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EP-4736873-A1 - ANTI-IL-4RALPHA ANTIBODY FORMULATION, PREPARATION METHOD THEREFOR, AND USE THEREOF

EP4736873A1EP 4736873 A1EP4736873 A1EP 4736873A1EP-4736873-A1

Abstract

An anti-IL-4Rα antibody formulation, a preparation method thereof, and a use thereof. The antibody formulation comprises an anti-IL-4Ra antibody at 10-300 mg/mL, a buffer, a stabilizer, and a surfactant, and the pH of the antibody formulation is 5.0-7.0. The antibody formulation exhibits good stability under conditions of high temperature, room temperature, refrigeration, light, and the like, and can be kept in a liquid form, thus possessing convenience of use.

Inventors

  • LI, YUANQIANG
  • LIU, CUIHUA
  • WU, YONG
  • LIU, Lulu
  • WU, Zhihao
  • MA, Zhimin

Assignees

  • Bio-Thera Solutions, Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. An antibody formulation, comprising an anti-IL-4Rα antibody at 10-300 mg/mL or 10-200 mg/mL, a buffer, a stabilizer, and a surfactant, wherein the anti-IL-4Rα antibody comprises the heavy chain variable region set forth in SEQ ID NO: 1 and the light chain variable region set forth in SEQ ID NO: 2; the stabilizer is selected from proline, methionine, glycine, and a combination thereof; the pH of the antibody formulation is 5.0-7.0, 5.3-6.5, or 5.9 ± 0.3.
  2. The antibody formulation according to claim 1, wherein the concentration of the stabilizer is 50-500 mM, 100-450 mM, 120-350 mM, or 145-330 mM.
  3. The antibody formulation according to claim 1 or 2, wherein the stabilizer comprises proline at 100-300 mM; or, the stabilizer comprises proline at 180-230 mM; or, the stabilizer comprises proline at about 217 mM; or, the stabilizer comprises proline at about 191 mM.
  4. An antibody formulation, comprising an anti-IL-4Rα antibody at 10-300 mg/mL or 10-200 mg/mL, a buffer, a stabilizer, and a surfactant, wherein the anti-IL-4Rα antibody comprises the heavy chain variable region set forth in SEQ ID NO: 1 and the light chain variable region set forth in SEQ ID NO: 2; the stabilizer comprises sucrose at 20-100 mM and arginine or a pharmaceutically acceptable salt thereof at 101-300 mM; the pH of the antibody formulation is 5.0-7.0, 5.3-6.5, or 5.9 ± 0.3.
  5. The antibody formulation according to any one of claims 1-4, wherein the buffer is selected from histidine, citric acid, acetic acid, histidine-acetic acid, and histidine-citric acid.
  6. The antibody formulation according to any one of claims 1-5, wherein the concentration of the buffer is 1-80 mM, 5-80 mM, 10-80 mM, 10-60 mM, 15-60 mM, or 20-55 mM.
  7. The antibody formulation according to any one of claims 1-6, wherein the concentration of the anti-IL-4Rα antibody is 20-200 mg/mL, 40-200 mg/mL, 20-150 mg/mL, 100-200 mg/mL, 120-180 mg/mL, 145-180 mg/mL, or 20-80 mg/mL.
  8. The antibody formulation according to any one of claims 2-7, further comprising methionine at 1-30 mM or EDTA at 0.01-0.5 mM.
  9. The antibody formulation according to any one of claims 1-8, wherein the surfactant is polysorbate or poloxamer; or the surfactant is polysorbate 80, polysorbate 20, or poloxamer 188.
  10. The antibody formulation according to any one of claims 1-9, wherein the concentration of the surfactant is 0.1-5 mg/mL, 0.5-5 mg/mL, or 0.5-3 mg/mL.
  11. An antibody formulation, wherein the antibody formulation comprises an anti-IL-4Rα antibody at 20-250 mg/mL, a buffer at 5-80 mM, a stabilizer at 100-450 mM, and polysorbate 80 or poloxamer 188 at 0.1-5 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 20-200 mg/mL, a buffer at 5-80 mM, a stabilizer at 100-450 mM, and polysorbate 80 or poloxamer 188 at 0.1-5 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 20-100 mg/mL, a buffer at 10-30 mM, a stabilizer at 120-350 mM, and polysorbate 80 or poloxamer 188 at 0.5-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 45-55 mg/mL, a buffer at 10-30 mM, a stabilizer at 145-330 mM, and polysorbate 80 or poloxamer 188 at 1-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 100-200 mg/mL, a buffer at 5-80 mM, a stabilizer at 120-350 mM, and polysorbate 80 or poloxamer 188 at 0.5-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 130-200 mg/mL, a buffer at 10-60 mM, a stabilizer at 145-330 mM, and polysorbate 80 or poloxamer 188 at 0.5-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5, wherein the buffer is selected from histidine, citric acid, acetic acid, histidine-acetic acid, and histidine-citric acid; the stabilizer is selected from proline, methionine, glycine, and a combination thereof; the anti-IL-4Rα antibody comprises the heavy chain variable region set forth in SEQ ID NO: 1 and the light chain variable region set forth in SEQ ID NO: 2.
  12. An antibody formulation, wherein the antibody formulation comprises an anti-IL-4Rα antibody at 20-250 mg/mL, a buffer at 5-80 mM, sucrose at 20-100 mM, arginine or a pharmaceutically acceptable salt thereof at 101-300 mM, and polysorbate 80 or poloxamer 188 at 0.1-5 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 20-200 mg/mL, a buffer at 5-80 mM, sucrose at 20-100 mM, arginine or a pharmaceutically acceptable salt thereof at 101-300 mM, and polysorbate 80 or poloxamer 188 at 0.1-5 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 20-200 mg/mL, a buffer at 5-80 mM, sucrose at 20-100 mM, arginine hydrochloride at 101-300 mM, and polysorbate 80 or poloxamer 188 at 0.5-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 45-55 mg/mL, a buffer at 10-30 mM, sucrose at 35-90 mM, arginine hydrochloride at 101-245 mM, and polysorbate 80 or poloxamer 188 at 1-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5; or the antibody formulation comprises an anti-IL-4Rα antibody at 100-200 mg/mL, a buffer at 5-80 mM, sucrose at 35-90 mM, arginine hydrochloride at 101-245 mM, and polysorbate 80 or poloxamer 188 at 0.5-3 mg/mL, and the pH of the antibody formulation is 5.3-6.5, wherein the buffer is selected from histidine, citric acid, acetic acid, histidine-acetic acid, and histidine-citric acid; the anti-IL-4Rα antibody comprises the heavy chain variable region set forth in SEQ ID NO: 1 and the light chain variable region set forth in SEQ ID NO: 2.
  13. An antibody formulation, wherein the antibody formulation comprises an anti-IL-4Rα antibody at about 150 mg/mL, histidine at about 20 mM, acetic acid at 26 ± 5 mM, proline at about 217 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, acetic acid at 26 ± 5 mM, proline at about 217 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 150 mg/mL, histidine at about 10 mM, acetic acid at 20 ± 5 mM, proline at about 191 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 10 mM, acetic acid at 20 ± 5 mM, proline at about 191 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, acetic acid at 33 ± 5 mM, proline at about 217 mM, methionine at about 10 mM, and polysorbate 80 at about 1 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, arginine hydrochloride at about 110 mM, sucrose at about 44 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, arginine hydrochloride at about 110 mM, sucrose at about 44 mM, and poloxamer 188 at about 0.5 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, proline at about 217 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 10 mM, proline at about 217 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, acetic acid at 31 ± 5 mM, proline at about 217 mM, methionine at about 10 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 50 mg/mL, histidine at about 20 mM, glycine at about 293 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 50 mg/mL, histidine at about 20 mM, sucrose at about 88 mM, arginine hydrochloride at about 237 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 50 mg/mL, histidine at about 20 mM, proline at about 217 mM, and polysorbate 80 at about 2 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, arginine hydrochloride at about 110 mM, sucrose at about 44 mM, and polysorbate 80 at about 1 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, arginine hydrochloride at about 110 mM, sucrose at about 44 mM, EDTA at about 0.05 mM, and polysorbate 80 at about 1 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, arginine hydrochloride at about 110 mM, sucrose at about 44 mM, methionine at about 10 mM, and polysorbate 80 at about 1 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3; or the antibody formulation comprises an anti-IL-4Rα antibody at about 175 mg/mL, histidine at about 20 mM, citric acid at about 20 mM, arginine hydrochloride at about 110 mM, sucrose at about 44 mM, and polysorbate 80 at about 1 mg/mL, and the pH of the antibody formulation is 5.9 ± 0.3, wherein the anti-IL-4Rα antibody comprises the heavy chain variable region set forth in SEQ ID NO: 1 and the light chain variable region set forth in SEQ ID NO: 2.
  14. The antibody formulation according to any one of claims 1-13, wherein the heavy chain of the anti-IL-4Rα antibody comprises the sequence set forth in SEQ ID NO: 3, or a sequence having at least 90% identity to the sequence set forth in SEQ ID NO: 3, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence set forth in SEQ ID NO: 3; and/or the light chain of the anti-IL-4Rα antibody comprises the sequence set forth in SEQ ID NO: 4, or a sequence having at least 90% identity to the sequence set forth in SEQ ID NO: 4, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence set forth in SEQ ID NO: 4.
  15. The antibody formulation according to any one of claims 1-14, wherein the anti-IL-4Rα antibody is dupilumab.
  16. A method for preparing the antibody formulation according to any one of claims 1-15, comprising: taking components according to the formula, dissolving in water, mixing the mixture thoroughly, and adjusting the pH value to 5.0-7.0 to obtain the antibody formulation; or, comprising: preparing a buffer, transferring the anti-IL-4Rα antibody into the buffer by ultrafiltration, adding an excipient, and diluting the antibody to a specified concentration to obtain the antibody formulation.
  17. A lyophilized formulation, obtained by lyophilizing the antibody formulation according to any one of claims 1-15.
  18. A reconstituted formulation, obtained by reconstituting the lyophilized formulation according to claim 17.
  19. Use of the antibody formulation according to any one of claims 1-15, the lyophilized formulation according to claim 17, or the reconstituted formulation according to claim 18 in preparing a medicament for treating a disease, wherein the disease is a disease associated with IL-4R overexpression; or, the disease is an immune disease or disorder; or, the disease is selected from asthma, nasal polyp, eczema, sinusitis, chronic sinusitis, chronic sinusitis with nasal polyp, allergic dermatosis, chronic obstructive pulmonary disease, allergic rhinitis, arthritis, inflammatory disease, allergic reaction, autoimmune lymphoproliferative syndrome, autoimmune hemolytic anemia, Barrett's esophagus, autoimmune uveitis, tuberculosis, nephropathy, prurigo, prurigo nodularis, eosinophilic esophagitis, atopic dermatitis, urticaria, chronic urticaria, pruritus, bullous pemphigoid, allergic bronchopulmonary aspergillosis, neurodermitis, ulcerative colitis, milk anaphylaxis, and peanut allergy.
  20. An article of manufacture, comprising the antibody formulation according to any one of claims 1-15, the lyophilized formulation according to claim 17, or the reconstituted formulation according to claim 18, and a container for storing the antibody formulation, the lyophilized formulation, or the reconstituted formulation.

Description

TECHNICAL FIELD The present disclosure relates to the field of biological formulations, and particularly, to an anti-IL-4Rα antibody formulation, preparation method thereof and use thereof. BACKGROUND Interleukin-4 (IL-4, also known as B cell stimulating factor or BSF-1) was initially characterized by its ability to stimulate B cell proliferation in response to low concentrations of anti-surface immunoglobulin antibodies. IL-4 has been demonstrated to have a wide range of biological activities, including stimulating the growth of T cells, mast cells, granulocytes, megakaryocytes, and erythrocytes. IL-4 induces the expression of major histocompatibility complex class II molecules on resting B cells and enhances the secretion of IgE and IgG1 isotypes in stimulated B cells. The biological activity of IL-4 is mediated by specific cell surface IL-4 receptors. Anti-IL-4R antibodies can be used to treat or prevent diseases such as atopic dermatitis, asthma, and other disorders. In order to utilize the anti-IL-4R antibody in the treatment of diseases, in-depth research is required on anti-IL-4R antibodies to develop a stable formulation suitable for clinical application. SUMMARY The present disclosure provides a stable antibody formulation comprising an antibody capable of specifically binding to human interleukin-4 receptor α (hIL-4Rα). In some embodiments, the antibody formulation of the present disclosure comprises an anti-IL-4Rα antibody at 10-300 mg/mL or 10-200 mg/mL, a buffer, a stabilizer, and a surfactant. In some embodiments, the anti-IL-4Rα antibody comprises the heavy chain variable region set forth in SEQ ID NO: 1 and the light chain variable region set forth in SEQ ID NO: 2. In some embodiments, the heavy chain of the anti-IL-4Rα antibody comprises the sequence set forth in SEQ ID NO: 3, or a sequence having at least 90% identity to the sequence set forth in SEQ ID NO: 3, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence set forth in SEQ ID NO: 3; and/or the light chain of the anti-IL-4Rα antibody comprises the sequence set forth in SEQ ID NO: 4, or a sequence having at least 90% identity to the sequence set forth in SEQ ID NO: 4, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence set forth in SEQ ID NO: 4. In some embodiments, the heavy chain of the anti-IL-4Rα antibody comprises the sequence set forth in SEQ ID NO: 3, and the light chain of the anti-IL-4Rα antibody comprises the sequence set forth in SEQ ID NO: 4. In some embodiments, the anti-IL-4Rα antibody is dupilumab (e.g., Dupixent® or biosimilars thereof). In some embodiments, the concentration of the anti-IL-4Rα antibody is 20-250 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody is 20-200 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody is 40-200 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody is 20-150 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody is 100-200 mg/mL. In some embodiments, the concentration of the anti-IL-4Ra antibody is 120-180 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody is 145-180 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody is 20-80 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody in the antibody formulation is about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 47 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, about 150 mg/mL, about 160 mg/mL, about 170 mg/mL, about 175 mg/mL, about 180 mg/mL, about 190 mg/mL, about 200 mg/mL, about 210 mg/mL, about 220 mg/mL, about 230 mg/mL, about 240 mg/mL, about 250 mg/mL, about 300 mg/mL, or a range between any two of these values (inclusive) or any value therein. In some embodiments, the concentration of the anti-IL-4Rα antibody in the antibody formulation is about 150 mg/mL. In some embodiments, the concentration of the anti-IL-4Rα antibody in the antibody formulation is about 175 mg/mL. In some embodiments, the stabilizer is selected from one or more of sucrose, trehalose, mannitol, arginine or a pharmaceutically acceptable salt thereof, glycine or a pharmaceutically acceptable salt thereof, proline or a pharmaceutically acceptable salt thereof, and methionine or a pharmaceutically acceptable salt thereof. In some embodiments, the stabilizer is selected from proline, methionine, glycine, and a combination thereof. In some embodiments, the stabilizer comprises glycine, proline, or a combination of proline and methionine, or a pharmaceutically acceptable salt thereof. In some embodiments, the stabilizer comprises proline or a pharmaceutically acceptable salt thereof. In some embodiments, the stabilizer comprises proline or a pharmaceutically acceptable salt