Antibody-containing formulations
The antibody stability problem was solved by adding arginine, sucrose and/or trehalose to the anti-IL-31RA antibody preparation, and the high stability and effectiveness of the preparation were achieved.
Patent Information
- Application Number
- CN202510483831.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2019-11-20
- Filing Date
- 2020-11-19
- Publication Date
- 2025-07-04
AI Technical Summary
There is a lack of effective stabilizing formulations in the prior art to inhibit aggregate formation and charge heterogeneity of anti-IL-31RA antibodies, affecting their stability.
The stability of the formulation is enhanced by adding arginine or its salt, sucrose and/or trehalose to the anti-IL-31RA antibody formulation, both in lyophilized or in solution.
The stability of anti-IL-31RA antibody preparations is significantly improved, the aggregate formation and charge heterogeneity are reduced, and the effectiveness and long-term storage of the preparations during the reconstruction process are ensured.
Smart Images
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Abstract
Description
[0001] This application is a divisional application of the patent application with the application date of November 19, 2020, the Chinese patent application number of 202080080856.8, and the invention title of "antibody-containing preparation". Technical Field
[0002] The present invention relates to a stable preparation comprising an interleukin-31 (IL-31) antagonist (e.g., a monoclonal antibody having the function of binding to IL-31 receptor A (IL-31RA) and inhibiting the binding of IL-31 to IL-31RA). Background Art
[0003] Monoclonal antibodies (PTL1-3) having the function of binding to interleukin 31 (IL-31) receptor A (IL-31RA) and inhibiting the binding of IL-31 to IL-31RA have been identified. The anti-IL-31RA antibody Nemolizumab (CIM331), a humanized IgG2 antibody, is used as an IL-31 antagonist to inhibit the function of IL-31, a so-called pruritogenic cytokine; thus, clinical trials for patients with atopic dermatitis are currently underway.
[0004] To improve stability, many lyophilized preparations (NPL 1) for therapeutic proteins (such as antibodies) have been developed to date. As additives for lyophilized preparations of non-antibody therapeutic proteins, saccharides such as sucrose and trehalose (NPL 2) are usually used, and there are also reports of using arginine as a stabilizer (PTL4 and 5).
[0005] However, there is no report on a stable preparation that inhibits the formation of aggregates and / or components having charge heterogeneity, which have a great influence on antibody stability, for a preparation comprising an anti-IL31RA antibody (CIM331) as an IL-31 antagonist.
[0006] Citation List
[0007] Patent Documents
[0008] [PTL 1] WO2007 / 142325
[0009] [PTL 2] WO2009 / 072604
[0010] [PTL 3] WO2010 / 064697
[0011] [PTL 4] US6887852B1
[0012] [PTL 5] WO2010 / 148253
[0013] Non-Patent Documents
[0014] [NPL 1] Pharm Res. 1997; 14(8): 969-975.
[0015] [NPL 2] J Pharm Sci. 1998; 87(11): 1412-1420. Summary of the Invention
[0016] Technical Problem
[0017] An object of the present invention is to provide a stable preparation containing an IL-31 antagonist, anti-IL-31RA antibody (CIM331), as an active ingredient.
[0018] Solution to the Problem
[0019] To achieve the above object, the present inventors conducted dedicated research and found that adding arginine or its salt to a preparation containing the above IL-31 antagonist (especially anti-IL-31RA antibody (CIM331)) increased the stability of the preparation containing the IL-31 antagonist, regardless of the presence or absence of a lyophilization step. It was also found that when the preparation was in a lyophilized state, adding sucrose or trehalose to the preparation increased the stability of the preparation containing the IL-31 antagonist. Further, it was found that when the preparation was in a solution state, adding a nonionic surfactant to the preparation increased the stability of the preparation containing the IL-31 antagonist.
[0020] In non-limiting embodiments, the present disclosure relates to the following.
[0021] [1] A lyophilized preparation containing an IL-31 antagonist as an active ingredient, wherein the preparation contains arginine and / or its salt, sucrose and / or trehalose.
[0022] [2] The lyophilized preparation according to [1], wherein the arginine and / or its salt is arginine hydrochloride, arginine aspartate or arginine glutamate.
[0023] [3] The lyophilized preparation according to [1] or [2], wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl).
[0024] [4] The lyophilized preparation according to any one of [1] to [3], further containing Tris buffer as a buffer.
[0025] [5] The lyophilized preparation according to [4], wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.
[0026] [6] The lyophilized preparation according to [5], wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane aspartate, tris(hydroxymethyl)aminomethane glutamate or tris(hydroxymethyl)aminomethane acetate.
[0027] [7] The lyophilized preparation according to [5] or [6], wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl).
[0028] [8] The lyophilized preparation according to any one of [1] to [7] further comprises poloxamer 188 or polysorbate as a nonionic surfactant.
[0029] [9] The lyophilized preparation according to [8], wherein the polysorbate is polysorbate 20 or polysorbate 80.
[0030]
[10] The lyophilized preparation according to any one of [1] to [9], wherein the pH is 6 to 8 when the preparation is reconstituted in water.
[0031]
[11] The lyophilized preparation according to any one of [1] to
[10] , wherein the pH is 6.5 to 7.5 when the preparation is reconstituted in water.
[0032]
[12] The lyophilized preparation according to any one of [1] to
[11] , wherein the pH is 7 when the preparation is reconstituted in water.
[0033]
[13] A solution preparation containing an IL-31 antagonist as an active ingredient, wherein the solution preparation contains arginine and / or its salt.
[0034]
[14] The solution preparation according to
[13] , wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl), arginine aspartate or arginine glutamate.
[0035]
[15] The solution preparation according to
[13] or
[14] , wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl).
[0036]
[16] The solution preparation according to any one of
[13] to
[15] further comprises Tris buffer as a buffer.
[0037]
[17] The solution preparation according to
[16] , wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.
[0038]
[18] The solution preparation according to
[17] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane aspartate, tris(hydroxymethyl)aminomethane glutamate, or tris(hydroxymethyl)aminomethane acetate.
[0039]
[19] The solution preparation according to
[17] or
[18] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl).
[0040]
[20] The solution preparation according to any one of
[13] to
[19] , further comprising a non-ionic surfactant, wherein the non-ionic surfactant is poloxamer 188 or polysorbate.
[0041]
[21] The solution preparation according to
[20] , wherein the polysorbate is polysorbate 20 or polysorbate 80.
[0042]
[22] The solution preparation according to any one of
[13] to
[21] , wherein the pH is 6 to 8.
[0043]
[23] The solution preparation according to any one of
[13] to
[22] , wherein the pH is 6.5 to 7.5.
[0044]
[24] The solution preparation according to any one of
[13] to
[23] , wherein the pH is 7.
[0045]
[25] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, which is a composition produced by lyophilizing a solution comprising:
[0046] - 1 to 200 mg / mL of an IL-31 antagonist;
[0047] - 1 to 200 mmol / L of Tris buffer;
[0048] - 4.5 to 1500 mmol / L of arginine or its salt;
[0049] - 7.5 to 2500 mmol / L of sucrose or trehalose; and
[0050] - 0.01 to 5 mg / mL of poloxamer 188 or polysorbate 20,
[0051] wherein the pH is 6 to 8 when the preparation is reconstituted in water:
[0052]
[26] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, which is a composition produced by lyophilizing a solution comprising:
[0053] - 6 to 100 mg / mL IL-31 antagonist;
[0054] - 6 to 20 mmol / L Tris buffer;
[0055] - 45 to 150 mmol / L arginine or its salt;
[0056] - 75 to 250 mmol / L sucrose or trehalose; and
[0057] - 0.15 to 0.50 mg / mL poloxamer 188 or polysorbate 20,
[0058] wherein the pH is 6 to 8 when the preparation is reconstituted in water:
[0059]
[27] A lyophilized preparation containing an IL-31 antagonist as an active ingredient, which contains, per vial, cartridge or syringe:
[0060] - 1 to 800 mg IL-31 antagonist;
[0061] - 0.1 to 40 mg tris(hydroxymethyl)aminomethane;
[0062] - 0.8 to 400 mg arginine;
[0063] - 3 to 1100 mg sucrose or trehalose; and
[0064] - 0.01 to 7 mg poloxamer 188 or polysorbate 20,
[0065] wherein the pH is 6 to 8 when the preparation is reconstituted in water.
[0066]
[28] A lyophilized preparation containing an IL-31 antagonist as an active ingredient, which contains, per vial, cartridge or syringe:
[0067] - 10 to 80 mg IL-31 antagonist;
[0068] - 0.8 to 4 mg tris(hydroxymethyl)aminomethane;
[0069] - 8 to 40 mg arginine;
[0070] - 30 to 110 mg sucrose or trehalose; and
[0071] - 0.1 to 0.7 mg poloxamer 188 or polysorbate 20,
[0072] wherein the pH is 6 to 8 when the preparation is reconstituted in water.
[0073]
[29] The preparation according to any one of [1] to
[28] , wherein the molar ratio of the arginine and / or its salt to the IL-31 antagonist is from 220:1 to 1100:1, and / or the weight ratio of the arginine to the IL-31 antagonist is from 0.3:1 to 1.3:1.
[0074]
[30] The lyophilized preparation according to any one of [1] to
[12] and
[25] to
[28] , wherein the molar ratio between the sucrose or trehalose and the IL-31 antagonist is from 370:1 to 1840:1 and / or the weight ratio is from 0.8:1 to 4.3:1.
[0075]
[31] The lyophilized preparation according to any one of
[25] to
[30] , wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl), arginine-aspartate or arginine-glutamate.
[0076]
[32] The lyophilized preparation according to any one of
[25] to
[31] , wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl).
[0077]
[33] The lyophilized preparation according to
[32] , wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.
[0078]
[34] The lyophilized preparation according to
[33] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.
[0079]
[35] The lyophilized preparation according to
[33] or
[34] , wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).
[0080]
[36] The preparation according to any one of [1] to
[35] , wherein the IL-31 antagonist is an antibody that inhibits IL-31 signal transduction.
[0081]
[37] The preparation according to
[36] , wherein the antibody that inhibits IL-31 signal transduction is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.
[0082]
[38] The preparation according to
[37] , wherein the anti-IL-31RA neutralizing antibody is:
[0083] (1) An anti-IL-31RA antibody, which comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2 and CDR3 of SEQ ID NO: 3, and the light chain variable region comprises CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5 and CDR3 of SEQ ID NO: 6;
[0084] (2) An anti-IL-31RA antibody, which comprises a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; or
[0085] (3) An anti-IL-31RA antibody, which comprises a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10.
[0086]
[39] The preparation according to
[37] or
[38] , wherein the anti-IL-31RA neutralizing antibody is an IgG antibody, preferably an IgG2 antibody.
[0087]
[40] The preparation according to any one of
[37] to
[39] , wherein the anti-IL-31RA neutralizing antibody is Nemolizumab.
[0088]
[41] The lyophilized preparation according to any one of
[37] to
[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 68 mg / mL.
[0089]
[42] The lyophilized preparation according to any one of
[37] to
[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 50 mg / mL.
[0090]
[43] The lyophilized preparation according to any one of
[37] to
[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 15 mg / mL.
[0091]
[44] The lyophilized preparation according to any one of
[37] to
[40] , which is a composition produced by lyophilizing a solution in which the concentration of the anti-IL-31RA neutralizing antibody is 7.5 mg / mL.
[0092]
[45] The lyophilized preparation according to any one of
[37] to
[41] , which is a composition produced by lyophilizing a solution in which the concentration of Tris-HCl is 13.6 mmol / L.
[0093]
[46] The lyophilized preparation according to any one of
[37] to
[40] and
[42] , which is a composition produced by lyophilizing a solution in which the concentration of Tris-HCl is 10 mmol / L.
[0094]
[47] The lyophilized preparation according to any one of
[37] to
[40] and
[43] to
[44] , which is a composition produced by lyophilizing a solution in which the concentration of Tris-HCl is 6 mmol / L.
[0095]
[48] The lyophilized preparation according to any one of
[37] to
[41] and
[45] , which is a composition produced by lyophilizing a solution in which the concentration of Arg-HCl is 102 mmol / L.
[0096]
[49] The lyophilized preparation according to any one of
[37] to
[40] ,
[42] and
[46] , which is a composition produced by lyophilizing a solution in which the concentration of Arg-HCl is 75 mmol / L.
[0097]
[50] The lyophilized preparation according to any one of
[37] to
[40] ,
[43] to
[44] and
[47] , which is a composition produced by lyophilizing a solution in which the concentration of Arg-HCl is 45 mmol / L.
[0098]
[51] The lyophilized preparation according to any one of
[37] to
[41] ,
[45] and
[48] , which is a composition produced by lyophilizing a solution in which the concentration of sucrose or trehalose is 170 mmol / L.
[0099]
[52] The lyophilized preparation according to any one of
[37] to
[40] ,
[42] ,
[46] and
[49] , which is a composition produced by lyophilizing a solution in which the concentration of sucrose or trehalose is 125 mmol / L.
[0100]
[53] The lyophilized preparation according to any one of
[37] to
[40] ,
[43] to
[44] ,
[47] and
[50] , which is a composition produced by lyophilizing a solution in which the concentration of sucrose or trehalose is 75 mmol / L.
[0101]
[54] The lyophilized preparation according to any one of
[37] to
[41] ,
[45] ,
[48] and
[51] , which is a composition produced by lyophilizing a solution in which the concentration of poloxamer 188 or polysorbate 20 is 0.34 mg / mL.
[0102]
[55] The lyophilized preparation according to any one of
[37] to
[40] ,
[42] ,
[46] ,
[49] and
[52] , which is a composition produced by lyophilizing a solution in which the concentration of poloxamer 188 or polysorbate 20 is 0.25 mg / mL.
[0103]
[56] The lyophilized preparation according to any one of
[37] to
[40] ,
[43] to
[44] ,
[47] ,
[50] and
[53] , which is a composition produced by lyophilizing a solution in which the concentration of poloxamer 188 or polysorbate 20 is 0.15 mg / mL.
[0104]
[57] The lyophilized preparation according to any one of
[37] to
[42] ,
[45] to
[46] ,
[48] to
[49] ,
[51] to
[52] and
[54] to
[55] , which is a composition produced by lyophilizing a solution in which the molar ratio between arginine and the anti-IL-31RA neutralizing antibody is 220:1 and / or the weight ratio is 0.3:1.
[0105]
[58] The lyophilized preparation according to any one of
[37] to
[40] ,
[43] ,
[47] ,
[50] ,
[53] and
[56] , which is a composition produced by lyophilizing a solution in which the molar ratio between arginine and the anti-IL-31RA neutralizing antibody is 440:1 and / or the weight ratio is 0.5:1.
[0106]
[59] The lyophilized preparation according to any one of
[37] to
[40] ,
[44] ,
[47] ,
[50] ,
[53] and
[56] , which is a composition produced by lyophilizing a solution in which the molar ratio between arginine and the anti-IL-31RA neutralizing antibody is 880:1 and / or the weight ratio is 1.0:1 to 1.1:1.
[0107]
[60] The lyophilized preparation according to any one of
[37] to
[42] ,
[45] to
[46] ,
[48] to
[49] ,
[51] to
[52] ,
[54] to
[55] and
[57] , which is a composition produced by lyophilizing a solution in which the molar ratio between sucrose and the anti-IL-31RA neutralizing antibody is 370:1 and / or the weight ratio is 0.8:1 to 0.9:1.
[0108]
[61] The lyophilized preparation according to any one of
[37] to
[40] ,
[43] ,
[47] ,
[50] ,
[53] ,
[56] and
[58] , which is a composition produced by lyophilizing a solution in which the molar ratio between sucrose and the anti-IL-31RA neutralizing antibody is 740:1 and / or the weight ratio is 1.7:1.
[0109]
[62] The lyophilized preparation according to any one of
[37] to
[40] ,
[44] ,
[47] ,
[50] ,
[53] ,
[56] and
[59] , which is a composition produced by lyophilizing a solution in which the molar ratio between sucrose and the anti-IL-31RA neutralizing antibody is 1470:1 and / or the weight ratio is 3.4:1 to 3.5:1.
[0110]
[63] The lyophilized preparation according to any one of
[25] to
[62] , wherein the pH when the preparation is reconstituted in water is 6.5 to 7.5.
[0111]
[64] The lyophilized preparation according to any one of
[25] to
[63] , wherein the pH when the preparation is reconstituted in water is 7.
[0112]
[65] The lyophilized preparation according to any one of
[25] to
[40] , which contains, per container such as a syringe:
[0113] - 75 mg of anti-IL-31RA neutralizing antibody;
[0114] - 1.8 mg of tris(hydroxymethyl)aminomethane;
[0115] - 19 mg of arginine;
[0116] - 64 mg of sucrose;
[0117] - 0.4 mg of poloxamer 188.
[0118]
[66] The lyophilized preparation according to any one of
[25] to
[40] , which contains, per container such as a syringe:
[0119] - 75 mg of anti-IL-31RA neutralizing antibody;
[0120] - 0.24 mg of tris(hydroxymethyl)aminomethane;
[0121] - 23.6 mg of L-arginine hydrochloride;
[0122] - 63.9 mg of sucrose;
[0123] - 0.37 mg of poloxamer 188; and
[0124] - Tris(hydroxymethyl)aminomethane-hydrochloride as a pH regulator.
[0125]
[67] The lyophilized preparation according to any one of
[25] to
[40] , which contains, per container such as a syringe:
[0126] - 39 mg of anti-IL-31RA neutralizing antibody;
[0127] - 0.9 mg tris(hydroxymethyl)aminomethane;
[0128] - 10 mg arginine;
[0129] - 33 mg sucrose; and
[0130] - 0.2 mg poloxamer 188.
[0131]
[68] The lyophilized preparation according to any one of
[25] to
[40] , which comprises, per container such as a cartridge:
[0132] - 36 mg anti-IL-31RA neutralizing antibody;
[0133] - 0.9 mg tris(hydroxymethyl)aminomethane;
[0134] - 9 mg arginine;
[0135] - 31 mg sucrose; and
[0136] - 0.2 mg poloxamer 188.
[0137]
[69] The lyophilized preparation according to any one of
[25] to
[40] , which comprises, per container such as a vial:
[0138] - 51 mg anti-IL-31RA neutralizing antibody;
[0139] - 2.5 mg tris(hydroxymethyl)aminomethane;
[0140] - 27 mg arginine;
[0141] - 88 mg sucrose; and
[0142] - 0.5 mg poloxamer 188.
[0143]
[70] The lyophilized preparation according to any one of
[25] to
[40] , which comprises, per container such as a vial:
[0144] - 30 mg anti-IL-31RA neutralizing antibody;
[0145] - 3.0 mg tris(hydroxymethyl)aminomethane;
[0146] - 32 mg arginine;
[0147] - 104 mg sucrose; and
[0148] - 0.6 mg poloxamer 188.
[0149]
[71] The lyophilized preparation according to any one of
[25] to
[40] , which comprises, per container such as a vial:
[0150] - 19 mg of an anti-IL-31RA neutralizing antibody;
[0151] - 1.9 mg of tris(hydroxymethyl)aminomethane;
[0152] - 20 mg of arginine;
[0153] - 66 mg of sucrose; and
[0154] - 0.4 mg of poloxamer 188.
[0155]
[72] The lyophilized preparation according to any one of
[25] to
[40] , which comprises, per container such as a vial:
[0156] - 14 mg of an anti-IL-31RA neutralizing antibody;
[0157] - 1.3 mg of tris(hydroxymethyl)aminomethane;
[0158] - 15 mg of arginine;
[0159] - 47 mg of sucrose; and
[0160] - 0.3 mg of poloxamer 188.
[0161]
[73] The lyophilized preparation according to any one of
[25] to
[40] , which is a composition produced by lyophilizing a solution, the solution comprising:
[0162] - 68 mg / mL of an anti-IL-31RA antibody, the anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;
[0163] - 13.6 mmol / L of tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer;
[0164] - 102 mmol / L of arginine hydrochloride (Arg-HCl);
[0165] - 170 mmol / L of sucrose; and
[0166] - 0.34 mg / mL of poloxamer 188,
[0167] wherein the pH is 7 when the preparation is reconstituted in water.
[0168]
[74] The lyophilized preparation according to any one of
[25] to
[40] , which is a composition produced by lyophilizing a solution, the solution comprising:
[0169] - 50 mg / mL anti-IL-31RA antibody, the anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;
[0170] - 10 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer;
[0171] - 75 mmol / L arginine hydrochloride (Arg-HCl);
[0172] - 125 mmol / L sucrose; and
[0173] - 0.25 mg / mL poloxamer 188,
[0174] wherein the pH is 7 when the preparation is reconstituted in water.
[0175]
[75] The lyophilized preparation according to any one of
[25] to
[40] , which is a composition produced by lyophilizing a solution, the solution comprising:
[0176] - 15 mg / mL anti-IL-31RA antibody, the anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;
[0177] - 6 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer;
[0178] - 45 mmol / L arginine hydrochloride (Arg-HCl);
[0179] - 75 mmol / L sucrose; and
[0180] - 0.15 mg / mL poloxamer 188,
[0181] wherein the pH is 7 when the preparation is reconstituted in water.
[0182]
[76] The lyophilized preparation according to any one of
[25] to
[40] , which is a composition produced by lyophilizing a solution, the solution comprising:
[0183] - 7.5 mg / mL anti-IL-31RA antibody, the anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10;
[0184] - 6 mmol / L Tris-HCl buffer;
[0185] - 45 mmol / L arginine hydrochloride (Arg-HCl);
[0186] - 75 mmol / L sucrose; and
[0187] - 0.15 mg / mL poloxamer 188,
[0188] wherein the pH is 7 when the preparation is reconstituted in water.
[0189]
[77] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, the lyophilized preparation further comprising a Tris buffer, arginine, sucrose or trehalose, and poloxamer 188 or polysorbate 20, wherein, when the preparation is reconstituted in water, it comprises:
[0190] - 1 to 200 mg / mL IL-31 antagonist;
[0191] - 1 to 200 mmol / L Tris buffer;
[0192] - 4.5 to 1500 mmol / L arginine or its salt;
[0193] - 7.5 to 2500 mmol / L sucrose or trehalose; and
[0194] - 0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,
[0195] and the pH is 6 to 8.
[0196]
[78] A lyophilized preparation comprising an IL-31 antagonist as an active ingredient, the lyophilized preparation further comprising a Tris buffer, arginine, sucrose or trehalose, and poloxamer 188 or polysorbate 20, wherein, when the preparation is reconstituted in water, it comprises:
[0197] - 20 to 100 mg / mL IL-31 antagonist;
[0198] - 10 to 20 mmol / L Tris buffer;
[0199] - 75 to 150 mmol / L arginine or its salt;
[0200] - 125 to 250 mmol / L sucrose or trehalose; and
[0201] - 0.25 to 0.50 mg / mL of poloxamer 188 or polysorbate 20,
[0202] and the pH is from 6 to 8.
[0203]
[79] ,
[77] or
[78] the lyophilized preparation, wherein the molar ratio of arginine and / or its salt to the IL-31 antagonist is from 220:1 to 1100:1, and / or the weight ratio of arginine to the IL-31 antagonist is from 0.3:1 to 1.3:1.
[0204]
[80] ,
[77] to
[79] any one of the lyophilized preparation, wherein the molar ratio between sucrose or trehalose and the IL-31 antagonist is from 370:1 to 1840:1 and / or the weight ratio is from 0.8:1 to 4.3:1.
[0205]
[81] ,
[77] to
[80] any one of the lyophilized preparation, wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl), arginine-aspartate or arginine-glutamate.
[0206]
[82] ,
[77] to
[81] any one of the lyophilized preparation, wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl).
[0207]
[83] ,
[77] to
[82] any one of the lyophilized preparation, wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.
[0208]
[84] ,
[83] the lyophilized preparation, wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate.
[0209]
[85] ,
[83] or
[84] the lyophilized preparation, wherein the tris(hydroxymethyl)aminomethane and / or its salt is tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl).
[0210]
[86] ,
[77] to
[85] any one of the lyophilized preparation, wherein the IL-31 antagonist is an antibody that inhibits IL-31 signal transduction.
[0211]
[87] ,
[86] the lyophilized preparation, wherein the antibody that inhibits IL-31 signal transduction is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.
[0212]
[88] The freeze-dried preparation according to
[87] , wherein the anti-IL-31RA neutralizing antibody is:
[0213] (1) An anti-IL-31RA antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and the light chain variable region comprises CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6;
[0214] (2) An anti-IL-31RA antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; or
[0215] (3) An anti-IL-31RA antibody comprising a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10.
[0216]
[89] The freeze-dried preparation according to
[87] or
[88] , wherein the anti-IL-31RA neutralizing antibody is an IgG antibody, preferably an IgG2 antibody.
[0217]
[90] The freeze-dried preparation according to any one of
[87] to
[89] , wherein the anti-IL-31RA neutralizing antibody is Nemolizumab.
[0218]
[91] The freeze-dried preparation according to any one of
[87] to
[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 100 mg / mL when the preparation is reconstituted in water.
[0219]
[92] The freeze-dried preparation according to any one of
[87] to
[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 61.5 mg / mL when the preparation is reconstituted in water.
[0220]
[93] The freeze-dried preparation according to any one of
[87] to
[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 50 mg / mL when the preparation is reconstituted in water.
[0221]
[94] The freeze-dried preparation according to any one of
[87] to
[90] , wherein the concentration of the anti-IL-31RA neutralizing antibody is 25 mg / mL when the preparation is reconstituted in water.
[0222]
[95] The freeze-dried preparation according to any one of
[87] to
[91] , wherein the concentration of Tris-HCl is 20 mmol / L when the preparation is reconstituted in water.
[0223]
[96] The lyophilized preparation according to any one of
[87] to
[90] and
[92] , wherein the concentration of Tris-HCl is 12.3 mmol / L when the preparation is reconstituted in water.
[0224]
[97] The lyophilized preparation according to any one of
[87] to
[90] and
[93] to
[94] , wherein the concentration of Tris-HCl is 20 mmol / L when the preparation is reconstituted in water.
[0225]
[98] The lyophilized preparation according to any one of
[87] to
[91] and
[95] , wherein the concentration of Arg-HCl is 150 mmol / L when the preparation is reconstituted in water.
[0226]
[99] The lyophilized preparation according to any one of
[87] to
[90] ,
[92] and
[96] , wherein the concentration of Arg-HCl is 92 mmol / L when the preparation is reconstituted in water.
[0227]
[100] The lyophilized preparation according to any one of
[87] to
[90] ,
[93] to
[94] and
[97] , wherein the concentration of Arg-HCl is 150 mmol / L when the preparation is reconstituted in water.
[0228]
[101] The lyophilized preparation according to any one of
[87] to
[91] ,
[95] and
[98] , wherein the concentration of sucrose or trehalose is 250 mmol / L when the preparation is reconstituted in water.
[0229]
[102] The lyophilized preparation according to any one of
[87] to
[90] ,
[92] ,
[96] and
[99] , wherein the concentration of sucrose or trehalose is 154 mmol / L when the preparation is reconstituted in water.
[0230]
[103] The lyophilized preparation according to any one of
[87] to
[90] ,
[93] to
[94] ,
[97] and
[100] , wherein the concentration of sucrose or trehalose is 250 mmol / L when the preparation is reconstituted in water.
[0231]
[104] The lyophilized preparation according to any one of
[87] to
[91] ,
[95] ,
[98] and
[101] , wherein the concentration of poloxamer 188 or polysorbate 20 is 0.50 mg / mL when the preparation is reconstituted in water.
[0232]
[105] The lyophilized preparation according to any one of
[87] to
[90] ,
[92] ,
[96] ,
[99] and
[102] , wherein the concentration of poloxamer 188 or polysorbate 20 is 0.31 mg / mL when the preparation is reconstituted in water.
[0233]
[106] The lyophilized preparation according to any one of
[87] to
[90] ,
[93] to
[94] ,
[97] ,
[100] and
[103] , wherein the concentration of poloxamer 188 or polysorbate 20 is 0.50 mg / mL when the preparation is reconstituted in water.
[0234]
[107] The lyophilized preparation according to any one of
[87] to
[91] ,
[95] ,
[98] ,
[101] and
[104] to
[105] , wherein the molar ratio between the arginine and the anti-IL-31RA neutralizing antibody is 220:1 and / or the weight ratio is 0.3:1.
[0235]
[108] The lyophilized preparation according to any one of
[87] to
[90] ,
[93] ,
[97] ,
[100] ,
[103] and
[106] , wherein the molar ratio between the arginine and the anti-IL-31RA neutralizing antibody is 440:1 and / or the weight ratio is 0.5:1.
[0236]
[109] The lyophilized preparation according to any one of
[87] to
[90] ,
[94] ,
[97] ,
[100] ,
[103] and
[106] , wherein the molar ratio between the arginine and the anti-IL-31RA neutralizing antibody is 880:1 and / or the weight ratio is 1.0:1 to 1.1:1.
[0237]
[110] The lyophilized preparation according to any one of
[87] to
[91] ,
[95] ,
[98] ,
[101] ,
[104] to
[105] and
[107] , wherein the molar ratio between the sucrose and the anti-IL-31RA neutralizing antibody is 370:1 and / or the weight ratio is 0.8:1 to 0.9:1.
[0238]
[111] The lyophilized preparation according to any one of
[87] to
[90] ,
[93] ,
[97] ,
[100] ,
[103] ,
[106] and
[108] , wherein the molar ratio between the sucrose and the anti-IL-31RA neutralizing antibody is 740:1 and / or the weight ratio is 1.7:1.
[0239]
[112] The lyophilized preparation according to any one of
[87] to
[90] ,
[94] ,
[97] ,
[100] ,
[103] and
[109] , wherein the molar ratio between the sucrose and the anti-IL-31RA neutralizing antibody is 1470:1 and / or the weight ratio is 3.4:1 to 3.5:1.
[0240]
[113] The lyophilized preparation according to any one of
[77] to
[112] , wherein the pH of the preparation when reconstituted in water is from 6.5 to 7.5.
[0241]
[114] The lyophilized preparation according to any one of
[77] to
[113] , wherein the pH of the preparation when reconstituted in water is from 6.7 to 7.3.
[0242]
[115] The lyophilized preparation according to any one of
[77] to
[114] , wherein the pH of the preparation when reconstituted in water is 7.
[0243]
[116] The lyophilized preparation according to any one of
[87] to
[91] ,
[95] ,
[98] ,
[101] ,
[104] ,
[107] and
[110] , wherein the lyophilized preparation is a pharmaceutical composition comprising an anti-IL-31RA antibody containing an H chain of SEQ ID NO: 9 and an L chain of SEQ ID NO: 10 as an active ingredient, and is prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient and a non-ionic surfactant, and wherein the following concentrations are produced when the lyophilized preparation is reconstituted in water:
[0244] - 100 mg / mL of anti-IL-31RA neutralizing antibody;
[0245] - 20 mmol / L of tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer;
[0246] - 150 mmol / L of arginine hydrochloride (Arg-HCl);
[0247] - 250 mmol / L of sucrose; and
[0248] - 0.50 mg / mL of poloxamer 188.
[0249]
[117] The lyophilized preparation according to any one of
[87] to
[90] ,
[92] ,
[96] ,
[99] ,
[102] ,
[105] ,
[107] and
[110] , wherein the lyophilized preparation is a pharmaceutical composition comprising an anti-IL-31RA antibody containing an H chain of SEQ ID NO: 9 and an L chain of SEQ ID NO: 10 as an active ingredient, and is prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient and a non-ionic surfactant, and when the lyophilized preparation is reconstituted in water, the following concentrations are produced:
[0250] - 61.5 mg / mL of anti-IL-31RA neutralizing antibody;
[0251] - 12.3 mmol / L Tris-HCl buffer;
[0252] - 92 mmol / L arginine hydrochloride (Arg-HCl);
[0253] - 154 mmol / L sucrose; and
[0254] - 0.31 mg / mL poloxamer 188.
[0255]
[118] The lyophilized preparation according to any one of
[87] to
[90] ,
[93] ,
[97] ,
[100] ,
[103] ,
[106] ,
[108] and
[111] , wherein the lyophilized preparation is a pharmaceutical composition comprising an anti-IL-31RA antibody containing an H chain of SEQ ID NO: 9 and an L chain of SEQ ID NO: 10 as an active ingredient, and is prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient and a non-ionic surfactant, and wherein when the lyophilized preparation is reconstituted in water, the following concentrations are produced:
[0256] - 50 mg / mL anti-IL-31RA neutralizing antibody;
[0257] - 20 mmol / L Tris-HCl buffer;
[0258] - 150 mmol / L arginine hydrochloride (Arg-HCl);
[0259] - 250 mmol / L sucrose; and
[0260] - 0.50 mg / mL poloxamer 188.
[0261]
[119] The lyophilized preparation according to any one of
[87] to
[90] ,
[94] ,
[97] ,
[100] ,
[103] ,
[109] and
[112] , wherein the lyophilized preparation is a pharmaceutical composition comprising an anti-IL-31RA antibody containing an H chain of SEQ ID NO: 9 and an L chain of SEQ ID NO: 10 as an active ingredient, and is prepared by lyophilizing a solution containing a buffer, a stabilizer, an excipient and a non-ionic surfactant, and wherein when the lyophilized preparation is reconstituted in water, the following concentrations are produced:
[0262] - 25 mg / mL anti-IL-31RA neutralizing antibody;
[0263] - 20 mmol / L Tris-HCl buffer;
[0264] - 150 mmol / L arginine hydrochloride (Arg-HCl);
[0265] - 250 mmol / L sucrose; and
[0266] - 0.50 mg / mL poloxamer 188.
[0267]
[120] A lyophilized preparation containing an IL-31 antagonist as an active ingredient, which is a composition produced from a lyophilized solution, and the solution contains:
[0268] - 1 to 200 mg / mL IL-31 antagonist;
[0269] - 1 to 200 mmol / L Tris buffer;
[0270] - 4.5 to 1500 mmol / L arginine or its salt;
[0271] - 7.5 to 2500 mmol / L sucrose or trehalose; and
[0272] - 0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,
[0273] wherein, when the preparation is reconstituted in water, it contains:
[0274] - 1 to 200 mg / mL IL-31 antagonist;
[0275] - 1 to 200 mmol / L Tris buffer;
[0276] - 4.5 to 1500 mmol / L arginine or its salt;
[0277] - 7.5 to 2500 mmol / L sucrose or trehalose; and
[0278] - 0.01 to 5 mg / mL poloxamer 188 or polysorbate 20,
[0279] and the pH is 6 to 8.
[0280]
[121] A lyophilized preparation containing an IL-31 antagonist as an active ingredient, which is a composition produced from a lyophilized solution, and the solution contains:
[0281] - 6 to 100 mg / mL IL-31 antagonist;
[0282] - 6 to 20 mmol / L Tris buffer;
[0283] - 45 to 150 mmol / L arginine or its salt;
[0284] - 75 to 250 mmol / L sucrose or trehalose; and
[0285] - 0.15 to 0.50 mg / mL poloxamer 188 or polysorbate 20,
[0286] wherein, when the preparation is reconstituted in water, it comprises:
[0287] - 20 to 100 mg / mL IL-31 antagonist;
[0288] - 10 to 20 mmol / L Tris buffer;
[0289] - 75 to 150 mmol / L arginine or its salt;
[0290] - 125 to 250 mmol / L sucrose or trehalose; and
[0291] - 0.25 to 0.50 mg / mL poloxamer 188 or polysorbate 20,
[0292] and the pH is 6 to 8.
[0293]
[122]
[120] or
[121] The lyophilized preparation as described, wherein the molar ratio of the arginine and / or its salt to the IL-31 antagonist is 220:1 to 1100:1.
[0294]
[123]
[120] to
[122] The lyophilized preparation as described in any one of them, wherein the molar ratio of the sucrose or trehalose to the IL-31 antagonist is 370:1 to 1840:1.
[0295]
[124]
[120] to
[123] The lyophilized preparation as described in any one of them, wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl), arginine-aspartate or arginine-glutamate.
[0296]
[125]
[120] to
[124] The lyophilized preparation as described in any one of them, wherein the arginine and / or its salt is arginine hydrochloride (Arg-HCl).
[0297]
[126]
[120] to
[125] The lyophilized preparation as described in any one of them, wherein the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt.
[0298]
[127] The lyophilized preparation according to any one of
[120] to
[126] , wherein the tris (hydroxymethyl) aminomethane and / or its salt is tris (hydroxymethyl) aminomethane hydrochloride (Tris-HCl), tris (hydroxymethyl) aminomethane aspartate, tris (hydroxymethyl) aminomethane glutamate or tris (hydroxymethyl) aminomethane acetate.
[0299]
[128] The lyophilized preparation according to any one of
[120] or
[127] , wherein the tris (hydroxymethyl) aminomethane and / or its salt is tris (hydroxymethyl) aminomethane hydrochloride (Tris-HCl).
[0300]
[129] The lyophilized preparation according to any one of
[120] to
[128] , wherein the IL-31 antagonist is an antibody that inhibits IL-31 signal transduction.
[0301]
[130] The lyophilized preparation according to
[129] , wherein the antibody that inhibits IL-31 signal transduction is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.
[0302]
[131] The lyophilized preparation according to
[130] , wherein the anti-IL-31RA neutralizing antibody is:
[0303] (1) An anti-IL-31RA antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3, and the light chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5, and CDR3 of SEQ ID NO: 6;
[0304] (2) An anti-IL-31RA antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; or
[0305] (3) An anti-IL-31RA antibody comprising a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10.
[0306]
[132] The lyophilized preparation according to
[130] or
[131] , wherein the anti-IL-31RA neutralizing antibody is an IgG antibody, preferably an IgG2 antibody.
[0307]
[133] The lyophilized preparation according to any one of
[130] to
[132] , wherein the anti-IL-31RA neutralizing antibody is Nemolizumab.
[0308]
[134] The preparation according to any one of [1] to
[133] , which is used for preventing and / or treating IL-31-related diseases or symptoms accompanying said diseases.
[0309]
[135] The preparation according to
[134] , wherein the IL-31-related disease is an inflammatory disease related to IL-31 signal transduction.
[0310]
[136] The preparation according to
[135] , wherein the inflammatory disease is selected from the group consisting of atopic dermatitis, dialysis-induced pruritus, and prurigo nodularis.
[0311]
[137] The preparation according to any one of [1] to
[136] , wherein the IL-31 antagonist is administered subcutaneously.
[0312]
[138] A method for stabilizing an antibody in an antibody-containing preparation, comprising preparing an antibody-containing solution comprising arginine and / or its salt, and / or sucrose and / or trehalose, wherein in said solution, the molar ratio of the arginine and / or its salt to the antibody is from 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is from 370:1 to 1840:1.
[0313]
[139] The method according to
[138] , wherein the antibody-containing solution further comprises 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.
[0314]
[140] The method according to
[138] or
[139] , further comprising preparing an antibody-containing lyophilized preparation by lyophilizing the antibody-containing solution.
[0315]
[141] Use of arginine and / or its salt, and / or sucrose and / or trehalose for stabilizing an antibody in an antibody-containing preparation, comprising preparing an antibody-containing solution comprising arginine and / or its salt, and / or sucrose and / or trehalose, wherein in said solution, the molar ratio of the arginine and / or its salt to the antibody is from 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is from 370:1 to 1840:1.
[0316]
[142] The use according to
[141] , wherein the antibody-containing solution further comprises 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.
[0317]
[143] The use described in
[141] or
[142] further includes preparing a lyophilized antibody-containing preparation by lyophilizing the antibody-containing solution.
[0318]
[144] A method for inhibiting antibody aggregation (aggregate formation) in an antibody-containing preparation, including preparing an antibody-containing solution containing arginine and / or its salt, and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is 370:1 to 1840:1.
[0319]
[145] The method described in
[144] , wherein the antibody-containing solution further contains 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.
[0320]
[146] The method described in
[144] or
[145] further includes preparing a lyophilized antibody-containing preparation by lyophilizing the antibody-containing solution.
[0321]
[147] The use of arginine and / or its salt, and / or sucrose and / or trehalose for inhibiting antibody aggregation (aggregate formation) in an antibody-containing preparation, including preparing an antibody-containing solution containing arginine and / or its salt and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is 370:1 to 1840:1.
[0322]
[148] The use described in
[147] , wherein the antibody-containing solution further contains 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.
[0323]
[149] The use described in
[147] or
[148] further includes preparing a lyophilized antibody-containing preparation by lyophilizing the antibody-containing solution.
[0324]
[150] A method for reducing components with charge heterogeneity in an antibody-containing preparation, including preparing an antibody-containing solution containing arginine and / or its salt, and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is 370:1 to 1840:1.
[0325]
[151]
[150] The method as described above, wherein the antibody-containing solution further comprises 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.
[0326]
[152] The method as described in
[150] or
[151] , further comprising preparing an antibody-containing lyophilized preparation by lyophilizing the antibody-containing solution.
[0327]
[153] Use of arginine and / or its salt, and / or sucrose and / or trehalose in reducing components with charge heterogeneity in an antibody-containing preparation, including preparing an antibody-containing solution comprising arginine and / or its salt and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is 370:1 to 1840:1.
[0328]
[154] The use as described in
[153] , wherein the antibody-containing solution further comprises 6 to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL poloxamer 188.
[0329]
[155] The use as described in
[153] or
[154] , further comprising preparing an antibody-containing lyophilized preparation by lyophilizing the antibody-containing solution.
[0330]
[156] A method for preventing and / or treating IL-31-related diseases, comprising administering an IL-31 antagonist to a subject suffering from or at risk of suffering from an IL-31-related disease, the method comprising:
[0331] Preparing a lyophilized preparation by lyophilizing a solution comprising 6 to 100 mg / mL IL-31 antagonist, 45 to 150 mmol / L arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L sucrose or trehalose; preparing a reconstituted solution by reconstituting the lyophilized preparation in water; and administering the reconstituted solution to the subject.
[0332]
[157] Use of an IL-31 antagonist in the preparation of a drug for preventing and / or treating IL-31-related diseases, characterized in that a lyophilized preparation is prepared by lyophilizing a solution comprising 6 to 100 mg / mL IL-31 antagonist, 45 to 150 mmol / L arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L sucrose or trehalose.
[0333]
[158] An IL-31 antagonist for preventing and / or treating IL-31 related disorders, characterized in that a lyophilized preparation produced from a solution containing 6 to 100 mg / mL of the IL-31 antagonist, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose is reconstituted in water before use.
[0334]
[159] The method as described in
[156] , the use as described in
[157] , or the IL-31 antagonist as described in
[158] , wherein the solution before lyophilization further contains 6 to 20 mmol / L of tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.
[0335]
[160] An injectable preparation or kit, comprising (i) a container, (ii) the lyophilized preparation as described in any one of [1] to
[12] and
[25] to
[137] , and (iii) water for injection for reconstituting the lyophilized preparation.
[0336]
[161] An injectable preparation, comprising (i) a container, (ii) the lyophilized preparation in the container, the lyophilized preparation being produced by lyophilizing a solution containing 6 to 100 mg / mL of an anti-IL-31RA neutralizing antibody, 45 to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 to 250 mmol / L of sucrose or trehalose, and (iii) optionally, water for injection for reconstituting the lyophilized preparation.
[0337]
[162] The injectable preparation as described in
[161] , wherein the solution before lyophilization further contains 6 to 20 mmol / L of tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl) buffer and 0.15 to 0.50 mg / mL of poloxamer 188.
[0338]
[163] An injectable preparation, comprising (i) a container, (ii) the lyophilized preparation in the container, the lyophilized preparation being produced by lyophilizing a solution containing an effective amount of an anti-IL-31RA neutralizing antibody and 220 to 1100 moles of arginine hydrochloride (Arg-HCl) and 370 to 1840 moles of sucrose or trehalose per 1 mole of the antibody, and (iii) optionally, water for injection for reconstituting the lyophilized preparation.
[0339]
[164] The injectable preparation or kit as described in any one of
[160] to
[163] , wherein the lyophilized preparation and the water for injection are encapsulated in separate compartments in the container.
[0340]
[165] The injectable preparation or kit according to any one of
[160] to
[164] , wherein the lyophilized preparation is reconstituted with the water for injection in the container during use. Detailed implementation manners
[0341] Preferred non-limiting embodiments of the present disclosure will be described below.
[0342] The description of all embodiments set forth in the following examples is intended such that, in countries where the protection of this patent application is sought, they are naturally construed as equivalently described in the "Description of Embodiments" of this specification, and are not limited by any patent practice, convention or law that may interpret the content of the examples in a restrictive manner.
[0343] For the description of numerical values in the present disclosure, the numerical value of the least significant digit (e.g., the units digit) may include a rounded value that is one digit smaller than the least significant digit (e.g., when the least significant digit is the units digit, one digit after the decimal point). For example, the numerical value "5" is intended to include numerical values within the range of 4.5 to 5.4.
[0344] In a non-limiting embodiment, the present disclosure relates to a lyophilized preparation comprising an IL-31 antagonist as an active ingredient, the lyophilized preparation comprising arginine and / or its salt, and sucrose and / or trehalose. In another non-limiting embodiment, the present disclosure relates to a solution preparation comprising an IL-31 antagonist as an active ingredient, the solution preparation comprising arginine and / or its salt. The arginine is preferably L-arginine. In one embodiment, the arginine and / or its salt is arginine hydrochloride, L-arginine hydrochloride, arginine-aspartate, L-arginine-aspartate, arginine-glutamate or L-arginine-glutamate. Those skilled in the art will understand that when referring to the weight of arginine (e.g., mg), the weight may be the weight of free arginine or the weight of arginine contained in a salt containing arginine. Further, in the present disclosure, the weight or concentration of arginine may be the sum of the weight or concentration of free arginine and the weight or concentration of arginine contained in a salt containing arginine. In one embodiment, the preparation of the present disclosure further comprises Tris buffer as a buffering agent. In one embodiment, the Tris buffer is tris(hydroxymethyl)aminomethane and / or its salt, such as tris(hydroxymethyl)aminomethane-hydrochloride (Tris-HCl), tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate, or tris(hydroxymethyl)aminomethane-acetate. In one embodiment, the preparation of the present disclosure further comprises poloxamer 188 or polysorbate as a nonionic surfactant. Poloxamer 188 may be referred to as "polyoxyethylene(160)polyoxypropylene(30)glycol" in the Japanese Pharmacopoeia standard. In one embodiment, the polysorbate is polysorbate 20 or polysorbate 80. In one embodiment, the pH of the reconstituted solution after reconstituting the lyophilized preparation of the present disclosure in water is from 6 to 8, such as from 6.5 to 7.5, such as from 6.7 to 7.3, and such as 7. In one embodiment, the pH of the solution preparation of the present disclosure is from 6 to 8, such as from 6.5 to 7.5, such as 7. At the same time, tris(hydroxymethyl)aminomethane is referred to as "aminobutanetriol" in the Japanese Pharmacopoeia standard. Those skilled in the art will understand that when referring to the weight of tris(hydroxymethyl)aminomethane (e.g., mg), the weight may be the weight of free tris(hydroxymethyl)aminomethane or the weight of tris(hydroxymethyl)aminomethane contained in a salt containing tris(hydroxymethyl)aminomethane. Further, in the present disclosure, the weight or concentration of tris(hydroxymethyl)aminomethane may be the sum of the weight or concentration of free tris(hydroxymethyl)aminomethane and the weight or concentration of tris(hydroxymethyl)aminomethane contained in a salt containing tris(hydroxymethyl)aminomethane).
[0345] The amount and concentration of the IL-31 antagonist contained in the formulations of the present disclosure are not particularly limited and can be appropriately adjusted according to the subject to be administered, for example, whether the formulation is for adults or children, or whether the formulation is for prophylaxis or treatment, or depending on the type, severity, etc. of the condition or symptom to be prevented or treated. Therefore, the molar ratio and weight ratio of the IL-31 antagonist to another component contained in the formulations of the present disclosure can be different values. In non-limiting embodiments, the molar ratio of arginine and / or its salt to the IL-31 antagonist is from 3:1 to 220500:1, such as from 22:1 to 6600:1, from 33:1 to 5500:1, from 44:1 to 4400:1, from 55:1 to 3300:1, from 110:1 to 2200:1, from 220:1 to 1100:1, from 220:1 to 880:1, from 220:1 to 440:1 or from 440:1 to 880:1. In non-limiting embodiments, the weight ratio of arginine to the IL-31 antagonist is from 0.004:1 to 261:1, such as from 0.03:1 to 9.6:1, from 0.1:1 to 4.8:1, from 0.2:1 to 3.2:1, from 0.3:1 to 1.6:1, from 0.3:1 to 1.3:1, from 0.3:1 to 1.1:1, from 0.5:1 to 1.1:1 or from 0.3:1 to 0.5:1. In non-limiting embodiments, the molar ratio of sucrose or trehalose to the IL-31 antagonist is from 6:1 to 367500:1, such as from 75:1 to 7360:1, from 100:1 to 5520:1, from 150:1 to 3680:1, from 300:1 to 1840:1, from 370:1 to 1840:1, from 370:1 to 1470:1, from 740:1 to 1470:1 or from 370:1 to 740:1. In non-limiting embodiments, the weight ratio of sucrose or trehalose to the IL-31 antagonist is from 0.013:1 to 856:1, such as from 0.18:1 to 16.8:1, from 0.23:1 to 12.6:1, from 0.35:1 to 8.4:1, from 0.7:1 to 4.2:1, from 0.8:1 to 4.3:1, from 0.8:1 to 3.5:1, from 1.7:1 to 3.5:1 or from 0.8:1 to 1.7:1. Also, in the Japanese Pharmacopoeia standard, sucrose is called "Seisei Hakutou (purified sucrose)".
[0346] In a non-limiting embodiment, the concentration of the IL-31 antagonist in the formulation of the present disclosure in solution state (i.e., the concentration in the solution formulation, the concentration in the solution before lyophilization of the lyophilized solution, or the concentration in the solution after reconstitution of the lyophilized formulation) is from 1 mg / mL to 200 mg / mL, such as from 2 mg / mL to 200 mg / mL, from 3 mg / mL to 200 mg / mL, from 3 mg / mL to 150 mg / mL, from 6 mg / mL to 100 mg / mL, from 10 mg / mL to 100 mg / mL, from 15 mg / mL to 100 mg / mL, from 30 mg / mL to 100 mg / mL, from 50 mg / mL to 100 mg / mL, from 6 mg / mL to 70 mg / mL, from 10 mg / mL to 70 mg / mL, from 15 mg / mL to 70 mg / mL, from 30 mg / mL to 70 mg / mL, from 50 mg / mL to 70 mg / mL, from 6 mg / mL to 50 mg / mL, from 10 mg / mL to 50 mg / mL, from 30 mg / mL to 50 mg / mL, or from 6 mg / mL to 30 mg / mL.
[0347] In one embodiment, the concentration of arginine and / or its salt in the formulation of the present disclosure in solution state is from 4.5 mmol / L to 1500 mmol / L, such as from 9 mmol / L to 750 mmol / L, from 15 mmol / L to 450 mmol / L, from 22.5 mmol / L to 300 mmol / L, from 45 mmol / L to 150 mmol / L, from 75 mmol / L to 150 mmol / L, or from 45 mmol / L to 75 mmol / L.
[0348] In one embodiment, the concentration of sucrose and / or trehalose in the formulation of the present disclosure in solution state is from 7.5 mmol / L to 2500 mmol / L, such as from 15 mmol / L to 1250 mmol / L, from 25 mmol / L to 750 mmol / L, from 37.5 mmol / L to 500 mmol / L, from 75 mmol / L to 250 mmol / L, from 125 mmol / L to 250 mmol / L, from 75 mmol / L to 170 mmol / L, from 125 mmol / L to 170 mmol / L, or from 75 mmol / L to 125 mmol / L.
[0349] In one embodiment, the concentration of Tris buffer in the formulations of the present disclosure in solution state is from 1 mmol / L to 200 mmol / L, such as from 1 mmol / L to 100 mmol / L, from 2 mmol / L to 60 mmol / L, from 3 mmol / L to 40 mmol / L, from 6 mmol / L to 20 mmol / L, from 3 mmol / L to 15 mmol / L, from 10 mmol / L to 20 mmol / L, from 10 mmol / L to 15 mmol / L, from 6 mmol / L to 15 mmol / L, or from 6 mmol / L to 10 mmol / L.
[0350] In one embodiment, the concentration of poloxamer 188 or polysorbate in the formulations of the present disclosure in solution state is from 0.015 mg / mL to 5 mg / mL, such as from 0.03 mg / mL to 2.5 mg / mL, from 0.05 mg / mL to 1.5 mg / mL, from 0.075 mg / mL to 1 mg / mL, from 0.15 mg / mL to 0.5 mg / mL, from 0.15 mg / mL to 0.4 mg / mL, from 0.25 mg / mL to 0.5 mg / mL, or from 0.15 mg / mL to 0.25 mg / mL.
[0351] In one embodiment, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:
[0352] 1 mg / mL to 200 mg / mL IL-31 antagonist;
[0353] 1 mmol / L to 200 mmol / L Tris buffer;
[0354] 4.5 mmol / L to 1500 mmol / L arginine or its salt;
[0355] 7.5 mmol / L to 2500 mmol / L sucrose or trehalose; and
[0356] 0.01 mg / mL to 5 mg / mL poloxamer 188 or polysorbate 20,
[0357] wherein, when the formulation is reconstituted in water, the pH is from 6 to 8, such as from 6.5 to 7.5, such as 7.
[0358] In certain embodiments, the lyophilized formulation of the present disclosure is a composition produced by lyophilizing a solution comprising:
[0359] IL-31 antagonist from 6 mg / mL to 100 mg / mL;
[0360] Tris buffer from 6 mmol / L to 20 mmol / L;
[0361] Arginine or its salt from 45 mmol / L to 150 mmol / L;
[0362] Sucrose or trehalose from 75 mmol / L to 250 mmol / L; and
[0363] Poloxamer 188 or polysorbate 20 from 0.15 mg / mL to 0.50 mg / mL,
[0364] wherein, when the preparation is reconstituted in water, the pH is from 6 to 8, such as from 6.5 to 7.5, such as 7.
[0365] In certain embodiments, the lyophilized preparation of the present disclosure is a composition produced from a lyophilized solution, the solution comprising, per vial, cartridge or syringe:
[0366] 1 mg to 800 mg of IL-31 antagonist;
[0367] 0.1 mg to 40 mg of tris(hydroxymethyl)aminomethane;
[0368] 0.8 mg to 400 mg of arginine;
[0369] 3 mg to 1100 mg of sucrose or trehalose; and
[0370] 0.01 mg to 7 mg of poloxamer 188 or polysorbate 20,
[0371] wherein, when the preparation is reconstituted in water, the pH is from 6 to 8, such as from 6.5 to 7.5, such as 7.
[0372] In certain embodiments, the lyophilized preparation of the present disclosure is a composition produced from a lyophilized solution, the solution comprising, per vial, cartridge or syringe:
[0373] 10 mg to 80 mg of IL-31 antagonist;
[0374] 0.8 mg to 4 mg of tris(hydroxymethyl)aminomethane;
[0375] 8 mg to 40 mg of arginine;
[0376] 30 mg to 110 mg of sucrose or trehalose; and
[0377] 0.1 mg to 0.7 mg of poloxamer 188 or polysorbate 20,
[0378] Among them, when the preparation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.
[0379] In one embodiment, the lyophilized preparation of the present disclosure is a composition produced from a lyophilized solution, and the solution contains:
[0380] 61 mg / mL to 75 mg / mL, such as 68 mg / mL anti-IL-31RA neutralizing antibody;
[0381] 11 mmol / L to 16 mmol / L, such as 13.6 mmol / L Tris-HCl;
[0382] 82 mmol / L to 122 mmol / L, such as 102 mmol / L Arg-HCl;
[0383] 153 mmol / L to 187 mmol / L, such as 170 mmol / L sucrose or trehalose; and
[0384] 0.17 mg / mL to 0.51 mg / mL, such as 0.34 mg / mL poloxamer 188 or polysorbate 20,
[0385] Among them, when the preparation is reconstituted in water, the pH is 6 to 8, such as 6.5 to 7.5, such as 7.
[0386] In another embodiment, the lyophilized preparation of the present disclosure is a composition produced from a lyophilized solution, and the solution contains:
[0387] 45 mg / mL to 55 mg / mL, such as 50 mg / mL anti-IL-31RA neutralizing antibody;
[0388] 8 mmol / L to 12 mmol / L, such as 10 mmol / L Tris-HCl;
[0389] 60 mmol / L to 90 mmol / L, such as 75 mmol / L Arg-HCl;
[0390] 113 mmol / L to 138 mmol / L, such as 125 mmol / L sucrose or trehalose; and
[0391] 0.13 mg / mL to 0.38 mg / mL, such as 0.25 mg / mL poloxamer 188 or polysorbate 20,
[0392] Wherein, when the formulation is reconstituted in water, the pH is from 6 to 8, such as from 6.5 to 7.5, such as 7.
[0393] In yet another embodiment, the lyophilized formulation of the present disclosure is a composition produced from a lyophilized solution comprising:
[0394] 14 mg / mL to 17 mg / mL, such as 15 mg / mL of an anti-IL-31RA neutralizing antibody;
[0395] 5 mmol / L to 7 mmol / L, such as 6 mmol / L of Tris-HCl;
[0396] 36 mmol / L to 54 mmol / L, such as 45 mmol / L of Arg-HCl;
[0397] 68 mmol / L to 83 mmol / L, such as 75 mmol / L of sucrose or trehalose; and
[0398] 0.08 mg / mL to 0.23 mg / mL, such as 0.15 mg / mL of poloxamer 188 or polysorbate 20,
[0399] Wherein, when the formulation is reconstituted in water, the pH is from 6 to 8, such as from 6.5 to 7.5, such as 7.
[0400] In a further embodiment, the lyophilized formulation of the present disclosure is a composition produced from a lyophilized solution comprising:
[0401] 7 mg / mL to 8 mg / mL, such as 7.5 mg / mL of an anti-IL-31RA neutralizing antibody;
[0402] 5 mmol / L to 7 mmol / L, such as 6 mmol / L of Tris-HCl;
[0403] 36 mmol / L to 54 mmol / L, such as 45 mmol / L of Arg-HCl;
[0404] 68 mmol / L to 83 mmol / L, such as 75 mmol / L of sucrose or trehalose; and
[0405] 0.08 mg / mL to 0.23 mg / mL, such as 0.15 mg / mL of poloxamer 188 or polysorbate 20,
[0406] Wherein, when the formulation is reconstituted in water, the pH is from 6 to 8, such as from 6.5 to 7.5, such as 7.
[0407] The amount of each ingredient contained in the lyophilized preparation of the present disclosure can also be expressed as the weight (mass) per container, such as a vial, cartridge, and syringe. The container can contain a single-dose or multi-dose (e.g., two doses, three doses, four doses, etc.) preparation. For example, the container contains a single-dose preparation. Multiple containers can also be used for a single dose. The dose administered each time can be appropriately determined according to the administration method (e.g., subcutaneous administration), target disease (e.g., atopic dermatitis), purpose of use (e.g., for prevention or treatment), patient type (e.g., adult or child), patient condition (e.g., severity of itching), etc. Accordingly, the amount of a solvent such as water to be added to the container for reconstituting the lyophilized preparation can be appropriately determined. When the preparation is administered subcutaneously, the liquid volume of a single dose (in the case of the lyophilized preparation, the liquid volume to be administered after reconstitution with water) can be, for example, 0.1 mL to 10 mL, 0.2 mL to 5 mL, 0.2 mL to 1.6 mL, 0.5 mL to 2 mL, 0.8 mL to 1.2 mL, or 0.9 mL to 1.1 mL, such as 1.0 mL, but is not limited thereto. It should be noted that those skilled in the art will understand that the container may be filled with the preparation to ensure that an amount sufficient for administering a single dose or multi-dose of the IL-31 antagonist can be obtained from one container (e.g., vial, cartridge, or syringe), taking into account the loss of the liquid medicine during administration.
[0408] In one embodiment, the lyophilized preparation of the present disclosure comprises, per container such as a syringe:
[0409] 68 mg to 83 mg, such as 75 mg of an anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody, which comprises the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0410] 1.4 mg to 2.2 mg, such as 1.8 mg of tris(hydroxymethyl)aminomethane;
[0411] 15 mg to 23 mg, such as 19 mg of arginine;
[0412] 58 mg to 70 mg, such as 64 mg of sucrose; and
[0413] 0.2 mg to 0.6 mg, such as 0.4 mg of poloxamer 188.
[0414] In the above embodiment, regarding the description of numerical values, it is intended that the numerical value of the least significant digit (e.g., the units digit) includes the value rounded up or down by one digit smaller than the least significant digit (e.g., when the least significant digit is the units digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure can also be said to comprise, per container such as a syringe:
[0415] 75 mg (74.5 mg to 75.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0416] 1.8 mg (1.75 mg to 1.84 mg) of tris(hydroxymethyl)aminomethane;
[0417] 19 mg (18.5 mg to 19.4 mg) of arginine;
[0418] 64 mg (63.5 mg to 64.4 mg) of sucrose; and
[0419] 0.4 mg (0.35 mg to 0.44 mg) of poloxamer 188.
[0420] In addition, in the above embodiments, the weight of the above tris(hydroxymethyl)aminomethane may be the sum of the weight of free tris(hydroxymethyl)aminomethane and the weight of tris(hydroxymethyl)aminomethane contained in tris(hydroxymethyl)aminomethane hydrochloride (which may be added as a pH regulator). In addition, the above arginine may be added as a salt containing arginine (for example, arginine hydrochloride). Those skilled in the art will understand that when a salt containing arginine is added, the weight of the above arginine is the weight of arginine contained in the salt.
[0421] Therefore, the lyophilized preparation of the present disclosure may also be referred to as containing, per container such as a syringe:
[0422] 75 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0423] 0.24 mg of tris(hydroxymethyl)aminomethane;
[0424] 23.6 mg of L-arginine hydrochloride;
[0425] 63.9 mg of sucrose;
[0426] 0.37 mg of poloxamer 188; and
[0427] Tris(hydroxymethyl)aminomethane hydrochloride as a pH regulator.
[0428] In another embodiment, the lyophilized preparation of the present disclosure contains, per container such as a syringe:
[0429] 35 mg to 43 mg, for example 39 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0430] From 0.7 mg to 1.1 mg, such as 0.9 mg of tris(hydroxymethyl)aminomethane;
[0431] From 8 mg to 12 mg, such as 10 mg of arginine;
[0432] From 30 mg to 36 mg, such as 33 mg of sucrose; and
[0433] From 0.1 mg to 0.3 mg, such as 0.2 mg of poloxamer 188.
[0434] In the above embodiments, for the description of numerical values, it is intended that the numerical value of the least significant digit (e.g., the units digit) includes the rounded value of one digit smaller than the least significant digit (e.g., when the least significant digit is the units digit, the first decimal digit). More specifically, the lyophilized preparation of the present disclosure may also be referred to as containing per container, for example a syringe:
[0435] 39 mg (from 38.5 mg to 39.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0436] 0.9 mg (from 0.85 mg to 0.94 mg) of tris(hydroxymethyl)aminomethane;
[0437] 10 mg (from 9.5 mg to 10.4 mg) of arginine;
[0438] 33 mg (from 32.5 mg to 33.4 mg) of sucrose; and
[0439] 0.2 mg (from 0.15 mg to 0.24 mg) of poloxamer 188.
[0440] In a further embodiment, the lyophilized preparation of the present disclosure contains, per container, for example a cartridge:
[0441] From 32 mg to 40 mg, such as 36 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0442] From 0.7 mg to 1.1 mg, such as 0.9 mg of tris(hydroxymethyl)aminomethane;
[0443] From 7 mg to 11 mg, such as 9 mg of arginine;
[0444] From 28 mg to 34 mg, such as 31 mg of sucrose; and
[0445] From 0.1 mg to 0.3 mg, such as 0.2 mg of poloxamer 188.
[0446] In the above embodiments, the description of numerical values is intended to include the rounded values of one digit smaller than the least significant digit (e.g., the units digit). More specifically, the lyophilized formulation of the present disclosure can also be referred to as containing per container, such as a cartridge:
[0447] 36 mg (from 35.5 mg to 36.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0448] 0.9 mg (from 0.85 mg to 0.94 mg) of tris(hydroxymethyl)aminomethane;
[0449] 9 mg (from 8.5 mg to 9.4 mg) of arginine;
[0450] 31 mg (from 30.5 mg to 31.4 mg) of sucrose; and
[0451] 0.2 mg (from 0.15 mg to 0.24 mg) of poloxamer 188.
[0452] In yet another embodiment, the lyophilized formulation of the present disclosure contains, per container such as a vial:
[0453] 46 mg to 56 mg, such as 51 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0454] 2.0 mg to 3.0 mg, such as 2.5 mg of tris(hydroxymethyl)aminomethane;
[0455] 22 mg to 32 mg, such as 27 mg of arginine;
[0456] 79 mg to 97 mg, such as 88 mg of sucrose; and
[0457] 0.3 mg to 0.8 mg, such as 0.5 mg of poloxamer 188.
[0458] In the above embodiments, the description of numerical values is intended to include the rounded values of one digit smaller than the least significant digit (e.g., the units digit). More specifically, the lyophilized formulation of the present disclosure can also be referred to as containing per container, such as a vial:
[0459] 51 mg (50.5 mg to 51.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0460] 2.5 mg (2.45 mg to 2.54 mg) of tris(hydroxymethyl)aminomethane;
[0461] 27 mg (26.5 mg to 27.4 mg) of arginine;
[0462] 88 mg (87.5 mg to 88.4 mg) of sucrose; and
[0463] 0.5 mg (0.45 mg to 0.54 mg) of poloxamer 188.
[0464] In addition, in another embodiment, the lyophilized formulation of the present disclosure comprises, per container such as a vial:
[0465] 27 mg to 33 mg, such as 30 mg of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0466] 2.4 mg to 3.6 mg, such as 3.0 mg of tris(hydroxymethyl)aminomethane;
[0467] 26 mg to 38 mg, such as 32 mg of arginine;
[0468] 94 mg to 114 mg, such as 104 mg of sucrose; and
[0469] 0.3 mg to 0.9 mg, such as 0.6 mg of poloxamer 188.
[0470] In the above embodiments, with respect to the description of numerical values, it is intended that the numerical values of the least significant digit (e.g., the units digit) include the rounded values of one digit less than the least significant digit (e.g., when the least significant digit is the units digit, the first decimal digit). More specifically, the lyophilized formulation of the present disclosure may also be referred to as comprising, per container such as a vial:
[0471] 30 mg (29.5 mg to 30.4 mg) of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0472] 3.0 mg (2.95 mg to 3.04 mg) of tris(hydroxymethyl)aminomethane;
[0473] 32 mg (31.5 mg to 32.4 mg) of arginine;
[0474] 104 mg (103.5 mg to 104.4 mg) of sucrose; and
[0475] 0.6 mg (0.55 mg to 0.64 mg) of poloxamer 188.
[0476] In yet another embodiment, the lyophilized formulation of the present disclosure comprises, per container such as a vial:
[0477] 17 mg to 21 mg, such as 19 mg of an anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody, which comprises the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0478] 1.5 mg to 2.3 mg, such as 1.9 mg of tris(hydroxymethyl)aminomethane;
[0479] 16 mg to 24 mg, such as 20 mg of arginine;
[0480] 59 mg to 73 mg, such as 66 mg of sucrose; and
[0481] 0.2 mg to 0.6 mg, such as 0.4 mg of poloxamer 188.
[0482] In the above embodiments, for the description of numerical values, it is intended that the numerical value of the least significant digit (e.g., the units digit) includes the rounded value one digit smaller than the least significant digit (e.g., when the least significant digit is the units digit, the first decimal digit). More specifically, the lyophilized formulation of the present disclosure may also be referred to as comprising, per container such as a vial:
[0483] 19 mg (18.5 mg to 19.4 mg) of an anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody, which comprises the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0484] 1.9 mg (1.85 mg to 1.94 mg) of tris(hydroxymethyl)aminomethane;
[0485] 20 mg (19.5 mg to 20.4 mg) of arginine;
[0486] 66 mg (65.5 mg to 66.4 mg) of sucrose; and
[0487] 0.4 mg (0.35 mg to 0.44 mg) of poloxamer 188.
[0488] In a further embodiment, the lyophilized formulation of the present disclosure comprises, per container such as a vial:
[0489] 13 mg to 15 mg, such as 14 mg of an anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0490] 1.0 mg to 1.6 mg, such as 1.3 mg of tris(hydroxymethyl)aminomethane;
[0491] 12 mg to 18 mg, such as 15 mg of arginine;
[0492] 42 mg to 52 mg, such as 47 mg of sucrose; and
[0493] 0.2 mg to 0.5 mg, such as 0.3 mg of poloxamer 188.
[0494] In the above embodiment, with respect to the description of numerical values, it is intended that the numerical value of the least significant digit (e.g., the units digit) includes the rounded value of one digit smaller than the least significant digit (e.g., when the least significant digit is the units digit, the first decimal digit). More specifically, the lyophilized formulation of the present disclosure can also be referred to as comprising, per container such as a vial:
[0495] 14 mg (13.5 mg to 14.4 mg) of an anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0496] 1.3 mg (1.25 mg to 1.34 mg) of tris(hydroxymethyl)aminomethane;
[0497] 15 mg (14.5 mg to 15.4 mg) of arginine;
[0498] 47 mg (46.5 mg to 47.4 mg) of sucrose; and
[0499] 0.3 mg (0.25 mg to 0.34 mg) of poloxamer 188.
[0500] In one embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstituted solution comprises:
[0501] 90 mg / mL to 110 mg / mL, such as 100 mg / mL of an anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0502] 16 mmol / L to 24 mmol / L, such as 20 mmol / L Tris-HCl;
[0503] 120 mmol / L to 180 mmol / L, such as 150 mmol / L Arg-HCl;
[0504] 225 mmol / L to 275 mmol / L, such as 250 mmol / L sucrose or trehalose; and
[0505] 0.25 mg / mL to 0.75 mg / mL, such as 0.50 mg / mL poloxamer 188 or polysorbate 20,
[0506] wherein the pH is from 6 to 8, such as from 6.7 to 7.3, such as 7.
[0507] In another embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstitution solution comprises:
[0508] 55 mg / mL to 68 mg / mL, such as 61.5 mg / mL anti-IL-31RA neutralizing antibody (anti-IL-31RA antibody, which comprises the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0509] 10 mmol / L to 15 mmol / L, such as 12.3 mmol / L Tris-HCl;
[0510] 74 mmol / L to 110 mmol / L, such as 92 mmol / L Arg-HCl;
[0511] 139 mmol / L to 169 mmol / L, such as 154 mmol / L sucrose or trehalose; and
[0512] 0.16 mg / mL to 0.47 mg / mL, such as 0.31 mg / mL poloxamer 188 or polysorbate 20,
[0513] wherein the pH is from 6 to 8, such as from 6.7 to 7.3, such as 7.
[0514] In addition, in another embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstitution solution comprises:
[0515] From 45 mg / mL to 55 mg / mL, such as 50 mg / mL of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0516] From 16 mmol / L to 24 mmol / L, such as 20 mmol / L of Tris-HCl;
[0517] From 120 mmol / L to 180 mmol / L, such as 150 mmol / L of Arg-HCl;
[0518] From 225 mmol / L to 275 mmol / L, such as 250 mmol / L of sucrose or trehalose; and
[0519] From 0.25 mg / mL to 0.75 mg / mL, such as 0.50 mg / mL of poloxamer 188 or polysorbate 20,
[0520] wherein the pH is from 6 to 8, such as from 6.7 to 7.3, such as 7.
[0521] In yet another embodiment, with respect to the lyophilized formulation of the present disclosure, when the formulation is reconstituted in water, the reconstituted solution comprises:
[0522] From 23 mg / mL to 28 mg / mL, such as 25 mg / mL of an anti-IL-31RA neutralizing antibody (an anti-IL-31RA antibody comprising the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10);
[0523] From 16 mmol / L to 24 mmol / L, such as 20 mmol / L of Tris-HCl;
[0524] From 120 mmol / L to 180 mmol / L, such as 150 mmol / L of Arg-HCl;
[0525] From 225 mmol / L to 275 mmol / L, such as 250 mmol / L of sucrose or trehalose; and
[0526] From 0.25 mg / mL to 0.75 mg / mL, such as 0.50 mg / mL of poloxamer 188 or polysorbate 20,
[0527] wherein the pH is from 6 to 8, such as from 6.7 to 7.3, such as 7.
[0528] Exemplary embodiments of the formulations of the present disclosure include, but are not limited to, the following formulations:
[0529]
[0530]
[0531] In non-limiting embodiments, the formulations of the present disclosure can be used for the prevention and / or treatment of IL-31 related disorders or their accompanying symptoms. In one embodiment, the IL-31 related disorder is an inflammatory disorder related to IL-31 signaling. In a particular embodiment, the IL-31 related disorder is atopic dermatitis, pruritus (e.g., dialysis pruritus or pruritus caused by atopic dermatitis), or prurigo nodularis. In another particular embodiment, the treatment of the IL-31 related disorder or its accompanying symptoms is to improve sleep disorders caused by pruritus (e.g., increasing the time from falling asleep to waking up and / or reducing the sleep latency (the time from going to bed to falling asleep)). In another embodiment, the treatment of the IL-31 related disorder or its accompanying symptoms is to inhibit at least one symptom caused by atopic dermatitis selected from the group consisting of redness, induration, papules, edema, epidermal exfoliation, and lichenification. In a particular embodiment, the atopic dermatitis is moderate or severe atopic dermatitis that is not sufficiently effective or not tolerable for topical treatment (e.g., treatment with topical steroids or topical calcineurin inhibitors). In one embodiment, the formulation of the present disclosure is a formulation for parenteral administration, e.g., for intravenous administration or for subcutaneous administration.
[0532] In non-limiting embodiments, the present disclosure relates to methods for stabilizing antibodies in antibody-containing formulations, the methods comprising preparing an antibody-containing solution comprising arginine and / or its salts, and / or sucrose and / or trehalose, wherein the molar ratio of arginine and / or its salts to the antibody in the solution is from 220:1 to 1100:1, and the molar ratio of sucrose or trehalose to the antibody is from 370:1 to 1840:1. In another non-limiting embodiment, the present disclosure relates to methods for inhibiting antibody aggregation (aggregate formation) in antibody-containing formulations, the methods comprising preparing an antibody-containing lyophilized formulation by lyophilizing an antibody-containing solution, the antibody-containing solution comprising 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose. In a further non-limiting embodiment, the present disclosure relates to methods for reducing components having charge heterogeneity in an antibody-containing lyophilized formulation, the methods comprising preparing an antibody-containing lyophilized formulation by lyophilizing an antibody-containing solution, the antibody-containing solution comprising 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose. In one embodiment, the antibody-containing solution prior to lyophilization further comprises 6 mmol / L to 20 mmol / L tris(hydroxymethyl)aminomethane-hydrochloride and 0.15 mg / mL to 0.50 mg / mL poloxamer 188.
[0533] In non-limiting embodiments, the present disclosure relates to methods for preventing and / or treating IL-31 related disorders, comprising administering an IL-31 antagonist to a subject having or at risk of having an IL-31 related disorder, the methods comprising preparing a lyophilized formulation by lyophilizing a solution comprising 6 mg / mL to 100 mg / mL IL-31 antagonist, 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose; preparing a reconstituted solution by reconstituting the lyophilized formulation; and administering the reconstituted solution to the subject.
[0534] In non-limiting embodiments, the present disclosure relates to the use of an IL-31 antagonist in the preparation of a medicament for preventing and / or treating an IL-31 related disorder, characterized in that a lyophilized formulation is prepared by lyophilizing a solution comprising 6 mg / mL to 100 mg / mL IL-31 antagonist, 45 mmol / L to 150 mmol / L arginine hydrochloride (Arg-HCl) and 75 mmol / L to 250 mmol / L sucrose or trehalose.
[0535] In a non-limiting embodiment, the present disclosure relates to an IL-31 antagonist for preventing and / or treating IL-31-related disorders, characterized in that a lyophilized preparation produced from a lyophilized solution containing 6 mg / mL to 100 mg / mL of the IL-31 antagonist, 45 mmol / L to 150 mmol / L of arginine hydrochloride (Arg-HCl), and 75 mmol / L to 250 mmol / L of sucrose or trehalose is reconstituted and used.
[0536] In one embodiment, the solution before lyophilization may further contain 6 mmol / L to 20 mmol / L of tris(hydroxymethyl)aminomethane hydrochloride and 0.15 mg / mL to 0.50 mg / mL of poloxamer 188.
[0537] In a non-limiting embodiment, the present disclosure relates to an injectable preparation or kit, which comprises (i) a container; (ii) the lyophilized preparation of the present disclosure; and (iii) optionally water for injection for reconstituting the lyophilized preparation. In one embodiment, the container of the injectable preparation or kit of the present disclosure is a glass syringe, a glass cartridge, or a glass vial. In a specific embodiment, the container of the injectable preparation or kit of the present disclosure is a dual-chamber syringe (DCS) or a dual-chamber cartridge (DCC), and the lyophilized preparation and the water for injection are encapsulated in separate compartments in the container, that is, the lyophilized preparation of the present disclosure is filled into any one of the two chambers, and the water for injection is filled into the other chamber. Preferably, the water for injection is water and optionally meets the standards of "water for injection" specified in the Japanese Pharmacopoeia.
[0538] IL-31 (Interleukin-31) is a T cell cytokine. It is known that IL-31 is associated with itching. In transgenic mice overexpressing IL-31, dermatitis-like symptoms similar to atopic dermatitis appear, and continuous scratching behavior is observed.
[0539] The nucleic acid sequence and amino acid sequence of human IL-31 are also referred to as RefSeq accession numbers NM_001014336 and NP_001014358, respectively.
[0540] The IL-31 receptor 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, also known as NR10, is known to have multiple splice variants (WO00 / 075314). The known splice variants are NR10.1 (652 amino acids), NR10.2 (252 amino acids), NR10.3 (662 amino acids, also known as IL-31RAv4), IL31RAv3 (764 amino acids), etc. Preferred examples of IL-31RA 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. 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.
[0541] In one embodiment, the IL-31 antagonist of the present disclosure refers to a compound that inhibits or blocks IL-31-induced intracellular signal transduction. Such a compound can also be expressed as a compound that inhibits IL-31 signaling. Such a compound can be a naturally occurring compound or a synthetic compound. In addition, such a compound can be a low molecular weight compound or a high molecular weight compound such as a protein.
[0542] IL-31, which is known to exist extracellularly, triggers 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 includes an IL-31 binding domain, and the binding of IL-31 thereto causes a conformational change in the IL-31 receptor. Thus, intracellular signal transduction starts from the intracellular domain of the IL-31 receptor.
[0543] In one method, it can be verified whether a compound inhibits IL-31 signaling by checking whether the compound inhibits the binding of IL-31 to the IL-31 receptor. Examples of methods for making such a determination include assays using ELISA or flow cytometry and assays using surface plasmon resonance. Taking ELISA as an example, it can be evaluated whether a compound inhibits the binding of IL-31 to the IL-31 receptor by immobilizing the IL-31 receptor (or IL-31RA) protein on a plate, preparing a system for detecting the amount of IL-31 protein bound thereto by using a secondary antibody such as an enzyme-labeled anti-IL-31 antibody, and determining whether the addition of the compound reduces the amount of detected IL-31 protein.
[0544] In an alternative method, it can be verified whether a compound inhibits IL-31 signaling by checking whether a biological activity induced by the action of IL-31 on cells is inhibited by the compound. The biological activity is not particularly limited as long as it can be quantitatively or qualitatively determined by any method, and examples of such biological activities include cell proliferation activity, protein phosphorylation activity, and gene / protein expression induction activity. For example, whether the compound inhibits IL-31 signaling can be evaluated by: preparing cells that express the IL-31 receptor on the surface and whose proliferation activity is induced in response to external IL-31 stimulation, and determining whether the addition of the compound reduces the IL-31-induced cell proliferation activity. As such cells, naturally occurring cells that inherently express the IL-31 receptor can be used, or recombinant cells that are artificially synthesized to express the IL-31 receptor can be used. Suitable examples of recombinant cells include Ba / F3 cells that express the IL-31 receptor. As a further alternative, the method described in the document by Dillon et al. (Nat Immunol (2004) 5, 752-760) can be used.
[0545] In the present invention, the degree of inhibition of IL-31 signaling by the IL-31 antagonist can be, but is not limited to, at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, particularly preferably 90% or more, 95% or more, and 98% or more.
[0546] In the present disclosure, preferred embodiments of compounds that inhibit IL-31 signaling include proteins that inhibit IL-31 signaling. The proteins used herein are not particularly limited as long as they have the property of specifically binding to IL-31 or an IL-31 receptor. Examples of preferred proteins include antibodies and antibody-like molecules (Curr Opin Biotechnol (2006) 17, 653-658; Curr Opin Struct Biol (1997) 7, 463-469; and Protein Sci (2006) 15, 14-27). Antibodies include any antibody, such as monoclonal antibodies (e.g., IgG, IgM, IgE, IgA, and IgD), polyclonal antibodies, engineered antibodies (e.g., chimeric antibodies, humanized antibodies, and glycoengineered antibodies (WO 99 / 54342 and WO00 / 61739)), antibody fragments (e.g., Fab, F(ab')2, Fv, and CDR), multispecific antibodies (e.g., bispecific antibodies), and conjugated antibodies (e.g., antibodies conjugated with polyethylene glycol (PEG), radioisotopes, or drugs). On the other hand, examples of antibody-like molecules include DARPin (WO 2002 / 020565), Affibody (WO 1995 / 001937), Avimer (WO 2004 / 044011), and Adnectin (WO 2002 / 032925). More preferred are antibodies that inhibit IL-31 signaling. Examples of other preferred proteins that inhibit IL-31 signaling include proteins containing the extracellular domain of IL-31RA and proteins containing each extracellular domain of the IL-31 receptor (heterodimer of IL-31RA and OSMR).
[0547] In the present disclosure, preferred embodiments of antibodies that inhibit IL-31 signaling include antibodies that inhibit IL-31 signaling by binding to IL-31 (anti-IL-31 neutralizing antibodies) and antibodies that inhibit IL-31 signaling by binding to the IL-31 receptor (anti-IL-31 receptor neutralizing antibodies). Anti-IL-31 receptor neutralizing antibodies include antibodies that inhibit IL-31 signaling by binding to IL-31RA (anti-IL-31RA neutralizing antibodies), antibodies that inhibit IL-31 signaling by binding to OSMR (anti-OSMR neutralizing antibodies), and antibodies that inhibit IL-31 signaling by binding to the heterodimer of IL-31RA and OSMR (anti-IL-31RA / OSMR heterodimer neutralizing antibodies). Among these anti-IL-31 receptor neutralizing antibodies, anti-IL-31RA neutralizing antibodies or anti-IL-31RA / OSMR heterodimer neutralizing antibodies are preferred, and anti-IL-31RA neutralizing antibodies are more preferred.
[0548] The antibodies used in the present invention are not particularly limited as long as they bind to the desired antigen to inhibit IL-31 signaling, and they can be polyclonal antibodies or monoclonal antibodies. Monoclonal antibodies are preferred because homogeneous antibodies can be produced stably.
[0549] The amino acids contained in the amino acid sequence of the present invention can be post-translationally modified (for example, modification of the N-terminal glutamine to pyroglutamic acid by pyroglutamylation is well known to those skilled in the art). Naturally, such post-translationally modified amino acids are included in the antibodies used in the present invention.
[0550] In a further embodiment or another embodiment, the antibodies that inhibit IL-31 signaling of the present disclosure preferably comprise an amino acid variant of the H-chain constant region sequence of IgG2, wherein the amino acid variant comprises glutamic acid at position 419 (EU numbering) in the H-chain constant region sequence of wild-type IgG2 (SEQ ID NO: 12). Compared with a reference antibody comprising the H-chain constant region sequence of wild-type IgG2 having the same amino acid sequence except for the amino acid change at position 419, the engineered antibody has the advantage that it exhibits an increased plasma half-life. It is believed that this increased plasma half-life is caused by a decrease in the isoelectric point (pI) induced by replacing the amino acid with glutamic acid at position 419 (Example 2 of WO 2016 / 167263).
[0551] Thus, in one embodiment, the lyophilized and solution formulations of the present disclosure are advantageous as they relate to lyophilized and solution formulations for providing an increased plasma half-life relative to (reference) lyophilized and solution formulations comprising a reference antibody, wherein the reference antibody comprises the H-chain constant region sequence of wild-type IgG2 having the same amino acid sequence except for an amino acid change at position 419.
[0552] In this case, in a preferred embodiment, the antibody that inhibits IL-31 signaling of the present disclosure is any one of the following anti-IL-31RA neutralizing antibodies:
[0553] (1) An anti-IL-31RA antibody comprising an H-chain variable region and an L-chain variable region, wherein the H-chain variable region comprises CDR1 shown in SEQ ID NO: 1, CDR2 shown in SEQ ID NO: 2, and CDR3 shown in SEQ ID NO: 3, and the L-chain variable region comprises CDR1 shown in SEQ ID NO: 4, CDR2 shown in SEQ ID NO: 5, and CDR3 shown in SEQ ID NO: 6;
[0554] (2) An anti-IL-31RA antibody comprising the H-chain variable region shown in SEQ ID NO: 7 and the L-chain variable region shown in SEQ ID NO: 8; and
[0555] (3) An anti-IL-31RA antibody comprising the H-chain shown in SEQ ID NO: 9 and the L-chain shown in SEQ ID NO: 10.
[0556] It should be understood that the isoelectric point (pI), also simply referred to as "pI", can be the theoretical isoelectric point or the experimentally measured isoelectric point, which is not explicitly described in this specification unless there is a contradiction in the context.
[0557] For example, the value of the isoelectric point can be measured by isoelectric focusing known to those skilled in the art. The value of the theoretical isoelectric point can be calculated using gene and amino acid sequence analysis software (e.g., Genetyx). Alternatively, the value of the theoretical isoelectric point can be measured by conducting pharmacokinetic studies of the antibody using, for example, plasma from mice, rats, rabbits, dogs, monkeys, humans, etc. in combination with methods known to those skilled in the art such as BIACORE, cell proliferation assays, ELISA, EIA (enzyme immunoassay), RIA (radioimmunoassay), or immunofluorescence.
[0558] Whether the plasma half-life of the antibody changes before and after amino acid variation (modification) can be verified by conducting pharmacokinetic studies of the antibody using, for example, plasma from mice, rats, rabbits, dogs, monkeys, humans, etc., which are known to those skilled in the art.
[0559] The antibody that inhibits IL-31 signaling according to the present disclosure, in yet another or another embodiment, preferably does not (substantially) exhibit cross-reactivity with IL-31RA from any one of mouse, rat, and rabbit, although it has cross-reactivity with IL-31RA from human and cynomolgus monkey.
[0560] Methods for preparing antibodies are well known to those skilled in the art. For example, antibodies can be prepared using the hybridoma method (Nature (1975) 256, 495) or the phage antibody library method (Nature (1991) 352, 624-628; J Mol Biol (1991) 222, 581-597). Using IL-31 protein or IL-31 receptor protein as an immunogen, a large number of anti-IL-31 antibodies or anti-IL-31 receptor antibodies can be obtained by these methods. In addition, screening these antibodies using any of the methods for detecting compounds that inhibit IL-31 signaling allows for the obtaining of anti-IL-31 neutralizing antibodies or anti-IL-31 receptor neutralizing antibodies. Genetic engineering techniques known to those skilled in the art can also be used to prepare proteins such as IL-31 or IL-31 receptor. Specifically, such proteins can be prepared by inserting a gene encoding the target protein into an expression vector, introducing the vector into an appropriate host cell, and then purifying the target protein expressed in the host cell or the culture supernatant of the host cell.
[0561] Examples of preferred anti-IL-31 neutralizing antibodies include the anti-IL-31 antibodies described in WO 2006 / 122079, WO 2008 / 028192, and WO2009 / 071696.
[0562] Examples of preferred anti-IL-31RA neutralizing antibodies include, but are not limited to, the anti-IL-31RA (NR10) antibody described in WO 2007 / 142325, the anti-IL-31RA (NR10) antibody described in WO 2009 / 072604, and the anti-IL-31RA (NR10) antibody described in WO 2010 / 064697.
[0563] In addition, other examples of preferred anti-IL-31RA neutralizing antibodies include anti-human IL-31RA (neutralizing) antibodies, specifically including anti-IL-31RA (neutralizing) antibodies that recognize domain 1 and / or domain 2 of human IL-31RA. As used herein, domain 1 of human IL-31RA refers to the region from amino acid position 53 to amino acid position 152 (LPAKP to LENIA) in the amino acid sequence shown in SEQ ID NO: 11. Domain 2 refers to the region from amino acid position 153 to amino acid position 259 (KTEPP to EEEAP) in the amino acid sequence shown in SEQ ID NO: 11.
[0564] Without any limitation, among anti-IL-31RA neutralizing antibodies, more preferred is the anti-IL-31RA antibody described in WO 2010 / 064697, which comprises an H-chain (heavy chain) variable region and an L-chain variable region, wherein the H-chain (heavy chain) variable region comprises CDR1 shown in SEQ ID NO: 1, CDR2 shown in SEQ ID NO: 2, and CDR3 shown in SEQ ID NO: 3, and the L-chain variable region comprises CDR1 shown in SEQ ID NO: 4, CDR2 shown in SEQ ID NO: 5, and CDR3 shown in SEQ ID NO: 6. Even more preferred is the anti-IL-31RA antibody that comprises the H-chain variable region shown in SEQ ID NO: 7 and the L-chain (light chain) variable region shown in SEQ ID NO: 8. Particularly preferred is Nemolizumab (CIM331), which is an anti-IL-31RA antibody comprising the H-chain shown in SEQ ID NO: 9 and the L-chain shown in SEQ ID NO: 10.
[0565] Known methods for defining CDRs include the method according to Kabat et al. (Sequences of Proteins of Immunological Interest, 5th Edition (1991), Bethesda, MD), the method according to Chothia et al. (Science (1986) 233, 755-758), and the method based on the antigen-antibody contact region (J Mol Biol (1996) 262, 732-745). Specifically, each method defines CDRs as follows:
[0566]
[0567] Examples of preferred anti-IL-31RA neutralizing antibodies of the present disclosure include anti-IL-31RA antibodies that comprise CDR1, CDR2, and CDR3 contained in the heavy chain variable region shown in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 contained in the light chain variable region shown in SEQ ID NO: 8, as heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3, respectively. The CDRs in such antibodies can be defined according to any one of the methods of Kabat et al., Chothia et al., and the method based on the antigen-antibody contact region, or according to a combination of these methods.
[0568] Similarly, as an anti-IL-31RA neutralizing antibody, an anti-IL-31RA antibody that preferably binds to the same epitope as the anti-IL-31RA antibody defined by the CDR sequences of the heavy and light chains, the heavy and light chain variable region sequences, and the full-length heavy and light chain sequences described above is preferred. An epitope refers to a specific structural unit of an antigen that an antibody recognizes and binds to. When the antigen is a polypeptide, an epitope usually consists of about 6 to 10 amino acids. Epitope identification can be carried out using methods known to those skilled in the art, such as the method of fragmenting the antigen to synthesize peptides, the method of introducing site-directed mutagenesis into the antigen (e.g., arginine / glutamic acid scanning, J Biol Chem (1995) 270, 21619-21625; J Biol Chem (2006) 281, 20464-20473), and the method of crystallizing the antigen-antibody complex (Using Antibodies: A Laboratory Manual (1999), Cold Spring Harbor Laboratory Press, New York). In the present disclosure, the statement "binds to the same epitope" means that the epitopes bound by the two antibodies at least partially overlap with each other. The degree of overlap is but not limited to at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, particularly preferably 90% or more, and most preferably 100%.
[0569] Similarly, preferred as the anti-IL-31RA neutralizing antibody is an anti-IL-31RA antibody that competes with the anti-IL-31RA antibody defined by the CDR sequences of the above-mentioned heavy and light chains, the variable region sequences of the heavy and light chains, and the full-length heavy and light chain sequences for binding to IL-31RA. For example, whether two antibodies compete with each other can be evaluated by a competitive binding assay using ELISA. The specific method is as follows: One of the two antibodies is pre-labeled with, for example, fluorescence. A system for detecting the binding of the antibody (labeled antibody) to the antigen is prepared. The case where the other unlabeled antibody (test antibody) coexists is compared with the case where the test antibody does not coexist in the system. If the binding level of the labeled antibody to the antigen decreases in the presence of the test antibody, it can be determined that the test antibody and the labeled antibody compete with each other. In the present disclosure, the degree of competition is, but not particularly limited to, at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, particularly preferably 90% or more, 95% or more, 98% or more (i.e., the binding level of the other antibody decreases).
[0570] Atopic dermatitis in the present disclosure may preferably be atopic dermatitis caused by or induced by IL-31 signaling, or atopic dermatitis that exhibits responsiveness to the prevention and / or treatment with an IL-31 antagonist, but is not limited thereto.
[0571] The pruritus in the present disclosure may be pruritus caused by atopic dermatitis, preferably pruritus caused by atopic dermatitis caused by or induced by IL-31 signaling, but is not limited thereto. In addition, the pruritus may be pruritus caused by atopic dermatitis that exhibits responsiveness to the prevention and / or treatment with an IL-31 antagonist.
[0572] For example, atopic dermatitis may be moderate to severe atopic dermatitis, and may preferably be moderate or severe atopic dermatitis in which topical treatment is not sufficiently effective or not tolerated, or standard topical treatment is not sufficiently effective or not tolerated, or standard topical treatment is prohibited (due to contraindications, etc.). More preferably, atopic dermatitis may be moderate or severe atopic dermatitis in which topical treatment is not sufficiently effective or not tolerated.
[0573] For topical treatment, for example, topical steroids (e.g., glucocorticoids or their derivatives, such as prednisolone and hydrocortisone) and topical calcineurin inhibitors known as immunosuppressants (e.g., tacrolimus and pimecrolimus) are known.
[0574] In addition to topical steroids and topical calcineurin inhibitors, agents such as cyclosporine, methotrexate (MTX), or azathioprine (AZA), or antihistamines (various drugs are called antihistamines and are roughly classified into first-generation antihistamines and second-generation antihistamines) are known as therapeutic agents for atopic dermatitis.
[0575] More specifically, without any limitation, the following treatment methods are known for the treatment of atopic dermatitis ("Therapeutic Guidelines for Atopic Dermatitis", Furue et al., the Japanese journal of dermatology: 119 (8), pp. 1515-1534, 2009; "Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents.", Sidbury R et al., J Am Acad Dermatol. (2014), pp. 327-337); and Saeki H et al., J Dermatol 2009, 36, pp. 563-77).
[0576] (1) Cyclosporine preparation (trade name: Neoral)
[0577] Usually, the cyclosporine preparation is orally administered to adults at a dose of 3 mg / kg per day, taken twice a day in terms of cyclosporine. The dose should not exceed 5 mg / kg per day, but may vary as appropriate according to symptoms.
[0578] (2) Oral administration of steroid preparation (trade name: Prednisolone tablets)
[0579] Usually, the steroid preparation is orally administered to adults at a dose of 5 to 60 mg per day, calculated as prednisolone (in the case of tablets, 1 to 12 tablets; in the case of powder, 0.5 grams to 6 grams), taken one to four times. The dose will vary as appropriate according to age or symptoms.
[0580] (3) Ultraviolet therapy
[0581] Although there is no established manual or guideline, it is generally said that patients need to go to the hospital once or twice a week.
[0582] (4) Antihistamine preparation (trade name: Allegra)
[0583] Typically, the antihistamine preparation is orally administered to adults at a single dose of 60 mg (calculated as fexofenadine hydrochloride) twice a day. Typically, the antihistamine preparation is orally administered to children aged 7 years or older and less than 12 years at a single dose of 30 mg (calculated as fexofenadine hydrochloride) twice a day, and to children 12 years or older at a single dose of 60 mg, calculated as fexofenadine hydrochloride, twice a day. The dose will vary as appropriate according to the symptoms.
[0584] (5) Topical steroid preparation (trade name: Fulmeta)
[0585] Typically, an appropriate amount of the topical steroid preparation is applied to the affected area once to several times a day. The dosage will vary as appropriate according to the symptoms.
[0586] (6) Topical steroid preparation (trade name: Locoid)
[0587] Typically, an appropriate amount of the topical steroid preparation is applied once to several times a day. The dosage will vary as appropriate according to the symptoms.
[0588] (7) Tacrolimus preparation (trade name: Protopic)
[0589] Typically, for adults, an appropriate amount of the tacrolimus preparation is applied to the affected area once or twice a day. The dosage for each application should be up to 5 grams.
[0590] (8) Pimecrolimus preparation (trade name: Elidel)
[0591] Typically, an appropriate amount of the pimecrolimus preparation is applied twice a day. The dosage will vary as appropriate according to the symptoms.
[0592] The severity of atopic dermatitis (e.g., mild, moderate, or severe) can be classified based on classification methods known to those skilled in the art for scoring the degree of rash or itching felt by a subject, such as Shiratori's severity criteria, the Visual Analogue Scale (VAS) described below, the Verbal Rating Scale for Itching (VRS), the Atopic Dermatitis Score (SCORAD) established by the European Task Force on Atopic Dermatitis, the Eczema Area and Severity Index (EASI) established in the United States, or, for example, the static Investigator's Global Assessment (sIGA).
[0593] For example, the VAS consists of a 100 mm straight line, and the subject (patient) indicates the intensity of itching during measurement by drawing a line between 0 and 100 mm on this straight line, where 0 mm indicates no itching and 100 mm represents the most severe itching imaginable. For example, a subject determined to have a VAS score of 40 mm or higher can be identified as having moderate to severe atopic dermatitis, and in one embodiment, the VAS score can be 45 mm or higher, or 50 mm or higher. Similarly, in the case of the VRS, for example, a subject classified at the "moderate itching" level or higher may be considered to have moderate to severe atopic dermatitis (Reich et al., 2012). Or, for example, in the evaluation of the degree of itching during the day or night based on Shirator's severity criteria, a subject determined to have an EASI score of 10 or more, an sIGA score of 3 or more, or an overall score of 4 or more can be considered to have moderate to severe atopic dermatitis. Or, a subject in whom a rash with severe inflammation affects, for example, 5% or more of the body surface area can be identified as having moderate to severe atopic dermatitis. Or, if appropriate, a subject who meets a combination of one or more of the indicators mentioned herein can be considered to have moderate to severe atopic dermatitis.
[0594] As used herein, a "subject" can preferably be an animal, more preferably a mammal (such as a mouse, rat, rabbit, dog, monkey (such as a cynomolgus monkey), etc.), and particularly preferably a human, but is not limited thereto. A human can be an adult (18 years old or older) or a child (0 to less than 18 years old, for example, 6 months to less than 18 years old).
[0595] In one embodiment, the present disclosure relates to a lyophilized preparation and a solution preparation for preventing and / or treating atopic dermatitis, which contain an IL-31 antagonist as an active ingredient.
[0596] In this case, using a predetermined dosing interval and a predetermined dose (dosage) that will be described in detail below, the IL-31 antagonist can be intended to be administered repeatedly in equal amounts at the same dosing interval.
[0597] In one embodiment, the lyophilized preparation and the solution preparation of the present disclosure can be used for preventing and / or treating itching caused by atopic dermatitis.
[0598] In yet another embodiment or another embodiment, the lyophilized preparation and the solution preparation of the present disclosure can be used to improve sleep disorders caused by atopic dermatitis, where the sleep disorders may be caused by itching caused by atopic dermatitis. The improvement of sleep disorders can be characterized, for example, by an increase in the time from falling asleep to waking up and / or a decrease in the sleep latency (the time from going to bed to falling asleep).
[0599] In yet another embodiment or another embodiment, the lyophilized and solution formulations of the present disclosure can be used to inhibit at least one symptom caused by atopic dermatitis selected from the group consisting of flushing, induration, papules, edema, exfoliation, and lichenification.
[0600] In one embodiment of the present disclosure, the prevention and / or treatment of atopic dermatitis can refer to, but is not limited to, for example, administering a drug or the like to a subject currently exhibiting atopic dermatitis or various symptoms caused by atopic dermatitis (e.g., itching, flushing, induration, papules, edema, exfoliation, lichenification, decreased quality of life, and sleep deprivation) to inhibit one or more of these symptoms, and / or for example, administering a drug or the like to a subject who has previously suffered from atopic dermatitis or various symptoms caused by atopic dermatitis to eliminate the development of one or more of these symptoms or reduce their incidence. As long as it improves any one of the various symptoms caused by atopic dermatitis, even if it cannot prevent and / or treat atopic dermatitis itself, the prevention and / or treatment of atopic dermatitis can be judged or determined to be useful for prevention and / or treatment.
[0601] Subjects who may have atopic dermatitis can be subjects who have previously had atopic dermatitis and may be at risk of symptom recurrence, or can be subjects suspected of having atopic dermatitis before a doctor or the like makes a diagnosis or determines that the subject has atopic dermatitis, but is not limited thereto.
[0602] In one embodiment, in some cases, the prevention and treatment of atopic dermatitis can be interpreted synonymously.
[0603] It is known that the IL-31 antagonist (CIM331) used in this example showed an improvement in sleep efficiency in the IL-31 antagonist-administered group in a single subcutaneous dose study of IL-31 antagonists in atopic dermatitis patients (WO 2016 / 167263).
[0604] Although atopic dermatitis is not necessarily a life-threatening serious disease, the symptoms associated with this disease can significantly affect daily life. In particular, pruritus (which is the most typical symptom) is an unpleasant sensation that can significantly reduce the quality of life (QOL) of patients and is reported to disrupt patients' sleep (Zuberbier T, Orlow SJ, Paller AS, Taieb A, Allen R, Hernanz-Hermosa JM, Ocampo-Candiani J, Cox M, Langeraar J, Simon JC. Patient perspective on the management of atopic dermatitis. J Allergy Clin Immunol 2006; 118: 226-32). In addition, when the patient is a child, there is a great burden not only on the affected child but also on the parents. It is reported that parents of children with moderate or severe atopic dermatitis spend 3 hours per day on treatment and lose 1 to 2 hours of sleep per day (Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial cost. Arch Dis Chil 1997; 76: 159-62).
[0605] Accordingly, in another embodiment, the present disclosure relates to a lyophilized preparation and a solution preparation for preventing and / or treating atopic dermatitis, which comprise an IL-31 antagonist as an active ingredient, and which are further used for improving sleep disorders caused by atopic dermatitis. Alternatively, in a further embodiment or another embodiment, the present disclosure relates to a lyophilized preparation and a solution preparation for improving the QOL reduction caused by atopic dermatitis. Improvement of sleep disorders can be characterized, for example, by an increase in the time from falling asleep to waking up and / or a decrease in the sleep latency (the time from going to bed to falling asleep).
[0606] As used herein, the recitation "repeated administration in equal amounts at the same dosing interval" means that the dose of the IL-31 antagonist of the present disclosure initially administered to a subject (initial dose) is equal to the successive doses of the IL-31 antagonist administered subsequently (i.e., the doses administered successively after the initial dose), and the IL-31 antagonist is administered at equal dosing intervals (the intervals between doses). Specifically, for example, the above description refers to the interval between the administration of the initial dose and the administration of the first successive dose, or each interval between the administration of the nth (n is an integer greater than 1) successive dose and the administration of the (n + 1)th successive dose being equal, and the doses being equal. Those skilled in the art will understand that for a determined dosing interval (e.g., every 4 weeks when the dosing interval is determined to be every 4 weeks), each dosing interval has a "tolerable range", and those skilled in the art can decide the tolerable range as appropriate.
[0607] In the present invention, the term "stable antibody-containing formulation" refers to a formulation in which it is difficult to generate aggregates and / or components having charge heterogeneity from proteins such as antibodies, that is, a formulation in which a deterioration reaction is difficult to occur in the formulation, and the deterioration reaction includes the generation of insoluble aggregates, soluble aggregates, and components having charge heterogeneity.
[0608] "Component having charge heterogeneity" refers to a component having a protein surface charge different from that of the main component due to deamidation, oxidation, hydrolysis, etc.
[0609] The amount of aggregates can be measured by size exclusion chromatography (SEC), SDS polyacrylamide gel electrophoresis (SDS-PAGE), capillary SDS gel electrophoresis (CE-SDS), dynamic light scattering (DLS), light obscuration automatic particle counter (HIAC), flow imaging, analytical ultracentrifuge (AUC), etc., and in the present invention, it is preferably measured by size exclusion chromatography (SEC). It is considered that as the measurement conditions, a chromatographic column (TOSOH, TSKgel G3000SWXL) is used, and 50 mmol / L phosphate buffer (pH 7.0), 300 mmol / L sodium chloride, and 0.05% sodium azide are used as the mobile phase, and the sample is measured at a flow rate of 0.5 mL / min, but the conditions are not limited thereto. In one embodiment, the amount of aggregates is measured by the method described in the examples herein.
[0610] Components with charge heterogeneity can be measured by ion exchange chromatography (IEC), specifically cation exchange chromatography or anion exchange chromatography, isoelectric focusing, etc. In the present invention, it is preferably measured by anion exchange chromatography. The amount of components with charge heterogeneity in a sample can be measured by ion exchange chromatography (IEC) using a chromatographic column (TOSOH, TSKgel DEAE-NPR), using 25 mmol / L Tris-HCl buffer (pH 7.5) as mobile phase A and 25 mmol / L Tris-HCl buffer (pH 7.5), 250 mmol / L sodium chloride as mobile phase B, with a flow rate of 1.0 mL / min, but the method is not limited thereto. In one embodiment, the components with charge heterogeneity are measured by the method described in the examples herein.
[0611] In the present invention, "polypeptide" generally refers to peptides and proteins having a length of about 10 amino acids or longer. Usually, they are polypeptides of biological origin, but are not particularly limited thereto, and may be, for example, polypeptides containing artificially designed sequences. In addition, they may be any naturally occurring polypeptides, synthetic polypeptides, recombinant polypeptides, etc. In addition, fragments of the above polypeptides are also included in the polypeptides of the present invention.
[0612] The term "antibody" is used in the broadest sense and includes monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), antibody derivatives, and modified antibodies (Miller K et al. J Immunol. 2003, 170(9), 4854-61), as long as they exhibit the desired biological activity. Antibodies can be murine antibodies, human antibodies, humanized antibodies, chimeric antibodies, or antibodies from another species, or artificially synthesized antibodies. The antibodies disclosed herein can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecules. Immunoglobulins can be derived from any species (e.g., human, murine, or rabbit). The terms "antibody", "immunoglobulin", and "immunoglobulin" are used interchangeably in the broad sense.
[0613] Recombinant antibodies produced by using genetic engineering techniques can be used as antibodies. Recombinant antibodies can be obtained by: cloning the DNA encoding the antibody from a hybridoma or antibody-producing cells such as antibody-producing sensitized lymphocytes; inserting it into a vector; and then introducing it into a host (host cell) to produce the antibody.
[0614] The antibodies of the present invention can be produced by methods known to those skilled in the art. Specifically, DNA encoding the target antibody is inserted into an expression vector. The insertion into the expression vector is such that the expression will be under the control of expression regulatory regions such as enhancers and promoters. Next, the host cell is transformed with the expression vector to express the antibody. In this case, an appropriate combination of host and expression vector can be used.
[0615] The antibodies of the present invention thus obtained can be separated from inside or outside the host cell (such as in the culture medium, etc.) and purified into a substantially pure and homogeneous antibody. The antibodies can be separated and purified by methods commonly used for separating and purifying antibodies, and these methods are not restricted in any way. For example, the antibodies are separated and purified by appropriately selecting and combining column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, etc.
[0616] The inventors of the present invention studied the effects of various additives through thermal acceleration tests to evaluate the stability of samples containing the above anti-IL-31RA antibody (CIM331) during storage. As a result, the inventors found that by preparing a lyophilized preparation from a solution added with arginine hydrochloride and sucrose or trehalose, compared with when they do not contain a stabilizer or a filler (filler), when sodium chloride is added as a stabilizer, or when other sugars are added as a filler, aggregate formation is inhibited. The inventors also found that subvisible particle formation and aggregate formation are inhibited by adding poloxamer 188 and / or polysorbate 20, which are nonionic surfactants, to the antibody-containing solution. In addition, the inventors found that in the antibody-containing solution containing arginine hydrochloride, sucrose or trehalose and a nonionic surfactant, aggregate formation and components with charge heterogeneity are inhibited at pH 6 to pH 8.
[0617] The concentration (amount) of arginine in the preparation of the present invention is preferably 45 mM to 150 mM. Examples of the arginine concentration (amount) include 45 mM, 75 mM, 92 mM, 102 mM, and 150 mM.
[0618] The solution pH of the preparation of the present invention is preferably 6 to 8, more preferably 6.5 to 7.5, and even more preferably 7.
[0619] The preparation of the present invention may contain, for example, Tris buffer as a buffering agent. Tris buffer includes, for example, tris(hydroxymethyl)aminomethane and / or its salts, such as tris(hydroxymethyl)aminomethane-hydrochloride, tris(hydroxymethyl)aminomethane-aspartate, tris(hydroxymethyl)aminomethane-glutamate or tris(hydroxymethyl)aminomethane-acetate. The amount of Tris buffer added to the preparation of the present invention is preferably from 6 mM to 20 mM, for example, 6 mM, 10 mM, 12.3 mM, 13.6 mM or 20 mM.
[0620] Surfactants contained in the preparation of the present invention are, for example, polysorbate 20 (PS20) and Pluronic F-68 (poloxamer 188: polyoxyethylene(160)polyoxypropylene(30)glycol), and poloxamer 188 is particularly preferred. The amount of poloxamer 188 (or PX188) added to the preparation of the present invention is preferably from 0.15 mg / mL to 0.5 mg / mL. Examples of the amount of poloxamer 188 added to the preparation include 0.15 mg / mL, 0.25 mg / mL, 0.31 mg / mL, 0.34 mg / mL and 0.50 mg / mL.
[0621] The preparation of the present invention may also contain sugars. Preferred sugars used in the present invention are sucrose, trehalose, mannitol and lactose, and sucrose and trehalose are particularly preferred.
[0622] The amount of sugar added to the preparation of the present invention is generally from 1 mM to 1000 mM, preferably from 5 mM to 500 mM, more preferably from 10 mM to 300 mM, for example from 75 mM to 250 mM, and for example 75 mM, 125 mM, 154 mM, 170 mM or 250 mM.
[0623] If necessary, the preparation of the present invention may additionally contain suitable cryoprotectants, suspending agents, solubilizers, tonicity agents, preservatives, adsorption inhibitors, diluents, excipients, pH regulators, analgesics, sulfur-containing reducing agents, antioxidants, etc.
[0624] Cryoprotectants include, for example, sugars, such as trehalose, sucrose and sorbitol.
[0625] Solubilizers include, for example, polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, polyethylene glycol and ethyl ricinoleate.
[0626] Tonicity agents include, for example, sodium chloride, potassium chloride and calcium chloride.
[0627] Preservatives include, for example, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
[0628] Adsorption inhibitors include, for example, human serum albumin, lecithin, dextran, ethylene oxide / propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, and polyethylene glycol.
[0629] Sulfur-containing reducing agents include, for example, those containing a mercapto group, such as N-acetylcysteine, N-acetylhomocysteine, lipoic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and thioalkanoic acids having one to seven carbon atoms.
[0630] Antioxidants include, for example, isoascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopheryl acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, tripentyl gallate, propyl gallate, and chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.
[0631] The antibody-containing preparation of the present invention can be administered to a patient by any suitable route, such as by rapid bolus injection or continuous infusion for a period of time, intravenously, intramuscularly, or subcutaneously. Intravenous administration or subcutaneous administration is preferred.
[0632] The dose of nemolizumab (CIM331) is, for example, from 0.001 mg / kg to 1000 mg / kg, and the dosing interval is at least one day or longer.
[0633] More specifically, for example, Nemolizumab (CIM331) is administered to subjects with atopic dermatitis or at risk of developing atopic dermatitis equally and at the same dosing interval in repeated doses of 0.1 mg to 1000 mg / subject / 2 weeks, 0.1 mg to 1000 mg / subject / 4 weeks, or 0.1 mg to 1000 mg / subject / 8 weeks, or 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, preferably 0.5 mg / kg / 4 weeks, or 50 mg to 75 mg / subject / 4 weeks. Alternatively, Nemolizumab (CIM331) is administered in repeated doses of 60 mg / subject / 4 weeks at the same dose and the same dosing interval. Alternatively, Nemolizumab (CIM331) is administered at a dosing interval of 4 weeks and repeated doses are given with an initial dose of 60 mg / subject and a subsequent dose of 30 mg / subject. Those skilled in the art will understand that when a lyophilized formulation containing a dose of Nemolizumab (CIM331) is encapsulated in a container (vial, cartridge or syringe), an excess of the lyophilized formulation is filled to ensure an amount sufficient to administer a dose of Nemolizumab (CIM331) from one container (vial, cartridge or syringe), taking into account the loss of the reconstituted drug solution upon administration.
[0634] Another embodiment of the invention is a method for stabilizing an antibody in an antibody-containing formulation. For example, this embodiment is a method for stabilizing an antibody in a solution formulation containing an antibody, the method comprising adding arginine and / or its salt, and sucrose and / or trehalose to the solution. Additionally, for example, this embodiment is a method for stabilizing an antibody in a lyophilized formulation containing an antibody, the method comprising preparing the lyophilized formulation containing an antibody by lyophilizing an antibody-containing solution comprising arginine and / or its salt, and sucrose and / or trehalose.
[0635] Furthermore, another embodiment of the invention is a method for inhibiting antibody aggregation (aggregate formation) in an antibody-containing formulation. For example, this embodiment is a method for inhibiting antibody aggregation (aggregate formation) in a solution formulation containing an antibody, the method comprising adding arginine and / or its salt, and sucrose and / or trehalose to the solution. Additionally, for example, this embodiment is a method for inhibiting antibody aggregation (aggregate formation) in a lyophilized formulation containing an antibody, the method comprising preparing the lyophilized formulation containing an antibody by lyophilizing an antibody-containing solution comprising arginine and / or its salt, and sucrose and / or trehalose.
[0636] Another embodiment of the present invention is a method for reducing components with charge heterogeneity in antibody-containing preparations. For example, this embodiment is a method for reducing components with charge heterogeneity in a solution preparation containing an antibody, the method comprising adding arginine and / or its salt, and sucrose and / or trehalose to the solution. Additionally, for example, this embodiment is a method for reducing components with charge heterogeneity in a freeze-dried preparation containing an antibody, the method comprising preparing the freeze-dried antibody-containing preparation by freeze-drying an antibody-containing solution comprising arginine and / or its salt, and sucrose and / or trehalose.
[0637] Furthermore, in the above methods for stabilizing an antibody, for inhibiting antibody aggregation (aggregate formation), and for reducing components with charge heterogeneity, the concentration of arginine hydrochloride (Arg-HCl) in the solution is preferably from 45 mmol / L to 150 mmol / L, and the concentration of sucrose or trehalose in the solution is preferably from 75 mmol / L to 250 mmol / L.
[0638] In the above methods for stabilizing an antibody, for inhibiting antibody aggregation (aggregate formation), and for reducing components with charge heterogeneity, the antibody is preferably Nemolizumab (CIM331).
[0639] As used herein, the aspect referred to by the expression "comprising" includes those aspects referred to by the expression "consisting essentially of", and those aspects referred to by "consisting of".
[0640] The numerical values recited herein can vary within a certain range, for example, depending on the instruments or equipment used by those skilled in the art, the measurement conditions and procedures, as long as they are within the range that allows the object of the present invention to be achieved, for example, they may include a deviation of about 10%.
[0641] All patents and references specifically cited herein are incorporated herein by reference in their entirety.
[0642] The present invention will be further illustrated by the following examples, but should not be construed as being limited thereto.
[0643] Examples
[0644] Definitions
[0645] [Experimental methods]
[0646] To adjust the pH value, the formulations prepared in each example contained 6 mmol / L to 20 mmol / L Tris-HCl, which did not contribute to the stability of CIM331, an anti-IL-31RA antibody that comprises the H chain of SEQ ID NO: 9 and the L chain of SEQ ID NO: 10.
[0647] Thermal accelerated studies of the solution formulations were conducted at 40°C / 75% RH. Meanwhile, since lyophilized formulations are generally more stable, thermal accelerated studies of the lyophilized formulations were conducted at a higher temperature, 50°C 75% RH.
[0648] In Example 3, to verify the effect of nonionic surfactants, vibration studies were conducted.
[0649] [Analytical methods]
[0650] Regarding the measurement of the amount of CIM331 aggregates, considering the accuracy of the analytical method, when the difference in the percentage of aggregates is 0.07% or higher, a significant difference can be judged to exist.
[0651] Regarding the measurement of the components of CIM331 with charge heterogeneity, considering the accuracy of the analytical method, when the difference in the basic region is 1.3% or higher, the difference in the main region is 1.4% or higher, and the difference in the acidic region is 0.6% or higher, a significant difference can be judged to exist.
[0652] Due to the different stabilities between solution formulations and lyophilized formulations, the results of the analytical method cannot be similarly interpreted between solution formulations and lyophilized formulations.
[0653] [Example 1] Aggregation inhibition of arginine on the humanized IgG2 antibody CIM331 during thermal accelerated storage
[0654] [1-1] Stability evaluation of lyophilized formulations
[0655] (1) Materials
[0656] CIM331 is a monoclonal antibody that binds to IL-31RA, a humanized IgG2 antibody, and is expected to treat atopic dermatitis and the like by inhibiting the function of IL-31, which has been identified as a pruritus-inducing cytokine.
[0657] (2) Test samples
[0658] Prepare various prepared solutions including 30 mg / mL CIM331, 6 mmol / L Tris-HCl, 75 mmol / L sucrose, 0.15 mg / mL poloxamer 188, and one of 45 mmol / L Arg-HCl or 45 mmol / L NaCl as a stabilizer, and the prepared solution without a stabilizer, and fill them into glass vials (2 mL / vial). The filled drug solutions are freeze-dried under the conditions shown below.
[0659]
[0660] After the freeze-dried preparation containing the humanized antibody thus prepared is left standing in a 50 °C / 75% RH incubator for 8 weeks, a prepared reconstitution solution in which the CIM331 concentration is made 100 mg / mL by adding ultrapure water is used as a test sample.
[0661] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0662] Use a chromatographic column (TOSOH, TSKgel G3000SWXL) and 50 mmol / L phosphate buffer (pH 7.0), 300 mmol / L sodium chloride, 0.05% sodium azide as the mobile phase, and measure the amount of aggregates in the sample by size exclusion chromatography (SEC) at a flow rate of 0.5 mL / min.
[0663] Among the detected peaks, the peak showing the largest area and height is defined as the monomer main body, and the peaks detected before the monomer main body are collectively referred to as aggregates (HMWS).
[0664] For all peaks, calculate the area and determine the peak area ratio of the target peak according to the following equation.
[0665]
[0666] (4) Results
[0667] The obtained results are shown in Table 1.
[0668] [Table 1]
[0669]
[0670] *: Calculate the relative increase rate compared to when no stabilizer is added based on the increase amount of HMWS when no stabilizer is added and the increase amount of HMWS when each stabilizer is added.
[0671] As shown in Table 1, after 8 weeks of thermal acceleration at 50°C / 75% RH, the sample added with arginine hydrochloride showed a high aggregate inhibition effect compared with the sample without stabilizer and the sample added with sodium chloride.
[0672] [1-2] Stability evaluation of solution preparations
[0673] (1) Materials
[0674] Use the antibody described in [1-1].
[0675] (2) Test samples
[0676] Prepare various prepared solutions including 100 mg / mL CIM331, 20 mmol / L Tris-HCl, 250 mmol / L sucrose, 0.5 mg / mL poloxamer 188, pH 7, and one of 150 mmol / L Arg-HCl or 150 mmol / L NaCl as a stabilizer and the prepared solution without stabilizer and fill them into glass vials (1 mL / vial). After the solution preparations containing the humanized antibody were placed in an incubator at 40°C / 75% RH for 4 weeks, they were used as test samples.
[0677] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0678] These methods were carried out according to the methods described in [1-1].
[0679] (4) Results
[0680] The obtained results are shown in Table 2.
[0681] [Table 2]
[0682]
[0683] *: Based on the increase amount of HMWS without stabilizer and the increase amount of HMWS with each stabilizer, calculate the relative increase rate compared with that without stabilizer.
[0684] As shown in Table 2, after 4 weeks of thermal acceleration at 40°C / 75% RH, the sample added with arginine hydrochloride showed a high aggregate inhibition effect compared with the sample without stabilizer and the sample added with sodium chloride.
[0685] [Example 2] Aggregate inhibition effect of sucrose and trehalose on humanized IgG2 antibody CIM331 during thermal accelerated storage
[0686] (1) Materials
[0687] Use the antibody described in Example 1.
[0688] (2) Test samples
[0689] Prepare various prepared solutions containing 30 mg / mL CIM331, 6 mmol / L Tris-HCl, 45 mmol / L Arg-HCl, 0.15 mg / mL poloxamer 188, and any one of 75 mmol / L sucrose, 75 mmol / L mannitol, 75 mmol / L glucose, 75 mmol / L lactose, or 75 mmol / L trehalose as a filler, and a prepared solution without a filler, and fill them into glass vials (2 mL / vial). The filled drug solutions are freeze-dried under the conditions shown below.
[0690]
[0691] After the freeze-dried preparation containing the humanized antibody thus prepared is left standing in a 50 °C / 75% RH incubator for 8 weeks, a prepared reconstitution solution in which the CIM331 concentration is made 100 mg / mL by adding ultrapure water is used as a test sample.
[0692] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0693] These methods are carried out according to the methods described in Example 1.
[0694] (4) Results
[0695] The obtained results are shown in Table 3.
[0696] [Table 3]
[0697]
[0698] *: Calculate the relative increase rate compared to when no filler is added based on the increase in HMWS when no filler is added and the increase in HMWS when each filler is added.
[0699] As can be seen from Table 3, after 8 weeks of thermal acceleration at 50 °C / 75% RH, the samples added with sucrose or trehalose showed a relative increase rate in the range of 10% and a high aggregate inhibition effect compared to the samples without a filler and the samples added with other fillers.
[0700] [Example 3] During the vibration stress test, the inhibitory effect on the formation of microscopically visible particles and the solution state stabilizing effect of a nonionic surfactant on the humanized IgG2 antibody CIM331
[0701] (1) Material
[0702] Use the antibody described in Example 1.
[0703] (2) Test sample
[0704] Prepare various prepared solutions including 100 mg / mL CIM331, 20 mmol / L Tris-HCl, pH 7, 150 mmol / L Arg-HCl, 250 mmol / L sucrose, and either 0.5 mg / mL poloxamer 188 or 0.5 mg / mL polysorbate 20 as a nonionic surfactant, and a prepared solution without a nonionic surfactant, and fill them into glass vials (1 mL / vial). After the solution preparations containing the humanized antibody thus prepared are vibrated at a speed of about 200 rpm at room temperature for three days, use them as test samples.
[0705] (3) Method for measuring particles visible under a microscope
[0706] Use a liquid particle counter (Hach Ultra Analytics, model 9703) to count the number of particles visible under a microscope.
[0707] (4) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0708] These methods are carried out according to the methods described in Example 1.
[0709] (5) Results
[0710] The obtained results are shown in Tables 4 and 5.
[0711] [Table 4]
[0712]
[0713] [Table 5]
[0714]
[0715] *: Calculate the relative increase rate compared to when no nonionic surfactant is added based on the increase amount of HMWS when no nonionic surfactant is added and the increase amount of HMWS when each nonionic surfactant is added.
[0716] As is clearly seen from Tables 4 and 5, samples containing poloxamer 188 or polysorbate 20 (which are nonionic surfactants) showed a high inhibitory effect on microscopic particle formation and a high inhibitory effect on aggregates in the samples after vibrating at about 200 rpm for 3 days at room temperature.
[0717] [Example 4] Effect of pH on the stability of humanized IgG2 antibody CIM331 during thermal accelerated storage
[0718] (1) Materials
[0719] The antibody described in Example 1 was used.
[0720] (2) Test samples
[0721] Various prepared solutions were prepared including 100 mg / mL CIM331, 20 mmol / L Tris-HCl, 150 mmol / L Arg-HCl, 250 mmol / L sucrose and 0.5 mg / mL poloxamer 188, where the pH was any one of pH 6, pH 7 or pH 8, and filled into glass vials (1 mL / vial). After the solution preparations containing the humanized antibody were left standing in an incubator at 40 °C / 75% RH for 4 weeks, they were used as test samples.
[0722] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0723] These methods were carried out according to the methods described in Example 1.
[0724] (4) Method for measuring and calculating the components of CIM331 with charge heterogeneity
[0725] Using a chromatographic column (TOSOH, TSKgel DEAE-NPR) and 25 mmol / L Tris-HCl buffer (pH 7.5) as mobile phase A and 25 mmol / L Tris-HCl buffer (pH 7.5), 250 mmol / L sodium chloride as mobile phase B, the amount of components with charge heterogeneity in the sample was measured by ion exchange chromatography (IEC) at a flow rate of 1.0 mL / min.
[0726] Among the detected peaks, the peak showing the largest area and height was defined as the main region, the peaks detected before the main region were collectively referred to as the basic region, and the peaks detected after the main region were collectively referred to as the acidic region.
[0727] For all peaks, the area was calculated, and the peak area ratio of the target peak was determined according to the following equation.
[0728]
[0729] (5) Results
[0730] The obtained results are shown in Table 6.
[0731] [Table 6]
[0732]
[0733] As can be seen from Table 6, the samples with pH from 6 to 8 showed sufficient stability after 4 weeks of thermal acceleration at 40 °C / 75% RH. Especially in the samples with pH 7, high aggregate inhibition effect and the effect of inhibiting the components with charge heterogeneity were achieved.
[0734] [Example 5] Influence of the concentration of humanized IgG2 antibody CIM331 and the concentrations of other formulation components on stability during thermal accelerated storage
[0735] (1) Materials
[0736] The antibody described in Example 1 was used.
[0737] (2) Test samples
[0738] Various prepared solutions were prepared including 100 mg / mL or 50 mg / mL CIM331, 20 mmol / L or 10 mmol / L Tris-HCl, 150 mmol / L or 75 mmol / L Arg-HCl as stabilizers, 250 mmol / L or 125 mmol / L sucrose as fillers, and 0.5 mg / mL or 0.25 mg / mL poloxamer 188 as non-ionic surfactants, and a prepared solution including 6 mmol / L Tris-HCl, 45 mmol / L Arg-HCl, 75 mmol / L sucrose, 0.15 mg / mL poloxamer 188 and 30 mg / mL, 15 mg / mL or 6 mg / mL CIM331, and filled into glass vials (2 mL / vial). The filled drug solutions were freeze-dried under the conditions shown below.
[0739]
[0740] After the freeze-dried preparations containing the humanized antibody were left standing in an incubator at 50 °C / 75% RH for 8 weeks, the reconstitution solutions prepared by adding ultrapure water to make the CIM331 concentration as shown below were used as test samples.
[0741]
[0742] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0743] These methods are carried out according to the methods described in Example 1.
[0744] (4) Method for measuring and calculating the components of CIM331 with charge heterogeneity
[0745] These methods are carried out according to the methods described in Example 4.
[0746] (5) Results
[0747] The obtained results are shown in Table 7.
[0748] [Table 7]
[0749]
[0750] It can be clearly seen from Table 7 that after 8 weeks of thermal acceleration at 50 °C / 75% RH, the samples containing the test concentrations of each component (i.e., samples containing 6 mg / mL to 100 mg / mL CIM331, 6 mmol / L to 20 mmol / L Tris-HCl, 45 mmol / L to 150 mmol / L Arg-HCl, 75 mmol / L to 250 mmol / L sucrose, and 0.15 mg / mL to 0.5 mg / mL poloxamer 188) have sufficient stability. Regarding HMWS, when the concentrations of formulation components other than the antibody are the same, the samples containing a lower concentration of the antibody exhibit more excellent stability.
[0751] [Example 6] Effect of arginine on inhibiting aggregates and components with charge heterogeneity of humanized IgG2 antibody CIM331 during thermal accelerated storage
[0752] [6-1] Stability evaluation of freeze-dried preparations
[0753] (1) Materials
[0754] The antibody described in Example 1 was used.
[0755] (2) Test samples
[0756] Prepare various prepared solutions containing 30 mg / mL CIM331, 6 mmol / L Tris-HCl, pH 7, 75 mmol / L sucrose, 0.15 mg / mL poloxamer 188, and any one of 45 mmol / L Arg-HCl, 45 mmol / L histidine, 45 mmol / L lysine-HCl, and 45 mmol / L glycine as stabilizers, and fill them into glass vials (2 mL / vial). Lyophilize the filled drug solutions under the conditions shown below.
[0757]
[0758] After the lyophilized preparation containing the humanized antibody prepared as described above is left standing in a 50°C / 75% RH incubator for 8 weeks, use the reconstitution solution prepared by adding ultrapure water to make the CIM331 concentration 100 mg / mL as the test sample.
[0759] (3) Method for measuring the amount of CIM331 aggregates and method for calculating the amount of CIM331 aggregates
[0760] These methods are carried out according to the methods described in Example 1.
[0761] (4) Method for measuring and calculating the components of CIM331 with charge heterogeneity
[0762] These methods are carried out according to the methods described in Example 4.
[0763] (5) Results
[0764] The obtained results are shown in Table 8.
[0765] [Table 8]
[0766]
[0767] As can be seen from Table 8, after 8 weeks of thermal acceleration at 50°C / 75% RH, the sample added with arginine hydrochloride showed the highest aggregate inhibition effect and the effect of inhibiting the components with charge heterogeneity compared with the samples added with histidine, lysine hydrochloride, or glycine.
[0768] [6-2] Stability evaluation of solution preparations
[0769] (1) Materials
[0770] Use the antibody described in Example 1.
[0771] (2) Test samples
[0772] Prepare various prepared solutions containing 100 mg / mL CIM331, 20 mmol / L Tris-HCl, pH 7, 250 mmol / L sucrose, 0.50 mg / mL poloxamer 188, and any one of 150 mmol / L Arg-HCl, 150 mmol / L histidine, 150 mmol / L lysine-HCl, and 150 mmol / L glycine as a stabilizer, and fill them into glass vials (1 mL / vial). After the prepared solution preparations containing the humanized antibody are placed in an incubator at 40°C / 75% RH for 4 weeks, they are used as test samples.
[0773] (3) Measurement and calculation methods for components of CIM331 with charge heterogeneity
[0774] These methods are carried out according to the methods described in Example 4.
[0775] (4) Results
[0776] The obtained results are shown in Table 9.
[0777] [Table 9]
[0778]
[0779] As can be seen from Table 9, after heat acceleration at 40°C / 75% RH for 4 weeks, the sample added with arginine hydrochloride showed the highest effect of inhibiting the components with charge heterogeneity compared with the samples added with histidine, lysine hydrochloride, or glycine.
[0780] Industrial applicability
[0781] The preparation of the present invention is a preparation having excellent stability in both the freeze-dried state and the solution state, and is characterized in that the formation of aggregates of proteins such as antibody molecules is inhibited after storage in the solution state and after storage in the freeze-dried state and reconstitution with water. The preparation of the present invention is itself hardly subject to deterioration reactions and can be used, for example, for treating atopic dermatitis by subcutaneous administration.
Claims
1. A solution preparation containing an IL-31 antagonist as an active ingredient, wherein the solution preparation contains arginine and / or its salt.
2. A lyophilized preparation containing an IL-31 antagonist as an active ingredient, wherein the preparation contains arginine and / or its salt, and sucrose and / or trehalose.
3. The preparation according to claim 1 or 2, wherein the arginine and / or its salt is arginine hydrochloride, arginine aspartate or arginine glutamate.
4. The preparation according to any one of claims 1 to 3, wherein the molar ratio of the arginine and / or its salt to the IL-31 antagonist is from 220:1 to 1100:1, and / or the weight ratio of the arginine to the IL-31 antagonist is from 0.3:1 to 1.3:
1.
5. The lyophilized preparation according to any one of claims 2 to 4, wherein, Between the sucrose or trehalose and the IL-31 antagonist, the molar ratio is from 370:1 to 1840:1 and / or the weight ratio is from 0.8:1 to 4.3:
1.
6. The preparation according to any one of claims 1 to 5, further comprising Tris buffer as a buffer.
7. The preparation according to any one of claims 1 to 6, further comprising poloxamer 188 or polysorbate as a nonionic surfactant.
8. The preparation according to any one of claims 1 to 7, wherein the pH in the solution state is from 6 to 8.
9. The preparation according to any one of claims 2 to 8, wherein the preparation is a lyophilized preparation, and the lyophilized preparation is a composition produced by lyophilizing a solution, and the solution contains: 1 to 200 mg / mL of IL-31 antagonist; 1 to 200 mmol / L of Tris buffer; 4.5 to 1500 mmol / L of arginine or its salt; 7.5 to 2500 mmol / L of sucrose or trehalose; and 0.01 to 5 mg / mL of poloxamer 188 or polysorbate 20, wherein the pH is from 6 to 8 when the preparation is reconstituted in water.
10. The preparation according to any one of claims 1 to 9, wherein the IL-31 antagonist is an antibody that inhibits IL-31 signal transduction.
11. The preparation according to any one of claims 1 to 10, wherein the IL-31 antagonist is: (1) an anti-IL-31RA antibody, which contains a heavy chain variable region and a light chain variable region, the heavy chain variable region contains CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2 and CDR3 of SEQ ID NO: 3, and the light chain variable region contains CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5 and CDR3 of SEQ ID NO: 6; (2) an anti-IL-31RA antibody, which contains the heavy chain variable region of SEQ ID NO: 7 and the light chain variable region of SEQ ID NO: 8; or (3) an anti-IL-31RA antibody, which contains the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO:
10.
12. The preparation according to any one of claims 2 to 10, wherein the preparation is a lyophilized preparation, and the lyophilized preparation is a composition produced by lyophilizing a solution, the solution comprising: 1 to 200 mg / mL of an IL-31 antagonist; 1 to 200 mmol / L of Tris buffer; 4.5 to 1500 mmol / L of arginine or its salt; 7.5 to 2500 mmol / L of sucrose or trehalose; and 0.01 to 5 mg / mL of poloxamer 188 or polysorbate 20, Among them, when the preparation is reconstituted in water, it comprises, 1 to 200 mg / mL of an IL-31 antagonist; 1 to 200 mmol / L of Tris buffer; 4.5 to 1500 mmol / L of arginine or its salt; 7.5 to 2500 mmol / L of sucrose or trehalose; and 0.01 to 5 mg / mL of poloxamer 188 or polysorbate 20, and has a pH of 6 to 8.
13. A method for stabilizing an antibody in an antibody-containing preparation, comprising preparing an antibody-containing solution comprising arginine and / or its salt, and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is from 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is from 370:1 to 1840:
1.
14. A method for inhibiting antibody aggregation (aggregate formation) in an antibody-containing preparation, comprising preparing an antibody-containing solution comprising arginine and / or its salt, and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is from 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is from 370:1 to 1840:
1.
15. A method for reducing components with charge heterogeneity in an antibody-containing preparation, comprising preparing an antibody-containing solution comprising arginine and / or its salt, and / or sucrose and / or trehalose, wherein in the solution, the molar ratio of the arginine and / or its salt to the antibody is from 220:1 to 1100:1, and the molar ratio of the sucrose or trehalose to the antibody is from 370:1 to 1840:
1.
16. An injectable preparation, which comprises: (i) a container; (ii) a lyophilized preparation contained in the container, the lyophilized preparation comprising: - 1 to 800 mg of an IL-31 antagonist; - 0.1 to 40 mg of tris(hydroxymethyl)aminomethane; - 0.8 to 400 mg of arginine; - 3 to 1100 mg of sucrose or trehalose; and - 0.01 to 7 mg of poloxamer 188 or polysorbate 20, wherein when the lyophilized preparation is reconstituted in water, the pH is 6 to 8; and (iii) optionally, water for injection for reconstituting the lyophilized preparation.
17. An injectable preparation, which comprises: (i) a container; (ii) a lyophilized preparation contained in the container, the lyophilized preparation comprising: - 10 to 80 mg of an anti-IL-31RA antibody, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2 and CDR3 of SEQ ID NO: 3, and the light chain variable region comprising CDR1 of SEQ ID NO: 4, CDR2 of SEQ ID NO: 5 and CDR3 of SEQ ID NO: 6; - 0.8 to 4 mg of tris(hydroxymethyl)aminomethane; - 8 to 40 mg of arginine hydrochloride; - 30 to 110 mg of sucrose; and - 0.1 to 0.7 mg of poloxamer 188, wherein the pH is 6 to 8 when the lyophilized preparation is reconstituted in water; and (iii) optionally, water for injection for reconstituting the lyophilized preparation.
Citation Information
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