg in stages (3, 10, 40, 60, 100 μg/kg) to 100 μg/kg. On the day after CIM331 administration at each stage, blood was collected to determine the CIM331 concentration in plasma. At the same time, the scratching behavior induced by intravenous administration of 1 μg/kg cynomolgus macaque IL-31 2 hours after administration was photographed and the number of scratching behaviors was counted. The number of scratching behaviors was counted by visually observing the monkey's behavior recorded by the camera (2 hours), and the action of scratching a part of the body with the forelimbs or hindlimbs was counted as one scratching behavior. However, the scratching behaviors that ended 1 and 2 times were considered to be sporadic and excluded from the number of scratching behaviors. By intravenously administering CIM331 and increasing the dosage in stages, the average plasma CIM331 concentration on the day after CIM331 administration increased stepwise depending on the dosage. CIM331 showed a significant inhibitory effect on IL-31-induced itch in the cynomolgus macaque after administration of 40 μg/kg (average plasma concentration on the day after administration was 670 ng/mL). This average plasma concentration of 670 ng/mL is defined as the estimated effective serum concentration of CIM331 in humans. The in vivo dynamics of antibodies in humans and cynomolgus macaques are reported to be similar (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, the PK parameters obtained from the nonlinear analysis of the plasma CIM331 concentration change data of the cynomolgus macaque PK study were defined as the predicted values of the human PK parameters. The nonlinear analysis uses the nonlinear analytical model introduced with the Michaelis-Menten equation as shown in Figure 8.

The average values of the plasma CIM331 concentration changes after intravenous and subcutaneous administration of CIM331 to cynomolgus macaques at 0.04 mg/kg, 0.2 mg/kg, and 1.0 mg/kg were applied to the above model to calculate the optimal parameters. The obtained parameters were used to predict the changes in the serum concentration of CIM331 when administered to humans. When administered to humans at 1 mg/kg, it is predicted that the estimated serum concentration of CIM331 in human effective serum is 670 ng/mL or more and will be maintained for 56 days (Figure 9). It is estimated that 1 mg/kg, which is the effective dose of CIM331 that can maintain the effect of inhibiting IL-31 signaling for more than 1 month, is used as the predicted clinical optimal dose.

[Example 3B] Single subcutaneous administration to patients with atopic dermatitis For the test drug group of the Phase I single-dose trial, 36 patients with atopic dermatitis who met the following criteria were given CIM331 at a dose of 0.3 mg/kg, 1 mg/kg, 3 mg/kg or placebo per unit body weight, and 9 patients in each group were subcutaneously administered to the abdomen in a single dose. The subjects to be administered CIM331 were atopic dermatitis patients who met the following criteria, regardless of whether they had been treated with steroids for more than 12 weeks. ・Eczema Area Severity Index is 10 or more and the rash with strong inflammation is more than 5% of the body surface area ・The total of the daytime and nighttime itching severity evaluation based on the white sampling is 4 or more ・Itching VAS average value ≧50mm In addition, the treatment test drug is filled with 1 mL of liquid containing 100 mg of CIM331 antibody in 1 mL, or the concentration of dilution is the target. The placebo is physiological saline.

(3-1) Evaluation item: Itch The evaluation of itching intensity was conducted based on the Visual Analog Scale (VAS). VAS is a 100 mm straight line, where 0 mm is set as no itching and 100 mm is set as the strongest itching the patient has experienced in the past due to atopic dermatitis. The itching intensity when getting up and going to bed is expressed by the patient himself between 0 and 100 mm. The patients recorded it every day during the trial. The results showed that the VAS of the placebo group decreased by about 20%, while the VAS of the CIM331-treated group began to decrease after 1 week of administration and maintained a decrease of about 50% after 4 weeks of administration (Figure 1).

(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 eczema degree and proportion of the affected area are evaluated for the four areas of the head and neck, upper limbs, trunk and lower limbs, with the degree of redness (erythema), thickness (nodules, papules, swelling), scratches (scratch marks) and lichenification being evaluated as none (0), mild (1), moderate (2) and severe (3). During the treatment trial, the frequency of the test is once a week or once every two weeks, as determined by the physician. The difference in the reduction rate of the itch VAS score after 4 weeks of administration (i.e., the group with a reduction rate of less than 50% and the group with a reduction rate of more than 50%) was analyzed from the average change in the EASI score from the baseline at the time point 4 weeks after administration. The results showed that in the group with a reduction rate of more than 50% in the itch VAS score, the average change in the EASI score was -11.5 points, which was a greater reduction in the EASI score than in the group with a reduction rate of less than 50% or the placebo group (Figure 2).

(3-3) Evaluation item: Quality of life (QOL) (3-3-1) Sleep Actiwatch (registered trademark) is a non-invasive measurement device worn on the wrist, designed to capture wrist movements as indicators of whole body movements during free movements, and record and save them. The subjects wore this device until 4 weeks after administration (Week 4). Other parameters including actual time from falling asleep to waking up, sleep latency, and sleep efficiency were measured objectively. Sleep efficiency was calculated according to the following formula. [Formula 1] As a result, the sleep efficiency of the whole group was about 60% before administration, but in each dosage group of the CIM331 administration group, sleep efficiency began to improve after 1 week of administration, and after 4 weeks of administration (Week 4), up to about 80% of them improved (Figure 3). (3-3-2) DLQI Dermatology Life Quality Index is a QOL evaluation tool used in dermatology (DLQI) (Finlay et al. 1994), which consists of 10 questions. The questions of DLQI are divided into the following 6 items: symptoms and emotions, daily activities, leisure, work and school, interpersonal relationships, and treatment. The scores of all question items are added together to calculate DLQI. The maximum is 30 and the minimum is 0. The higher the score, the lower the QOL. Patients record every 2 weeks or every 4 weeks. As a result, the changes after 4 weeks of administration were that the placebo group had an average decrease of 0.7 points, while the CIM331 group had an average decrease of 5.4-6.3 points.

(3-4) Evaluation item: Amount of topical steroids used Each patient was given a topical steroid (Roclot (registered trademark); hydrocortisone butyrate). In addition, the amount of topical steroids used can be appropriately increased or decreased depending on the patient's condition. As a result, the amount of Roclot used tended to increase in the placebo group, while in the CIM331 group, each dosage group began to show a tendency to decrease after 1 week of administration (Figure 4).

(3-5) Evaluation items: Changes in serum concentration of CIM331 and drug dynamic parameter values The changes in serum CIM331 concentration of Japanese atopic dermatitis patients are shown in Figure 5, and the drug dynamic parameter values are shown in Table 1.

[Table 1]

As a result, CIM331 reached its highest serum concentration 4.46 to 5.66 days after administration (average value, the same below). After that, the disappearance half-life (t _1/2 ) in serum was 12.6 to 14.6 days, showing a slow disappearance. The C _max of the 0.3 mg/kg group, 1 mg/kg group, and 3 mg/kg group were 2.20, 6.50, and 19.4 μg/mL, respectively, and the AUC _inf were 49.2, 161, and 489 day*μg/mL, respectively. In addition, the AUC _inf , AUC _last , and C _max of CIM331 increased in proportion to the dose when administered subcutaneously once. The concentration of CIM331 in serum is dependent on the dosage, and the period of maintaining a certain concentration is considered to be prolonged. In this study, the relationship between the itch suppression effect and exposure after administration of CIM331 is unclear. In the table, each term has the following meaning. AUC _inf : AUC extrapolated from time 0 to infinity AUC _last : AUC from time 0 to the last time point at which the plasma concentration can be quantified CL/F: Apparent clearance C _max : Maximum plasma concentration MRT: Mean residence time t _1/2 : Disappearance half-life T _max : Time to reach maximum plasma concentration

(3-6) Evaluation items explored: Effectiveness The results showed that CIM331 improves itching, dermatitis, and QOL in patients with atopic dermatitis. This trial is the first clinical trial report showing that IL-31 antagonists are effective for itching caused by atopic dermatitis. Based on this new mechanism of action of blocking the itch scratch cycle, CIM331 can be expected to improve not only itching caused by atopic dermatitis, but also dermatitis and QOL. In addition, it is known that scratching accompanied by itching is a worsening factor that worsens the rash, because scratching causes mechanical damage to the skin, which reduces the barrier function. The inflammatory response caused by foreign antigens that invade through the epidermis is enhanced, causing the dermatitis to worsen and the itching to increase. Such a vicious cycle of scratching-dermatitis worsening-itching worsening is known as the Itch Scratch Cycle (for example: Wahlgren CF et al. J Allergy Clin Immunol 2006;118:178-89).

[Example 4] Repeated subcutaneous administration to patients with atopic dermatitis (4-1) Phase II repeated administration trial In the Phase II repeated administration trial, approximately 250 patients with moderate and severe atopic dermatitis who were ineffective or intolerant to topical treatments were selected as subjects. Either CIM331 or a placebo was subcutaneously administered to the abdomen according to the following guidelines. The dosage per body weight and the concentration of the CIM331 solution are shown below. The solution is slowly administered at a volume of 20 μL/kg per body weight. When the subject's body weight exceeds 120 kg, the body weight is set to 120 kg and the treatment trial drug is prepared. In addition, the experimental treatment drug is prepared by dissolving a preparation obtained by freeze-drying a liquid containing 100 mg of CIM331 antibody in 1 mL into 1.53 mL of a small glass bottle and dissolving it in water for injection to prepare a dosing solution, and using a placebo solution dissolved separately, further dilute it to the target dosing concentration.

[Table 2]

Patients who are eligible for CIM331 are patients with atopic dermatitis who have not been able to obtain adequate results from topical steroids or topical calcitonin inhibitors for more than 4 weeks, or who are intolerant to standard topical treatments, or who are unable to take standard topical treatments (contraindications, etc.), and who meet the following criteria. ・Eczema Area Severity Index is 10 or higher ・sIGA score is 3 or higher ・Itch VAS ≧50mm

This treatment trial consists of 2 parts. Part A is a randomized, double-blind, placebo-controlled, parallel group comparison trial (Week 0~Week 12). Part B is a double-blind trial continued, and CIM331 is continued to be administered to the subjects for another 52 weeks (Week 12~Week 64). Approximately 250 subjects in Part A were randomly assigned to one of the 4 test drug groups (about 50 subjects in each group) and the placebo group (about 50 subjects) in a ratio of 1:1:1:1:1. Part A ・Subcutaneous administration of CIM331 (0.1 mg/kg) every 4 weeks (administered on Day 1, Week 4, and Week 8) ・Subcutaneous administration of CIM331 (0.5 mg/kg) every 4 weeks (administered on Day 1, Week 4, and Week 8) ・Subcutaneous administration of CIM331 (2.0 mg/kg) every 4 weeks (administered on Day 1, Week 4, and Week 8) ・Subcutaneous administration of CIM331 (2.0 mg/kg) every 8 weeks (administered on Day 1 and Week 8, and placebo administered on Week 4) ・Subcutaneous administration of placebo every 4 weeks (administered on Day 1, Week 4, and Week 8) More specifically, in Part A, there were 264 patients who received more than one dose of the trial drug or placebo, 53 patients who received subcutaneous administration of placebo 0.1 mg/kg, 0.5 mg/kg, 2.0 mg/kg every 4 weeks, and 53 patients who received subcutaneous administration of 2.0 mg/kg every 8 weeks. Part B The subjects assigned to the placebo group in Part A were randomly assigned to the group that received subcutaneous administration of CIM331 (0.1 mg/kg, 0.5 mg/kg, 2.0 mg/kg) every 4 weeks in Part B. The subjects who were randomly assigned to the trial drug group in Part A were assigned to the same dosage group as Part A, and continued the same treatment after Week 12. ・CIM331 (0.1 mg/kg) was administered subcutaneously every 4 weeks for a total of 52 weeks ・CIM331 (0.5 mg/kg) was administered subcutaneously every 4 weeks for a total of 52 weeks ・CIM331 (2.0 mg/kg) was administered subcutaneously every 4 weeks for a total of 52 weeks ・CIM331 (2.0 mg/kg) was administered subcutaneously every 8 weeks for a total of 52 weeks (For this group of subjects, CIM331 and placebo were administered alternately every 4 weeks.)

(4-2) Rescue treatment For subjects who do not perceive improvement in itch VAS or skin symptoms, topical medications may be used as rescue treatment at the discretion of the physician 4 weeks after the initial administration. The definition of "not perceived improvement" refers to all of the following situations: (1) No improvement in sIGA score since baseline. (2) sIGA score is 3 or above. (3) The improvement rate of itch VAS since baseline is less than 10%, and the most recent itch VAS is 50 mm or above.

(4-3) Evaluation items: ・Itch intensity was evaluated based on the Visual Analog Scale (VAS) (Furue et al. 2013). VAS is a 100 mm straight line, with 0 mm representing no itching and 100 mm representing the worst itching imaginable. The patient himself/herself expressed the itching intensity in the past 24 hours with a line between 0 and 100 mm. ・Itch Verbal Rating Scale (VRS) is a 5-level VRS (Reich et al. 2012) in which the subjects rated the itching intensity in the past 24 hours: no itching (0), mild itching (1), moderate itching (2), severe itching (3), or very severe itching (4). ・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 the affected area are evaluated in four areas: head and neck, upper limbs, trunk and lower limbs, with redness (erythema), thickness (nodules, papules, swelling), scratches (scratch marks) and lichenification as none (0), mild (1), moderate (2) and severe (3). ・SCORing Atopic dermatitis (SCORAD) is a clinical tool for evaluating the extent and severity of eczema (European Task Force on Atopic Dermatitis 1993). ・Static Investigator's Global Assessment (sIGA) is a 6-stage scale from clear to very severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease, 5 = very severe disease), using the clinical characteristics of erythema, infiltration, papules, exudation and crust to evaluate the comprehensive severity at the time of evaluation. ・Body surface area (BSA) of atopic dermatitis lesions represents the proportion of the lesions to the whole body. ・Sleep disturbance VAS, in which the subjects evaluate the degree of sleep disturbance in the past 24 hours using a VAS ranging from "no sleep problems" (0) to "completely unable to sleep" (10) (Furue et al. 2013). ・Dermatology Life Quality Index is a QOL assessment tool used in dermatology, DLQI (Finlay et al. 1994), which consists of 10 questions. The questions of DLQI are divided into the following 6 items: Symptoms and emotions, daily activities, leisure, work and school, interpersonal relationships, and treatment. The scores of all question items are added up to calculate the DLQI. The maximum is 30 and the minimum is 0. The higher the score, the lower the QOL. ・Activity recording (actigraphy) Actiwatch is a non-invasive measurement device worn on the wrist, designed to capture the movements of the wrist as an indicator of the whole body movement during free movement, and record and save them. The subjects wore this device from the beginning of the previous observation period until Week 4. Objectively measure the actual time from falling asleep to waking up, sleep latency, and other parameters of sleep efficiency. Sleep efficiency is calculated using the following formula.

(4-4) Analytical means and methods: In the group that subcutaneously administered CIM331 every 4 weeks, the main evaluation item was to compare the itch VAS 12 weeks after the start of administration and the improvement rate at the start of administration, and to confirm the superiority and effectiveness of each dose group of CIM331 administered once every 4 weeks compared with the placebo. The main analytical method was to use covariance analysis (ANCOVA). Specifically, the itch VAS 12 weeks after the start of administration and the improvement rate compared at the start of administration were set as the response variable, and the treatment group was applied to a model with fixed effects, itch VAS at the start of administration, and region (Japan, Europe, and the United States) as covariates. In the main analysis, the significance level of the test was 0.025 on one side. Based on the principle of closed testing procedure, the two groups were compared successively from high dosage, and the multiplicity caused by repeated tests was considered. As the main analysis target group, the per-protocol (PP) group was used, which excluded some subjects who were considered to have seriously deviated from the treatment trial implementation plan, subjects who terminated the treatment trial early, and subjects who had been administered different treatment trial drugs. Data measured after receiving rescue treatment were excluded, and the missing values were supplemented by LOCF (Last Observation value Carrying Forward after baseline).

Among the patients who received the trial drug or placebo in Part A, the main analysis subjects were the group that subcutaneously administered placebo 0.1mg/kg, 0.5mg/kg, 2.0mg/kg every 4 weeks, and the group that subcutaneously administered 2.0mg/kg every 8 weeks, with 46 cases, 46 cases, 45 cases, 47 cases, and 45 cases, respectively. In the group that administered every 4 weeks, the main evaluation item was the difference between the improvement rate (least square mean) of the itch VAS from the beginning of 12 weeks after the start of administration and the placebo, which was -21.39% (p=0.0027), -41.16% (p＜0.0001), and -40.39% (p＜0.0001) for 0.1mg/kg, 0.5mg/kg, and 2.0mg/kg, respectively. In addition, this example is an exploratory dose setting test, so in addition to the main analysis, a secondary analysis can be performed to comprehensively explore the dosage. At this time, although it is an exploratory discussion, the significance level of the test is set at 0.025 on one side. Although not intended to be limiting, specifically, in addition to ANCOVA, mixed-effects model repeated measures approach (MMRM), counting of summary statistics regardless of the model, intent-to-treat (ITT) analysis of the subject group using all available data obtained at specified observation points after the administration of the test drug, using data measured after receiving rescue treatment, or the results of analysis to appropriately confirm the lack of compensation can be used for comprehensive discussion. In addition, for itch VAS, the evaluation object can be a model analysis using the time point other than 12 weeks after the start of administration, or the change amount corresponding to the improvement rate at the start of administration or the value at each time point, and the proportion of improved cases based on these continuous amounts or a certain threshold as the benchmark. For such an analysis, important partial groups can be considered. The secondary effectiveness evaluation items other than itch VAS can also be analyzed in the same way. An exploratory comparison can also be performed for the group that subcutaneously administers CIM331 every 8 weeks.

・Proportion of subjects with improvement: Itch VAS, EASI, SCORAD For each item, the proportion of subjects who felt that there was a 25%, 50% and 75% improvement from baseline to each time point was calculated. For the results of the 4-weekly administration group in Part A, all data measured after rescue treatment in the PP group were excluded and the missing values were supplemented by LOCF. The proportion of subjects who felt that there was a 50% improvement in itch VAS after 12 weeks of administration was 21% in the placebo group, 41% in the 0.1mg/kg group, 67% in the 0.5mg/kg group, and 59% in the 2.0mg/kg group. The proportion of subjects who felt that they had 75% improvement was 12% in the placebo group, while 14%, 49%, and 44% in the 0.1mg/kg group, 0.5mg/kg group, and 2.0mg/kg group, respectively. Similarly, the proportion of subjects who felt that they had 50% improvement in EASI 12 weeks after the start of administration was 33% in the placebo group. On the other hand, 43%, 51%, and 41% in the 0.1mg/kg group, 0.5mg/kg group, and 2.0mg/kg group, respectively. The proportion of subjects who felt that they had 75% improvement was 14% in the placebo group, while 23%, 37%, and 22% in the 0.1mg/kg group, 0.5mg/kg group, and 2.0mg/kg group, respectively. After 12 weeks of administration, the proportion of subjects who felt that SCORAD had improved by 50% was 15% in the placebo group, while the proportions in the 0.1mg/kg group, 0.5mg/kg group, and 2.0mg/kg group were 18%, 39%, and 31%, respectively. The proportion of subjects who felt that SCORAD had improved by 75% was 3% in the placebo group, while the proportions in the 0.1mg/kg group, 0.5mg/kg group, and 2.0mg/kg group were 0%, 15%, and 17%, respectively.

・Proportion of subjects with improvement of 2 points or more: sIGA, VRS for Itch The proportion of subjects with improvement of 2 points or more from the baseline to each time point of each item was calculated. The results of the 4-weekly administration group in Part A showed that the proportion of subjects with improvement of 2 points or more in sIGA was 12% in the placebo group 12 weeks after the start of administration, while the proportions in the 0.1mg/kg group, 0.5mg/kg group, and 2.0mg/kg group were 21%, 30%, and 22%, respectively. The proportion of subjects with improvement of 2 points or more in VRS for Itch was 5% in the placebo group 14%, 47%, and 30%, respectively, after the start of administration 12 weeks.

・Improvement: Itch VAS, EASI, SCORAD, sIGA, BSA of atopic dermatitis lesions, Itch VRS, Sleep disturbance VAS The improvement of each item from baseline to each time point is summarized for statistical purposes. The results of the 4-weekly dosing group in Part A, excluding all data measured after the PP group received rescue treatment, showed a 12% improvement in the improvement rate of itch VAS after 4 weeks of administration in the placebo group, while the 0.1 mg/kg group showed a 39% improvement, the 0.5 mg/kg group showed a 55% improvement, and the 2.0 mg/kg group showed a 46% improvement. After 12 weeks of administration, the placebo group had an improvement rate of 24%, while the 0.1mg/kg group had an improvement rate of 47%, the 0.5mg/kg group had an improvement rate of 68%, and the 2.0mg/kg group had an improvement rate of 67%. Similarly, the improvement rate of EASI after 12 weeks of administration was 38% for the placebo group, while the 0.1mg/kg group was 34%, the 0.5mg/kg group was 54%, and the 2.0mg/kg group was 48%. The improvement rate of SCORAD after 12 weeks of administration was 22% for the placebo group, while the 0.1mg/kg group was 37%, the 0.5mg/kg group was 45%, and the 2.0mg/kg group was 47%. The improvement rate of sIGA after 12 weeks of administration was 13% in the placebo group, while it was 25% in the 0.1mg/kg group, 34% in the 0.5mg/kg group, and 28% in the 2.0mg/kg group. The improvement rate of BSA after 12 weeks of administration was 31% in the placebo group, 25% in the 0.1mg/kg group, 26% in the 0.5mg/kg group, and 33% in the 2.0mg/kg group. The improvement rate of itch VRS after 12 weeks of administration was 18% in the placebo group, while it was 42% in the 0.1mg/kg group, 58% in the 0.5mg/kg group, and 58% in the 2.0mg/kg group. The improvement rate of sleep disturbance VAS after 12 weeks of administration was 31% in the placebo group, 57% in the 0.1mg/kg group, 65% in the 0.5mg/kg group, and 67% in the 2.0mg/kg group.

・Time to response: Itch VAS, EASI, SCORAD, sIGA The time to 25%, 50%, and 75% improvement from baseline for itch VAS, EASI, and SCORAD, and the time to 2 points improvement from baseline for sIGA were summarized as the cumulative incidence rate over time using Kaplan-Meier estimates. The results of the 4-weekly administration group in Part A were: the time for 50% of the patients to achieve 25%, 50%, and 75% improvement from baseline in itch VAS was 11 weeks, not achieved, and not achieved for the placebo group, respectively; on the other hand, it was 2 weeks, 4 weeks, and not achieved for the 0.1 mg/kg group, 2 weeks, 2 weeks, and 5 weeks for the 0.5 mg/kg group, and 2 weeks, 4 weeks, and not achieved for the 2.0 mg/kg group. In addition, using Kaplan-Meier estimates, the achievement rates of 25%, 50%, and 75% improvement from baseline at 12 weeks after the start of administration were 52%, 38%, and 22% for the placebo group, 84%, 66%, and 38% for the 0.1 mg/kg group, 95%, 80%, and 68% for the 0.5 mg/kg group, and 94%, 71%, and 48% for the 2.0 mg/kg group. Similarly, in EASI, the time for 50% of patients to improve 25%, 50%, and 75% from baseline was 6 weeks, 12 weeks, and not achieved in the placebo group, while it was 2 weeks, 4 weeks, and not achieved in the 0.1 mg/kg group, 2 weeks, 4 weeks, and 12 weeks in the 0.5 mg/kg group, and 2 weeks, 6 weeks, and not achieved in the 2.0 mg/kg group. In addition, the achievement rates of improvement from baseline to 25%, 50%, and 75% 12 weeks after the start of administration using Kaplan-Meier estimates were 68%, 51%, and 23% in the placebo group, 71%, 66%, and 37% in the 0.1 mg/kg group, 84%, 73%, and 53% in the 0.5 mg/kg group, and 93%, 67%, and 28% in the 2.0 mg/kg group. In SCORAD, the time for 50% of patients to achieve 25%, 50%, and 75% improvement from baseline was 6 weeks, not achieved, and not achieved for the placebo group, respectively; on the other hand, it was 2 weeks, not achieved, and not achieved for the 0.1 mg/kg group, 3 weeks, 10 weeks, and not achieved for the 0.5 mg/kg group, and 2 weeks, not achieved, and not achieved for the 2.0 mg/kg group. In addition, the achievement rates of 25%, 50%, and 75% improvement from baseline 12 weeks after the start of administration using Kaplan-Meier estimates were 57%, 40%, and 6% for the placebo group, 78%, 46%, and 9% for the 0.1 mg/kg group, 78%, 55%, and 30% for the 0.5 mg/kg group, and NE (unable to calculate), 46%, and 25% for the 2.0 mg/kg group. In sIGA, 50% of the patients did not achieve a 2-point improvement from baseline until 12 weeks after the placebo, 0.1mg/kg, 0.5mg/kg, and 2.0mg/kg groups. In addition, the rate of improvement from baseline to 2 points 12 weeks after the start of administration using Kaplan-Meier estimates was 30% for the placebo group, 36% for the 0.1mg/kg group, 47% for the 0.5mg/kg group, and 38% for the 2.0mg/kg group.

・Period until rescue treatment was received The period until rescue treatment was received was summarized using Kaplan-Meier estimates as the cumulative incidence over time. Subjects who did not receive rescue treatment were censored at the earlier of Week 12 visit in Part A (or Week 64 visit in Part B) or early discontinuation of treatment. The results for the 4-week dosing group in Part A were: the time from baseline to the end of rescue treatment for 50% of patients, which was not reached until after 12 weeks in the placebo group, 0.1 mg/kg group, 0.5 mg/kg group, and 2.0 mg/kg group. In addition, the time from baseline to rescue treatment for 25% of patients was 5 weeks, 9 weeks, not reached, and 9 weeks for the placebo group, 0.1 mg/kg group, 0.5 mg/kg group, and 2.0 mg/kg group, respectively.

・Proportion of subjects receiving rescue treatment The proportion of subjects receiving rescue treatment was calculated at each time point. The results of the 4-week administration group in Part A were as follows: the proportion of subjects receiving rescue treatment was 39.1% in the placebo group, 26.1% in the 0.1mg/kg group, 24.4% in the 0.5mg/kg group, and 29.8% in the 2.0mg/kg group. ・Activity records According to the results of the activity records of the 4-week administration group in Part A, the actual time from falling asleep to waking up increased by 7.3 minutes in the placebo group after 4 weeks of administration, while it increased by 49.5 minutes in the 0.1mg/kg group, 53.1 minutes in the 0.5mg/kg group, and 48.2 minutes in the 2.0mg/kg group. Sleep latency (the time from going to bed until falling asleep) was shortened by 4.3 minutes in the placebo group after 4 weeks of administration, while it was shortened by 17.6 minutes in the 0.1mg/kg group, 14.8 minutes in the 0.5mg/kg group, and 12.7 minutes in the 2.0mg/kg group.

In addition, in the group of Part A who received CIM331 once every 8 weeks, the average improvement rate of itch VAS from the beginning of administration 12 weeks after administration was 70% by excluding all the data measured after receiving rescue treatment.

Based on the results of Part A related to dermatitis indicators such as itch VAS at 12 weeks of administration, which was the primary endpoint, EASI, and sIGA, it was considered that the 0.5 mg/kg/4 week administration group had the greatest effect on itch and dermatitis.

・Simulation of optimal dosage Regarding dosage, from the perspective of improving convenience, the optimal dosage from dosage per unit weight to fixed dosage was modeled, simulated and evaluated. First, the exposure of dosage per unit weight and fixed dosage was compared, and the optimal dosage was discussed from the perspective of drug dynamics. The drug concentration in serum of CIM331 fits well to the one-compartment model with one absorption process. In addition, body weight was used as a covariate and the model parameters were fitted using the allometry formula. The model parameters are shown below.

[Table 3] Parameters Unit Estimate Bootstrapped 90% interval CL/F L/day 0.327 0.312-0.343 Covariation effect of ALB -1.72 -2.00- -1.38 V/F L 7.46 7.12-7.83 Ka 1/day 0.514 0.442-0.609 Inter-individual variability CL/F variables 0.186 0.142-0.239 V/F variable 0.179 0.123-0.244 ka variable 0.276 0.182-0.377 Covariate between CL/F and V/F 0.134 0.0871-0.185 Residual variables Lognormal error (CV) % 15.5 14.0-17.1

The simulation was performed using the aforementioned 1-chamber model, and the relationship between body weight and exposure is shown in Figure 10. A in the figure represents the hypothetical exposure when 0.5 mg/kg or 2 mg/kg is administered, B, C and D in the figure represent the hypothetical exposure when 50, 75 and 100 mg/body are administered, respectively, and the reference line in the figure represents the hypothetical upper limit of exposure (1060 μg*day/mL) of 2 mg/kg and the lower limit of exposure (44 μg*day/mL) of 0.5 mg/kg. When the dosage is fixed at 50 mg, it is estimated that the lower limit of exposure of 0.5 mg/kg is approximately exceeded when the body weight is less than 100 kg, and when it is fixed at 100 mg, it is estimated that the upper limit of exposure of 2 mg/kg is exceeded at low body weight. In addition, when 75 mg is fixed, it is estimated that 0.5 mg/kg or 2 mg/kg will fall within the range of exposure obtained. Based on these, it is believed that a fixed dose of 50 mg (100 mg if the body weight exceeds 100 kg) or 75 mg once every 4 weeks can achieve the same exposure as that obtained in the Phase II trial.

Then, we used PK-PD analysis to model and simulate the itch VAS. We used the indirect turnover model and scaled the itch VAS. We confirmed that the model predictions mimicked the measured values well. The calculated model parameters are shown below.

[Table 4] Parameters Unit Estimate Bootstrapped 90% interval Kout l/day 0.0710 0.0578-0.0839 Placebo Effect - 0.554 0.400-0.769 Imax - 0.893 0.490-1.50 IC50 μg/mL 3.21 0.956-9.43 Inter-individual variability Kout variables - 0.581 0.396-0.809 Placebo Effect Variables - 0.983 0.737-1.46 Imax variables - 1.81 0.712-3.01 Residual variables Additional Error - 0.0276 0.0193-0.0354 Proportional Error (CV) % 25.9 23.3-28.7

The simulation was performed using the model. The estimated VAS of itch after 1 year of CIM331 administration is shown in Figure 11. When the fixed dosage every 4 weeks is 25 mg/body or more, preferably 50 mg/body or more, the estimated VAS of itch is the same as that of 0.5 mg/kg or 2 mg/kg.

(4-5) Predicted results and beneficial effects By repeating the administration of CIM331 every 4 or 8 weeks, the concentration of CIM331 in the serum becomes stable, and the effect on the itch of patients with atopic dermatitis can be continuously exerted. In addition, the maintenance of the itch improvement effect, that is, the interruption of the itch scratch cycle, can improve dermatitis and improve QOL. The long-term effectiveness profile of a total of 64 weeks can be confirmed. Furthermore, for example, the current systemic treatment of atopic dermatitis requires taking medicine several times a day, or applying medicine to the affected area, or ultraviolet therapy requires visiting the hospital 1-2 times a week. In view of this, the treatment of repeated administration of CIM331 every 4 or 8 weeks can be expected to significantly reduce the burden of medication and hospital visits for patients, and contribute to the improvement of patients' QOL.

[Example 5] Single subcutaneous administration to hemodialysis patients with itch (5-1) Phase II clinical trial In the Phase II clinical trial, approximately 60 hemodialysis patients, more specifically 69 subjects, who had not adequately responded to systemic or local therapies other than nalfurazone hydrochloride for itch were administered CIM331 or a placebo subcutaneously to the abdomen in a single dose according to the following guidelines, or nalfurazone hydrochloride capsules (2.5 μg) were orally administered once a day for 12 consecutive weeks after dinner or before bedtime as a reference group. The dosage per body weight and the concentration of the CIM331 solution are shown below. The solution is slowly administered at a volume of 20 μL per body weight. The test drug is prepared by dissolving 100 mg of CIM331 antibody in 1 mL of a solution in a small glass bottle filled with 1.53 mL and freeze-dried, and then dissolved in water for injection to prepare the dosage solution. The solution is further diluted with a placebo solution dissolved separately to achieve the target dosage concentration.

[Table 5]

Patients with dialysis pruritus who have not been adequately treated with antihistamines or antiallergic drugs other than nalfurazone hydrochloride for more than 2 weeks or who have been treated with nalfurazone hydrochloride for itch for 1 year (regardless of the treatment period) were selected as candidates for CIM331. ・Patients who had itch VAS measured for 5 or more days during the previous observation week and met any of the following criteria: (1) The number of days with a measurement value of 20 mm or more was 5 or more days (2) The average measurement value was 50 mm or more

This trial is a randomized double-blind placebo-controlled parallel group comparison trial including an unblinded reference drug group (nalfurafine hydrochloride group). There are approximately 60 subjects, more specifically, 69 subjects were randomly assigned to any of the five groups at a ratio of 1:1:1:1:1. ・Placebo group: CIM331 placebo administered subcutaneously once ・CIM331 0.125 mg/kg group: CIM331 (0.125 mg/kg) administered subcutaneously once ・CIM331 0.5 mg/kg group: CIM331 (0.5 mg/kg) administered subcutaneously once ・CIM331 2.0 mg/kg group: CIM331 (2.0 mg/kg) administered subcutaneously once ・Nalfurafenib hydrochloride group: Nalfurafenib hydrochloride capsules are orally administered at a dose of 1 capsule (2.5 μg) once a day for 12 consecutive weeks. The dose may be increased according to symptoms, but is limited to 2 capsules (5 μg) once a day.

(5-2) Rescue treatment After all observations and examinations are completed on the 29th day, for patients who do not think that the itch has improved or think that the effect has weakened (the decrease in itch VAS from the baseline is less than 10 mm), the trial responsible physician or the trial co-responsible physician may change the type, usage and dosage of treatment for itch if the treatment needs to be changed.

(5-3) Evaluation items: ・Itch intensity was evaluated based on the Visual Analog Scale (VAS) (Furue et al. 2013). VAS is a 100 mm straight line, with 0 mm representing no itching and 100 mm representing the worst itching imaginable. The patient himself/herself expressed the itching intensity in the past 24 hours with a line between 0 and 100 mm, and the test was performed as much as possible in the same time period. ・The Shiratori Severity Scale (Shiratori et al. 1983) is based on an itch severity scale ranging from 0 (no symptoms) to 4 (severe itching), which determines the severity of daytime symptoms and nighttime symptoms in the past 24 hours. Regarding this evaluation, in addition to the subjects, the trial physician or the trial co-contracting physician also conducted the evaluation. The evaluation of the trial physician was carried out in the same time period as much as possible. ・5-D itch scale (Ebata et al. 2015) is scored based on the duration, degree, course of disease, degree of disturbance, and distribution of itching found in the past 2 weeks. ・Sleep disturbance VAS is a VAS (Furue et al. 2013) in which the subjects evaluated the degree of sleep disturbance in the past 24 hours from "no sleep problems" (0) to "completely unable to sleep" (10). ・Insomnia Severity Index (Murosawa et al. 2009) uses a 5-item Insomnia Severity Questionnaire to score insomnia. ・EQ-5D-5L (Ikeda et al. 2015) uses 5 levels to investigate 5 health conditions: "mobility", "personal management", "daily activities", "pain/discomfort", and "anxiety/depression". ・Activity Recording Actiwatch is a non-invasive measurement device that is worn on the wrist and is designed to capture wrist movements as an indicator of whole body movements during free movements, and records and saves them. It objectively measures other parameters from falling asleep to waking up, including actual time, sleep latency, and sleep efficiency. ・The evaluation of skin symptoms (doctor evaluation) is conducted by the responsible doctor or the doctor who shares the trial, referring to the "Standards of Severity" of the "Ministry of Health, Labor and Welfare Scientific Research Group Atopic Dermatitis Treatment Guidelines 2008", and evaluating skin symptoms in four stages from mild to severe. ・The evaluation of skin symptoms (image evaluation) is conducted by the responsible physician or the sub-contracting physician, referring to the rashes (erythema, dryness, scaling, papules, erosion, infiltration, and lichenification) shown in the "Criteria for Severity" of the "Guidelines for the Treatment of Atopic Dermatitis 2008 of the Ministry of Health, Labor and Welfare Scientific Research Group", and the rash with scratch marks is used as the photography object, and the representative symptoms (the most severe position) of each subject are selected. The evaluation of skin symptoms is based on the evaluation criteria of the Japanese Dermatological Society Atopic Dermatitis Severity Classification (Simplified Method), and is carried out by an evaluation committee independent of medical experts in a range of 5 stages from 0 (none) to 4 (most severe).

(5-4) Analytical means, analytical methods, etc.: The main analysis was a paired comparison of each CIM331-administered group and the placebo-administered group with respect to the change in itch VAS after 4 weeks of administration from baseline. The evaluation was performed assuming a 20% significance level on both sides. No multiplicity adjustment was performed for the exploratory trial. As the main evaluation, a covariate analysis (ANCOVA) was performed using the change in itch VAS after 4 weeks of administration from baseline as the target variable and the itch VAS at baseline as the covariate to compare the placebo group and each CIM331 dosage group. The 95% confidence interval of the mean difference was calculated from the ANCOVA. The missing value was supplemented by LOCF (Last Observation value Carrying Forward after baseline). For the nalfurafine hydrochloride group, an exploratory comparison was made between each CIM331-administered group and the placebo group. The analysis was performed in the same manner as the main analysis of each CIM331-administered group and the placebo group. Other exploratory analyses are described in the SAP (Statistical Analysis Plan).

In the Phase II clinical trial, among the patients who received placebo, CIM331 or the reference group of nalfurafenibine hydrochloride capsules, the main analysis subjects were 14 cases, 14 cases, 13 cases, 14 cases and 12 cases in the placebo, CIM331 0.125 mg/kg, CIM331 0.5 mg/kg, CIM331 2.0mg/kg, and nalfurafenibine hydrochloride groups, respectively. The main evaluation item was the change (least squared mean) from the baseline of itch VAS 4 weeks after the start of administration and the difference with the placebo. The changes of CIM331 0.125 mg/kg, CIM331 0.5 mg/kg, and CIM331 2.0 mg/kg were -2.4 mm (p=0.7806), -8.7 mm (p=0.3317), and 0.4 mm (p=0.9678), respectively. In addition, the difference between nalfuraline hydrochloride and placebo in the reference group was 5.7 mm (p=0.5154).

・Changes in VAS of itch at each evaluation point The changes from baseline one week after administration were -18.6 mm for the placebo group, -17.4 mm for the nalfuraline hydrochloride group, -27.4 mm for the 0.125 mg/kg group, -30.3 mm for the 0.5 mg/kg group, and -25.9 mm for the 2.0 mg/kg group of CIM331, indicating a rapid improvement in itch in all CIM331 groups. The change from baseline 4 weeks after administration was -32.8 mm for the placebo group and -27.3 mm for the nalfuraline hydrochloride group. Among the CIM331 0.125 mg/kg group -34.7 mm, 0.5 mg/kg group -40.1 mm, and 2.0 mg/kg group -31.5 mm, the CIM331 0.5 mg/kg group had the largest change (Figure 12). ・The proportion of subjects who believed that the VAS of itch had improved by less than 30 mm The proportion of subjects who believed that the VAS of itch had improved by less than 30 mm 4 weeks after the start of the injection of the main evaluation items was 35.7% in the placebo group and 33.3% in the nalfurazone hydrochloride group. The proportion of subjects who believed that the VAS of mild itch had improved by less than 30 mm in the CIM331 0.125 mg/kg group was 57.1%, the proportion of subjects who believed that the VAS of mild itch had improved by less than 30 mm was 69.2% and the proportion of subjects who believed that the VAS of mild itch had improved by less than 30 mm in the CIM331 group was 42.9% compared with the placebo group and the nalfurazone hydrochloride group (Figure 13).

・White-eye score of severity standard The change in white-eye score (daily) 4 weeks after the start of administration was -0.89 for the placebo group and -0.67 for the nalfuraline hydrochloride group. Among the CIM331 0.125 mg/kg group, -1.00 for the 0.5 mg/kg group, -1.30 for the 0.5 mg/kg group, and -0.79 for the 2.0 mg/kg group, the CIM331 0.5 mg/kg group showed the greatest improvement. The change in white blood cell count (night) 4 weeks after administration was the greatest improvement in the CIM331 0.5 mg/kg group, compared to the placebo group (-0.81), the nalfurazone hydrochloride group (-0.51), the CIM331 0.125 mg/kg group (-0.64), the 0.5 mg/kg group (-1.16), and the 2.0 mg/kg group (-0.79). ・5-D itch scale score The change in the 5-D itch scale score 4 weeks after the start of administration was -5.4 for the placebo group and -3.7 for the nalfurazone hydrochloride group. Among the CIM331 0.125 mg/kg group, -5.6 for the 0.5 mg/kg group, -6.5 for the 0.5 mg/kg group, and -3.1 for the 2.0 mg/kg group, the CIM331 0.5 mg/kg group showed the greatest improvement.

[Example 6] Biomarker analysis of hemodialysis patients with itching (6-1) Biomarker evaluation Biomarker evaluation was performed to evaluate the correlation between the IL-31 concentration in serum before CIM331 administration and the clinical trial results after CIM331 administration.

(6-2) Analytical means, analytical methods, etc.: Serum samples were obtained from all trial patients (n=68) who agreed to store serum for use in biomarker analysis. The IL-31 concentration in serum was measured by thawing the serum samples frozen at below -70°C at room temperature using an ultra-high sensitivity enzyme-linked immunosorbent assay (ELISA; SiMoA ^™ , Quanterix, Billerica, MA, USA). Using the data obtained from the 68 samples, a cutoff median value of 0.86 pg/mL for the IL-31 concentration in serum during the screening phase (before CIM331 administration) was derived. Using this IL-31 cutoff value, the correlation between IL-31 and clinical trial results was evaluated for patients (n=48) who received trial administration as described in Example 5. In addition, samples from trial patients were compared with commercially available samples from healthy volunteers using a psot hoc analysis.

(6-3) Analysis results: The results of the biomarker analysis of IL-31 distribution by psot hoc analysis are shown in Figure 14. Compared with healthy volunteers (healthy volunteers: HV; n = 20), patients with uremic pruritus (UP; n = 68) had significantly higher levels of IL-31 in their serum (Figure 14). Among the 48 subjects who underwent the trial, patients with serum IL-31 levels of 0.86 pg/mL or more were found to have significantly lower itch VAS after CIM331 administration compared with patients with serum IL-31 levels of less than 0.86 pg/mL (Figure 15). This tendency was not observed in the placebo-administered group or the nalfuraline hydrochloride-administered group.

It has been reported that among patients undergoing maintenance dialysis, patients with itch had higher IL-31 concentrations in their serum compared to those without itch. Since then, it is believed that the IL-31 concentration in serum has the possibility of affecting the effect of CIM331 administration. As shown in Figure 14, in the psot hoc analysis, the IL-31 level in the serum of UP patients was significantly higher than that of healthy volunteers. However, there was no significant correlation between the serum IL-31 level in the screening phase and the itch VAS value at baseline. Nevertheless, a tendency for CIM331 administration to significantly reduce itch VAS was observed in patients with higher serum IL-31 levels in the screening phase. On the other hand, such results were not observed in the placebo-administered group or the nalfuraline hydrochloride-administered group. These results support the hypothesis that IL-31 is one of the pathogenic factors of UP.

(6-4) Expected results and beneficial effects A single subcutaneous administration of CIM331 increases the concentration of CIM331 in the serum, which can continuously exert its effect on the itching of dialysis patients. In addition, the maintenance of the itching improvement effect, that is, the interruption of the itching scratch cycle, can improve dermatitis and improve QOL. Furthermore, for example, given that current systemic treatments for dialysis pruritus require taking medication several times a day or applying medication to the affected area, or requiring return visits 1-2 times a week in the case of ultraviolet therapy, a single subcutaneous administration of CIM331 can suppress itch for a period of 4 weeks or more, and it is expected that this can significantly reduce the burden of medication or return visits for patients, and can help further improve the QOL of patients. In addition, for patients with dialysis pruritus whose serum IL-31 concentration is above a predetermined value before the start of CIM331 administration, it is expected that the administration of CIM331 can achieve a higher itch improvement effect. Thus, the predetermined IL-31 concentration in serum that can be expected to exert a high itch improvement effect can be, for example, 0.86 pg/mL. By administering CIM331 to patients with dialysis itch whose serum IL-31 concentration is above the predetermined value, it can help further improve the patient's QOL.

(6-5) One implementation of CIM331 after approval Although not limited, CIM331 can also be administered to patients with dialysis pruritus who have not been adequately treated with existing itch treatments other than nalfurafine hydrochloride. CIM331 can be administered, for example, every 2 to 12 weeks, specifically, once every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, or every 12 weeks, or once every month, every 2 months, or every 3 months, subcutaneously in equal doses and at the same administration interval. The dosage per unit body weight and the concentration of the injection solution of CIM331 can be appropriately determined based on the results of the Phase II clinical trial, other test results, etc. For example, when the weight of a patient with dialysis pruritus exceeds 120kg, a therapeutic trial drug can be prepared for a body weight of 120kg. In addition, when it is intended to administer CIM331 to patients with dialysis pruritus in mg/body, the dosage of CIM331 can be converted from mg/kg to mg/body based on the results of the Phase II clinical trial, etc., and an appropriate and proper dosage (mg/body) can be selected and administered. At this time, although the conversion logic from mg/kg to mg/body is not limited, it should be understood that the following logic can be used to appropriately determine it by a person with ordinary knowledge in the technical field. Assuming that there is a minimum effective serum concentration and a maximum tolerated (empirical) serum concentration of CIM331, the results of the Phase II trial are used to explore the change of the mg/kg dosage to mg/body dosage within this concentration range to obtain the serum CIM331 concentration regardless of body weight. In addition, the dosage for low-weight children may significantly increase the exposure if it is mg/body, so the mg/kg dosage method is used at this time. From the results of the Phase II trial currently being implemented, the minimum effective serum concentration and the maximum tolerated serum concentration are determined, and the exposure is organized in the above manner to convert to mg/body. Alternatively, the weight of a general dialysis pruritus patient can be estimated based on statistical data, and based on the estimated weight, the unit weight dosage (mg/kg) can be converted into a fixed dosage (mg/body) by the formula "unit weight dosage x estimated weight = fixed dosage". In a non-limiting embodiment, for an adult or child dialysis pruritus patient, a dosage can be selected from 0.1mg~1000mg/body, for example, 0.2mg~360mg/body, preferably 10mg~200mg/body, 10mg~100mg/body, 25mg~100mg/body, 50mg~100mg/body, or 50mg~75mg/body, and repeated administration is performed at the above-mentioned dosage intervals with equal amounts and the same dosage intervals. Or in another non-limiting embodiment, for children with dialysis pruritus, a dosage selected from 0.01mg~10mg/kg, for example, 0.1mg~3mg/kg, preferably 0.2mg~2mg/kg, and more preferably 0.5mg~1.5mg/kg can be selected, and the same dosage and the same dosage interval can be repeatedly administered subcutaneously at the above dosage interval.

[Reference Example 1] Expression and purification of IgG antibodies The expression of antibodies was performed using the following method. HEK293H cells from human fetal renal carcinoma (Invitrogen) were suspended in DMEM medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen), and 10 mL of each culture dish for adherent cells (diameter 10 cm, CORNING) was inoculated at a cell density of 5-6 × 10 ⁵ cells/mL. After culturing in a CO2 incubator (37°C, 5% CO2) for one day and one night, the medium was removed by aspiration, and 6.9 mL of CHO-S-SFM-II (Invitrogen) medium was added. The prepared plasmid was introduced into the cells by lipofection. After the obtained culture supernatant is recovered, the cells are removed by centrifugation (about 2000 g, 5 minutes, room temperature), and then sterilized by passing through a 0.22 μm filter MILLEX(R)-GV (Millipore) to obtain the culture supernatant. The obtained culture supernatant is purified using rProtein A SepharoseTM Fast Flow (Amersham Biosciences) by a method known to those skilled in the art. The concentration of the purified antibody is determined by the absorbance at 280 nm using a spectrophotometer. The antibody concentration is calculated from the obtained value using the absorbance coefficient calculated by the method described in Protein Science 1995;4:2411-2423.

without.

Figure 1 shows the itch suppression effect of atopic dermatitis (AD) patients after a single subcutaneous administration of CIM331 or placebo based on VAS. Figure 2 shows the improvement effect of dermatitis after a single subcutaneous administration of CIM331 or placebo based on EASI score. Figure 3 shows whether the quality of life (QOL) of atopic dermatitis patients is improved after a single subcutaneous administration of CIM331 or placebo, using sleep efficiency as an indicator. Figure 4 shows the amount of topical steroids (Locoid) used after a single subcutaneous administration of CIM331 or placebo in atopic dermatitis patients. FIG. 5 is a graph showing the change of serum CIM331 concentration after a single subcutaneous administration of CIM331 to patients with atopic dermatitis. FIG. 6 is a graph showing the number of IL-31-induced itching movements after a single subcutaneous administration of 0.2 mg/kg CIM331 to cynomolgus macaques (Macaca fascicularis). FIG. 7 is a graph showing the number of IL-31-induced itching movements after a single subcutaneous administration of 1 mg/kg CIM331 to cynomolgus macaques. FIG. 8 shows the nonlinear analytical model introduced with Michaelis &Menten's formula. In the figure, the meanings of the symbols are as follows: _Xsc : drug amount in the subcutaneous administration site, _X1 : drug amount in the central compartment, _X2 : drug amount in the peripheral compartment, F: bioavailability, _k12 : drug migration rate constant from the central compartment to the peripheral compartment, _k21 : drug migration rate constant from the peripheral compartment to the central compartment, _ka : absorption rate constant, _kel : non-saturation disappearance rate constant, _V1 : distribution volume of the central compartment, _Vmax : antibody disappearance rate when all receptors bind to the antibody, _Km : antibody concentration that binds to 50% of the total antigen amount, _Cp : antibody concentration. Figure 9 shows the predicted concentration change of CIM331 in human serum. Figure 10 is a graph showing the relationship between body weight and exposure in the simulation of the optimal dose of CIM331 using a 1-compartment model. Figure 11 is a graph showing the estimated itch VAS after 1 year of CIM331 administration using an indirect turnover model. Figure 12 is a graph showing the itch suppression effect at each evaluation time point based on VAS in patients with dialysis itch after administration of placebo, CIM331, or nalfurafen hydrochloride capsules. Figure 13 is a graph showing the proportion of patients with dialysis itch who had a higher itch suppression effect than expected (VAS less than 30 mm) after administration of placebo, CIM331, or nalfurafen hydrochloride capsules. FIG. 14 is a graph showing the correlation between itch VAS and serum IL-31 levels. The distribution of serum IL-31 concentrations in healthy volunteers (HV) and uremic pruritus (UP) patients is presented on a log scale. FIG. 15 shows the change from baseline (BL) of itch VAS in uremic pruritus patients divided into two categories according to serum IL-31 concentration (cut-off value 0.86 pg/mL) as mean ± standard deviation (SD).

without.

Claims (41)

A use of an IL-31 antagonist for the manufacture of a pharmaceutical composition for the prevention and/or treatment of dialysis pruritus, wherein the IL-31 antagonist is an anti-IL-31RA antibody, and the anti-IL-31RA antibody comprises: an H chain variable region recorded in sequence number: 7, and an L chain variable region recorded in sequence number: 8. The use as described in claim 1, wherein the anti-IL-31RA antibody comprises the H chain recorded in sequence number: 9 and the L chain recorded in sequence number: 10. The use as described in claim 1, wherein the IL-31 antagonist is repeatedly administered in equal amounts and at the same administration interval to a subject suffering from or at risk of suffering from dialysis pruritus 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. The use as described in claim 3, wherein the IL-31 antagonist is administered at 25 mg to 100 mg/body/4 weeks. The use as described in claim 4, wherein the IL-31 antagonist is administered at 50 mg to 100 mg/body/4 weeks. The use as described in claim 5, wherein the IL-31 antagonist is administered at 50 mg to 75 mg/body/4 weeks. The use as described in claim 4, wherein the IL-31 antagonist is administered at 30 mg/body/4 weeks. The use as described in claim 6, wherein the IL-31 antagonist is administered at 60 mg/body/4 weeks. The use as described in claim 1, wherein the IL-31 antagonist is administered to a subject suffering from or at risk of suffering from dialysis pruritus at an initial dose of 60 mg/body and a continued dose of 30 mg/body/4 weeks, and the interval between the initial dose and the first continued dose is 4 weeks. The use as described in claim 1, wherein the IL-31 antagonist is repeatedly administered in equal amounts and at the same administration interval to a subject suffering from or at risk of suffering from dialysis pruritus at 0.01 mg-10 mg/kg/2 weeks, 0.01 mg-10 mg/kg/4 weeks, or 0.01 mg-10 mg/kg/8 weeks. The use as described in claim 10, wherein the IL-31 antagonist is administered at 0.1 mg to 3 mg/kg/4 weeks. The use as described in claim 10, wherein the IL-31 antagonist is administered at 0.2 mg~2 mg/kg/4 weeks. The use as described in claim 11, wherein the IL-31 antagonist is administered at 0.125 mg/kg/4 weeks. The use as described in claim 11, wherein the IL-31 antagonist is administered at 0.5 mg/kg/4 weeks. The use as described in claim 12, wherein the IL-31 antagonist is administered at 1 mg/kg/4 weeks. The use as described in claim 12, wherein the IL-31 antagonist is administered at 2 mg/kg/4 weeks. The use according to any one of claims 1 to 16, wherein the IL-31 antagonist is administered to a subject suffering from dialysis pruritus or at risk of suffering from dialysis pruritus whose serum IL-31 concentration is above a predetermined value. The use as described in claim 17, wherein the predetermined value is determined using an ultra-high sensitivity enzyme-bound immunosorbent assay. The use as described in any one of claims 1 to 16, which is for administering the pharmaceutical composition only to subjects who respond to prevention and/or treatment with an IL-31 antagonist by predicting that the subject will respond to prevention and/or treatment with an IL-31 antagonist, the method comprising the steps of: measuring the IL-31 concentration in serum obtained from a subject suffering from or at risk of suffering from dialysis pruritus; and determining the subject whose IL-31 concentration is above a predetermined value as a responder to prevention and/or treatment with an IL-31 antagonist. The use as described in any one of claims 1 to 16, which is a method for predicting that the subject will respond to prevention and/or treatment caused by an IL-31 antagonist, so that the pharmaceutical composition is administered only to subjects who become responders to prevention and/or treatment caused by an IL-31 antagonist, the method comprising the following steps: among subjects suffering from dialysis pruritus or at risk of suffering from dialysis pruritus whose IL-31 concentration in serum is measured, the subject whose IL-31 concentration is above a predetermined value is determined as a responder to prevention and/or treatment caused by an IL-31 antagonist. The use as claimed in any one of claims 1 to 16, wherein the dialysis pruritus is dialysis pruritus for which systemic or local therapy other than nalfurafine hydrochloride is not sufficiently effective. The use as described in claim 21, wherein the systemic treatment is treatment with antihistamines or antiallergic drugs, and the local treatment is treatment with moisturizers or steroids. The use according to any one of claims 1 to 16, wherein the dialysis pruritus is dialysis pruritus caused by IL-31 signaling. The use as described in any one of claims 1 to 16, wherein the pharmaceutical composition is used to improve sleep disorders caused by dialysis pruritus. The use as described in claim 24, wherein the improvement of the sleep disorder is an increase in the time from falling asleep to waking up, and/or a shortening of sleep latency. The use as described in claim 1 or 2, wherein the antibody does not show cross-reactivity to IL-31RA of any of mouse, rat, and rabbit. The use as claimed in claim 17, wherein the dialysis pruritus is dialysis pruritus for which systemic or local therapy other than nalfurafine hydrochloride is not sufficiently effective. The use as described in claim 27, wherein the systemic treatment is treatment with antihistamines or antiallergic drugs, and the local treatment is treatment with moisturizers or steroids. The use as described in claim 17, wherein the aforementioned dialysis pruritus is dialysis pruritus caused by IL-31 signaling. The use as described in claim 17, wherein the pharmaceutical composition is used to improve sleep disorders caused by dialysis pruritus. The use as described in claim 30, wherein the improvement of the sleep disorder is an increase in the time from falling asleep to waking up, and/or a shortening of sleep latency. The use as claimed in claim 19, wherein the dialysis pruritus is dialysis pruritus for which systemic or local therapy other than nalfurafine hydrochloride is not sufficiently effective. The use as described in claim 32, wherein the systemic treatment is treatment with antihistamines or antiallergic drugs, and the local treatment is treatment with moisturizers or steroids. The use as described in claim 19, wherein the aforementioned dialysis pruritus is dialysis pruritus caused by IL-31 signaling. The use as described in claim 19, wherein the pharmaceutical composition is used to improve sleep disorders caused by dialysis pruritus. The use as described in claim 35, wherein the improvement of the sleep disorder is an increase in the time from falling asleep to waking up, and/or a shortening of sleep latency. The use as claimed in claim 20, wherein the dialysis pruritus is dialysis pruritus for which systemic or local treatments other than nalfurafine hydrochloride have not been sufficiently effective. The use as described in claim 37, wherein the systemic treatment is treatment with antihistamines or antiallergic drugs, and the local treatment is treatment with moisturizers or steroids. The use as described in claim 20, wherein the aforementioned dialysis pruritus is dialysis pruritus caused by IL-31 signaling. The use as described in claim 20, wherein the pharmaceutical composition is used to improve sleep disorders caused by dialysis pruritus. The use as described in claim 40, wherein the improvement of the sleep disorder is an increase in the time from falling asleep to waking up, and/or a shortening of sleep latency.