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US-12624115-B2 - Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies

US12624115B2US 12624115 B2US12624115 B2US 12624115B2US-12624115-B2

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-4 receptor (hIL-4R). The formulations may contain, in addition to an anti-hIL-4R antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

Inventors

  • Daniel B. DIX
  • Xiaolin Tang

Assignees

  • REGENERON PHARMACEUTICALS, INC.

Dates

Publication Date
20260512
Application Date
20250918

Claims (20)

  1. 1 . A pharmaceutical formulation comprising: (i) an anti-human interleukin-4 receptor alpha (anti-hIL4Rα) antibody at a concentration of about 100 mg/ml to about 200 mg/ml, wherein the anti-hIL4Rα antibody is a human antibody, wherein the anti-hIL4Rα antibody is an immunoglobulin molecule comprising two heavy chains and two light chains interconnected by disulfide bonds, wherein each heavy chain comprises a heavy chain variable region (HCVR), wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1, wherein each light chain comprises a light chain variable region (LCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 5; (ii) a thermal stabilizer at a concentration from about 0.9%±0.135% w/v to about 10%±1.5% w/v; (iii) a non-ionic surfactant; and (iv) arginine at a concentration from about 20 to 100 mM; wherein the pharmaceutical formulation has a pH from about 5.6 to about 6.2; wherein the viscosity of the pharmaceutical formulation is less than 35 cPoise; and wherein less than about 5% of the anti-hIL4Rα antibody recovered from the pharmaceutical formulation after 3 months of storage at 5° C. is aggregated, as determined by size exclusion chromatography.
  2. 2 . The pharmaceutical formulation of claim 1 , wherein the non-ionic surfactant is a poloxamer or a polyethylene glycol.
  3. 3 . The pharmaceutical formulation of claim 2 , wherein the non-ionic surfactant is poloxamer 188.
  4. 4 . The pharmaceutical formulation of claim 1 , wherein the non-ionic surfactant is a polysorbate.
  5. 5 . The pharmaceutical formulation of claim 4 , wherein the polysorbate is polysorbate 20 or polysorbate 80.
  6. 6 . The pharmaceutical formulation of claim 5 , wherein the polysorbate 20 or polysorbate 80 is at a concentration of about 0.2% w/v.
  7. 7 . The pharmaceutical formulation of claim 5 , wherein the pharmaceutical formulation has a pH of about 5.9.
  8. 8 . The pharmaceutical formulation of claim 5 , wherein the anti-hIL4Rα antibody is at a concentration of about 175 mg/mL.
  9. 9 . The pharmaceutical formulation of claim 8 , wherein the arginine is at a concentration of about 50 mM±7.5 mM.
  10. 10 . The pharmaceutical formulation of claim 5 , wherein the anti-hIL4Rα antibody is at a concentration of about 150 mg/mL.
  11. 11 . The pharmaceutical formulation of claim 10 , wherein the arginine is at a concentration of about 50 mM±7.5 mM.
  12. 12 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation has an osmolality of less than about 450 mOsm/kg.
  13. 13 . The pharmaceutical formulation of claim 1 , wherein the thermal stabilizer is a sugar or a sugar alcohol at a concentration from about 2.5% w/v to about 10% w/v.
  14. 14 . The pharmaceutical formulation of claim 13 , wherein the sugar or sugar alcohol is sucrose, sorbitol, mannitol, or trehalose.
  15. 15 . The pharmaceutical formulation of claim 14 , wherein the sugar or sugar alcohol is sucrose.
  16. 16 . The pharmaceutical formulation of claim 15 , wherein the sucrose is at a concentration of about 5%±0.75% w/v.
  17. 17 . The pharmaceutical formulation of claim 15 , wherein the sucrose is at a concentration of about 5.5%±0.825% w/v.
  18. 18 . The pharmaceutical formulation of claim 14 , wherein the pharmaceutical formulation has an osmolality of less than about 450 mOsm/kg.
  19. 19 . The pharmaceutical formulation of claim 14 , wherein the non-ionic surfactant is a poloxamer or a polyethylene glycol.
  20. 20 . The pharmaceutical formulation of claim 19 , wherein the non-ionic surfactant is poloxamer 188.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/432,780, filed Feb. 5, 2024, which is a continuation of U.S. application Ser. No. 17/342,949, filed Jun. 9, 2021, now U.S. Pat. No. 11,926,670, which is a continuation of U.S. application Ser. No. 16/543,832, filed Aug. 19, 2019, now U.S. Pat. No. 11,059,896, which is a continuation of U.S. application Ser. No. 15/424,578, filed Feb. 3, 2017, now U.S. Pat. No. 10,435,473, which is a continuation of U.S. application Ser. No. 14/963,712, filed Dec. 9, 2015, which is a continuation of U.S. application Ser. No. 14/578,179, filed Dec. 19, 2014, now U.S. Pat. No. 9,238,692, which is a continuation of U.S. application Ser. No. 13/253,103, filed Oct. 5, 2011, now U.S. Pat. No. 8,945,559, which claims the benefit of priority under 35 U.S.C. § 119 (e) of U.S. Provisional Application No. 61/390,283, filed Oct. 6, 2010, each of which is herein incorporated by reference in its entirety. SEQUENCE LISTING This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 6032US09_Sequence, created on Sep. 18, 2025, and containing 23,111 bytes. FIELD The present invention relates to the field of therapeutic antibody formulations. More specifically, the present invention relates to the field of pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-4 receptor. BACKGROUND Therapeutic macromolecules (e.g., antibodies) must be formulated in a manner that not only makes the molecules suitable for administration to patients, but also maintains their stability during storage and subsequent use. For example, therapeutic antibodies in liquid solution are prone to degradation, aggregation or undesired chemical modifications unless the solution is formulated properly. The stability of an antibody in liquid formulation depends not only on the kinds of excipients used in the formulation, but also on the amounts and proportions of the excipients relative to one another. Furthermore, other considerations aside from stability must be taken into account when preparing a liquid antibody formulation. Examples of such additional considerations include the viscosity of the solution and the concentration of antibody that can be accommodated by a given formulation, and the visual quality or appeal of the formulation. Thus, when formulating a therapeutic antibody, great care must be taken to arrive at a formulation that remains stable, contains an adequate concentration of antibody, and possesses a suitable viscosity as well as other properties which enable the formulation to be conveniently administered to patients. Antibodies to the human interleukin-4 receptor alpha (hIL-4Rα) are one example of a therapeutically relevant macromolecule that requires proper formulation. Anti-hIL-4Rα antibodies are clinically useful for the treatment or prevention of diseases such as atopic dermatitis and allergic asthma, and other conditions. Exemplary anti-IL-4Rα antibodies are described, inter alia, in U.S. Pat. Nos. 7,605,237; 7,608,693; 7,465,450; and 7,186,809; and US Patent Applications No. 2010-0047254 and 2010-0021476. Although anti-hIL-4Rα antibodies are known, there remains a need in the art for novel pharmaceutical formulations comprising anti-hIL-4Rα antibodies which are sufficiently stable and suitable for administration to patients. SUMMARY The present invention satisfies the aforementioned need by providing pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-4 receptor alpha (hIL-4Rα). In one aspect, a liquid pharmaceutical formulation is provided, comprising: (i) a human antibody that specifically binds to human interleukin-4 receptor alpha (hIL-4Rα); (ii) a buffer; (iii) an organic cosolvent; (iv) a thermal stabilizer; and (v) a viscosity reducer. In one embodiment, the antibody is provided at a concentration of about 150 mg/ml±50 mg/ml. In another embodiment, the antibody is provided at a concentration of about 150 mg/ml±15 mg/ml. In a specific embodiment, the antibody is provided at a concentration of about 150 mg/ml. In one embodiment, the antibody comprises any one or more of an amino acid sequence of SEQ ID NO:1-8. In one embodiment, the antibody comprises (a) a heavy chain variable region (HCVR) comprising heavy chain complementarity determining regions 1, 2 and 3 (HCDR1-HCDR2-HCDR3) each comprising a sequence of SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, respectively; and (b) a light chain variable region (LCVR) comprising light chain complementarity determining regions 1, 2 and 3 (LCDR1-LCDR2-LCDR3) each comprising a sequence of SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, respectively. In a specific embodiment, the antibody comprises an HCVR and an LCVR, each of which comprises the amino acid sequence of SEQ ID NO:1 and SEQ ID NO:5, respectively. In one embodiment, the antibody comprises any one or mor