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CN-115605231-B - Formulations comprising anti-IL-23 p19 antibodies, methods of making and uses thereof

CN115605231BCN 115605231 BCN115605231 BCN 115605231BCN-115605231-B

Abstract

The present invention relates to formulations comprising anti-IL-23 p19 antibodies, and in particular to pharmaceutical formulations comprising anti-IL-23 p19 antibodies, buffers, stabilizers and surfactants. Furthermore, the invention relates to the use of these formulations for the treatment or prophylaxis of diseases.

Inventors

  • CAO WEI
  • MA LIQIANG
  • WANG YINJUE
  • ZHOU KAISONG

Assignees

  • 信达生物制药(苏州)有限公司

Dates

Publication Date
20260508
Application Date
20210512
Priority Date
20200513

Claims (20)

  1. 1. A liquid antibody preparation comprising (I) An anti-IL-23 p19 antibody; (ii) The buffer agent is used to store the buffer agent, (Iii) A stabilizer, and (Iv) The surfactant is used as a surfactant in the preparation of the water-soluble polymer, Wherein the anti-IL-23 p19 antibody comprises the following 6 CDRs, -GYTFTSYLMH (SEQ ID NO: 1) heavy chain VH CDR1; -YINPYNEGTN (SEQ ID NO: 2) heavy chain VH CDR2; -NWDLPY (SEQ ID NO: 3) heavy chain VH CDR3; -RASQSISDYLH (SEQ ID NO: 4) light chain VL CDR1; -YASQSMS (SEQ ID NO: 5), and -QQGHSFPFT (SEQ ID NO: 6) light chain VL CDR3, The CDRs are bordered by AbM rules.
  2. 2. The liquid antibody formulation of claim 1, wherein the pH of the liquid antibody formulation is 5.2-6.3.
  3. 3. The liquid antibody formulation of claim 1, wherein the pH of the liquid antibody formulation is 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2 or 6.3.
  4. 4. The liquid antibody formulation of claim 1, wherein the pH of the liquid antibody formulation is 6.0±0.3.
  5. 5. The liquid antibody formulation of any one of claims 1-4, wherein the concentration of anti-IL-23 p19 antibody in the liquid antibody formulation is 25-250 mg/mL.
  6. 6. The liquid antibody formulation of claim 5, wherein the concentration of anti-IL-23 p19 antibody in the liquid antibody formulation is 50-200 mg/mL.
  7. 7. The liquid antibody formulation according to any one of claims 1-4 and 6, wherein the liquid antibody formulation comprises a buffer system selected from the group consisting of histidine-histidine hydrochloride buffer system, citric acid-sodium citrate buffer system.
  8. 8. The liquid antibody formulation of claim 7, wherein the buffer in the liquid antibody formulation is selected from the group consisting of histidine, histidine hydrochloride, and combinations thereof.
  9. 9. The liquid antibody formulation of claim 7, wherein the buffer is selected from the group consisting of: (i) 0.775-3.1 mg/mL histidine or (Ii) A combination of histidine and histidine hydrochloride, wherein the histidine content is 0.38-1.52 mg/mL and the histidine hydrochloride content is 0.54-2.16 mg/mL.
  10. 10. The liquid antibody formulation of claim 7, wherein the buffer is selected from the group consisting of: (i) 1.55 mg/mL histidine, or (Ii) Histidine and histidine hydrochloride in combination, wherein the histidine and histidine hydrochloride concentrations are 0.76 mg/mL and 1.08 mg/mL, respectively.
  11. 11. The liquid antibody formulation according to any one of claims 1-4, 6 and 8-10, wherein the stabilizing agent is selected from the group consisting of: (i) 25-100mg/ml sorbitol; (ii) Sucrose 40-160 mg/ml; (iii) Comprises a combination of sorbitol and arginine, wherein the combination comprises sorbitol in an amount of 15-60mg/ml and arginine in an amount of 6.97-27.88 mg/ml, or (Iv) Comprises a combination of sucrose and arginine, wherein the combination comprises 25-100mg/ml sucrose and 6.97-27.88 mg/ml arginine.
  12. 12. The liquid antibody formulation of claim 11, wherein the stabilizing agent is selected from the group consisting of: (i) 40-60mg/ml sorbitol; (ii) 70-90 mg/ml sucrose; (iii) Comprises a combination of sorbitol and arginine, wherein the combination has a sorbitol content of 20-40 mg/ml and an arginine content of 10.45-17.42 mg/ml, or (Iv) Comprises a combination of sucrose and arginine, wherein the combination comprises sucrose of 40-60 mg/ml and arginine of 10.45-17.42 mg/ml.
  13. 13. Liquid antibody formulation according to any one of claims 1-4, 6, 8-10 and 12, characterized in that the surfactant in the liquid antibody formulation is selected from polysorbate surfactants, poloxamers, polyethylene glycols or combinations thereof.
  14. 14. The liquid antibody preparation according to claim 13, characterized in that the surfactant in the liquid antibody preparation is polysorbate-80 or polysorbate-20.
  15. 15. The liquid antibody formulation according to claim 11, characterized in that the surfactant in the liquid antibody formulation is selected from the group consisting of polysorbate surfactants, poloxamers, polyethylene glycols or combinations thereof.
  16. 16. Liquid antibody formulation according to any one of claims 1-4, 6, 8-10, 12, 14 and 15, characterized in that the concentration of the surfactant is 0.1-1 mg/ml.
  17. 17. The liquid antibody formulation according to claim 16, characterized in that the concentration of the surfactant is 0.2-0.8 mg/ml.
  18. 18. The liquid antibody formulation according to claim 16, characterized in that the concentration of the surfactant is 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 mg/ml.
  19. 19. Liquid antibody formulation according to any one of claims 1-4, 6, 8-10, 12, 14, 15, 17 and 18, characterized in that the anti-IL-23 p19 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID No. 7 or a sequence having at least 90% identity thereto and the light chain variable region comprises the sequence of SEQ ID No. 8 or a sequence having at least 90% identity thereto.
  20. 20. The liquid antibody preparation according to claim 19, characterized in that the anti-IL-23 p19 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID No.7 or a sequence having at least 99% identity thereto and the light chain variable region comprises the sequence of SEQ ID No.8 or a sequence having at least 99% identity thereto.

Description

Formulations comprising anti-IL-23 p19 antibodies, methods of making and uses thereof The present application claims priority from China patent application 2020104048344 with the application date 2020/5/13. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The present invention relates to the field of antibody formulations. More particularly, the present invention relates to pharmaceutical formulations, in particular stable liquid formulations, lyophilized formulations and reconstituted stable liquid formulations, comprising anti-IL-23 p19 antibodies, as well as to methods for preparing said pharmaceutical formulations, and to therapeutic and/or prophylactic uses of said pharmaceutical formulations. Background Interleukin (IL) -12 is a secreted heterodimeric cytokine consisting of two disulfide-linked glycosylated protein subunits, designated p35 and p40 due to their approximate molecular weights. It was found that the p40 protein subunit of IL-12 can also be linked to an isolated protein subunit designated p19 to form a novel cytokine, interleukin-23 (IL-23). Interleukin-23 (IL-23) is a heterodimeric cytokine comprising 2 subunits, p19 (I1-23 p 19) specific for IL-23 and p40 (IL-12 p 40) common to IL-12 (IL-12). The p19 subunit is structurally related to IL-6, granulocyte colony-stimulating factor (G-CSF), and the p35 subunit of IL-12. IL-23 mediates signaling through binding to heterodimeric receptors comprising two subunits, IL-23R, which is characteristic of the IL-23 receptor, and IL-12Rb1, which is common to the IL-12 receptor. Many early studies demonstrated that the consequences of genetic defects in p40 (p 40 knockout mice; p40KO mice) were more severe than those observed in p35 deficient mice (e.g., p35 KO). These results are generally interpreted as p40 knockdown not only preventing the expression of IL-12, but also IL-23. See, for example, oppmann et al (2000) Immunity 13:715-725; wiekowski et al (2001) J.Immunol.166:7563-7570; parham et al (2002) J.Immunol.168:5699-708; frucht (2002) Sci STKE 2002, E1-E3; elkins et al (2002) Infection Immunity 70:1936-1948). Recent studies have demonstrated that IL-23 inhibition can provide benefits comparable to anti-IL-12 p40 strategies through IL-23p19 deficient mice or IL-23 specific antibody neutralization (Cua et al, 2003, murphy et al, 2003, benson et al 2004). Thus, there is evidence for an increased specific role of IL-23 in immune-mediated diseases. Neutralizing IL-23 does not inhibit the IL-12 pathway and thus can provide effective treatment of immune-mediated diseases while having limited impact on important host defense immune mechanisms. This would represent a significant improvement over current treatment options. Thus, there is a need in the art for new IL-23p19 antibodies. The IL-23p19 antibody is described, for example, in patent application PCT/CN 2019/121261. Drug stability is one of the important indicators to ensure drug effectiveness and safety. Obtaining a good formulation prescription is a key condition to ensure that the drug remains effective and safe over its shelf life. However, due to the complexity of the antibody itself and its degradation pathways, it is currently not possible to make predictions about the formulation conditions required to optimize antibody stability. In particular, it is contemplated that different antibodies typically have very different CDR sequences, and that these sequence differences can result in different antibodies having different stability properties in solution. Therefore, based on stringent requirements on safety and effectiveness of human antibodies, it is necessary to optimize the optimal formulation for each antibody individually. Although some IL-23p19 antibody formulations have been proposed, there remains a need in the art for new pharmaceutical formulations containing IL-23p19 that are sufficiently stable and suitable for administration to human subjects. Furthermore, for such antibody formulations, it would also be advantageous to find the simplicity and ease of formulation prescription. Disclosure of Invention The present invention meets the above-described need by providing pharmaceutical formulations containing antibodies that specifically bind to IL-23p 19. The antibody preparation of the invention has excellent stability under different temperature and time conditions. In one aspect, the invention therefore provides a liquid antibody formulation comprising (i) an anti-IL-23 p19 antibody, (ii) a buffer, (iii) a stabilizer, and (iv) a surfactant. In one embodiment, an anti-IL-23 p19 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID No. 7 or a sequence having at least 90% identity thereto, and the light chain variable region comprises the sequence of SEQ ID No. 8 or a sequence having at least 90% identity theret