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EP-3939609-B1 - LIQUID COMPOSITION COMPRISING ANTIBODY OF HUMAN INTERLEUKIN-4 RECEPTOR ALPHA

EP3939609B1EP 3939609 B1EP3939609 B1EP 3939609B1EP-3939609-B1

Inventors

  • ZHENG, WEI
  • PAN, Wubin
  • YANG, XIN
  • ZHANG, LIMIN
  • JIANG, JIE

Dates

Publication Date
20260506
Application Date
20200313

Claims (18)

  1. A liquid composition comprising an antibody against human interleukin-4 receptor alpha, wherein the antibody comprises a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 4, a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 8, a light chain constant region comprising the amino acid sequence as set forth in SEQ ID NO: 9 and a heavy chain constant region comprising the amino acid sequence as set forth in SEQ ID NO: 10; and wherein the liquid composition further comprises the antibody at a concentration of 100-165 mg/ml, and 5-20 mmol/L histidine hydrochloride buffer, 60-150 mmol/L trehalose, 80-120 mmol/L sodium chloride and 0.01%-0.2% Tween 80, wherein the liquid composition has a pH of 6.2±0.2.
  2. The liquid composition according to Claim 1, wherein the liquid composition comprises the antibody at a concentration of 130-165 mg/ml.
  3. The liquid composition according to Claim 2, wherein the liquid composition comprises the antibody at a concentration of 150±5 mg/ml.
  4. The liquid composition according to any one of Claims 1 to 3, wherein the liquid composition comprises 10 mmol/L histidine hydrochloride buffer.
  5. The liquid composition according to any one of Claims 1 to 4, wherein the liquid composition comprises 60 mmol/L trehalose and 100 mmol/L sodium chloride.
  6. The liquid composition according to any one of Claims 1 to 5, wherein the liquid composition comprises 0.01-0.03% Tween 80.
  7. The liquid composition according to Claim 6, wherein the liquid composition comprises 0.02% Tween 80.
  8. The liquid composition according to any one of Claims 1 to 7, wherein the liquid composition is a formulation for injection; or wherein the liquid composition is a formulation for subcutaneous or intravenous injection; or the liquid composition comprises: the antibody at a concentration of 130-165 mg/ml; 10 mmol/L histidine hydrochloride buffer; 60 mmol/L trehalose; 100 mmol/L sodium chloride; 0.02% Tween 80; and the liquid composition has a pH of 6.2±0.2.
  9. The liquid composition according to claim 8, wherein the liquid composition has a pH of 6.2±0.05.
  10. A container or a kit comprising the container, wherein the container comprises the liquid composition according to any one of Claims 1 to 9.
  11. The liquid composition according to any one of Claims 1 to 9 for use in a method of preventing, treating or ameliorating inflammation or allergic disease, wherein the method includes administering to a subject in need thereof the liquid composition according to any one of Claims 1 to 9.
  12. The liquid composition for the use according to Claim 11, wherein the subject is a mammal.
  13. The liquid composition for the use according to Claim 11 or 12, wherein the subject is a human.
  14. The liquid composition for the use according to any one of Claims 11 to 13, wherein the inflammation or allergic disease includes autoimmune disease.
  15. The liquid composition for the use according to Claim 14, wherein the inflammation or allergic disease is allergic dermatitis, asthma, eosinophilic esophagitis, eczema, allergic rhinitis, nasal polyp, or rheumatoid arthritis.
  16. The liquid composition for the use according to Claim 15, wherein the inflammation or allergic disease is allergic dermatitis, asthma, or nasal polyp.
  17. The liquid composition for the use according to any one of Claims 11 to 16, wherein the method comprises administering the liquid composition to the subject by injection.
  18. The liquid composition for the use according to any one of Claims 11 to 17, wherein the method comprises administering the liquid composition to the subject by subcutaneous injection or intravenous injection.

Description

The present application claims the priority benefit of Chinese Patent Application No. 201910187179.9, filed on 13 March 2019. TECHNICAL FIELD The present invention relates to the field of biopharmaceutical formulation. Particularly, the present invention relates to a stable liquid formulation comprising an antibody at high concentration. BACKGROUND OF THE INVENTION Human interleukin-4 receptor is known to produce a soluble form of protein (shIL-4Rα) that inhibits cell proliferation mediated by IL-4 and IL-5 up-regulation mediated by T cells. Two forms of the receptor are associated with allergic reaction, which manifests as diseases like allergic rhinitis, sinusitis, asthma, eczema, and the like. Therefore, a blocking antibody that targets the protein helps to treat and relieve such diseases. Currently, monoclonal antibody medicaments targeting hIL-4R have entered clinical trials, such as Dupilumab, which has shown good efficacy in phase II clinical trial for the treatment of atopic dermatitis. However, for antibody medicaments, the best mode of administration is subcutaneous injection and relatively high doses are required to exert their effects, and accordingly high-concentration antibody formulations are generally required to be prepared. As is known in the prior art, the manufacture and application of a high-concentration antibody formulation are usually accompanied with many difficulties. For example, high viscosity of such a formulation may be difficult to be drawn and injected with a syringe, lead to large deviations in administration dosage due to high drug residue in a container or cartridge holding the formulation, cause pain at injection site, and the like. In addition, the high viscosity of the formulation may create serious process problems during manufacturing. For example, extremely high pressure may be needed during concentration and filtration steps, or even the formulation cannot pass through a filter membrane at all. Or, the high concentration antibody in such a formulation is prone to aggregate and form insoluble particles, thereby resulting in an instable formulation, increased immunogenicity, and more medication side effects, etc. Therefore, there remains a need in the art to develop a novel antibody formulation targeting human interleukin-4 receptor which can meet manufacturing and clinical application requirements for high antibody concentration, long-term stability, no aggregation, and low viscosity, among the others. SUMMARY OF THE INVENTION The purpose of the present invention is to provide a liquid composition comprising an antibody against human interleukin-4 receptor alpha and a formulation thereof, and such liquid composition and the formulation thereof can enable the antibody to be present stably at a high concentration and have a low viscosity. Technical solutions provided by the present invention are as follows. In one aspect, the present invention provides a liquid composition comprising an antibody against human interleukin-4 receptor alpha, wherein the liquid composition comprises the antibody at a concentration of 50-200 mg/ml; and a buffer, a protective agent and a surfactant and the like which serve as excipients, and the liquid composition has a pH of 5.4-6.4. In the liquid composition, the antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the light chain variable region comprises CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 1, CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, and CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 3, and the heavy variable region comprises CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 5, CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7. The antibody comprises a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 4, and a heavy variable region comprising the amino acid sequence as set forth in SEQ ID NO: 8. The antibody comprises a light chain constant region comprising the amino acid sequence as set forth in SEQ ID NO: 9 and a heavy chain constant region comprising the amino acid sequence as set forth in SEQ ID NO: 10. More preferably, the antibody is a monoclonal antibody comprising two light chains and two heavy chains. SEQ ID NO: 1 (LCDR1): RASQSVSSSYLA;SEQ ID NO: 2 (LCDR2): GASSRAT;SEQ ID NO: 3 (LCDR3): QQYDHSAGWT;SEQ ID NO: 4 (VL): SEQ ID NO: 5 (HCDR1): RNAMF;SEQ ID NO: 6 (HCDR2): GIGTGGATSYADSVKGR;SEQ ID NO: 7 (HCDR3): GRYYFDY;SEQ ID NO: 8 (VH): SEQ ID NO: 9 (CL): SEQ ID NO: 10 (CH): SEQ ID NO: 11 (L): SEQ ID NO: 12 (H): Preferably, the antibody is present at a concentration of 100-200 mg/ml, more preferably 130-165 mg/ml, and further preferably 150±5 mg/ml. In the liquid composition, the buffer is one or more selected from the group consisting of an acetate buffer, a