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CN-114007647-B - Stable formulations containing anti-ANGPTL 3 antibodies

CN114007647BCN 114007647 BCN114007647 BCN 114007647BCN-114007647-B

Abstract

The present invention provides stable pharmaceutical formulations comprising human antibodies that specifically bind to human angiopoietin-like protein 3 (ANGPTL 3). In addition to the anti-ANGPTL 3 antibody, the formulation may further comprise a buffer, an organic co-solvent, at least one viscosity modifier, and optionally at least one amino acid. The pharmaceutical formulations of the present invention may be administered by intravenous infusion or subcutaneously and exhibit a substantial degree of antibody stability after storage for several months.

Inventors

  • D.LIU
  • A. Skinner

Assignees

  • 瑞泽恩制药公司

Dates

Publication Date
20260508
Application Date
20200524
Priority Date
20190524

Claims (16)

  1. 1. A liquid pharmaceutical formulation comprising i) 150 mg/mL+ -22.25 mg/mL anti-ANGPTL 3 antibody or antigen binding fragment thereof, ii) 5mM + -1 mM to 20mM + -4 mM histidine, iii) 0.1% w/v+ -0.05% to 0.5% w/v+ -0.25% polysorbate 80, iv) 50mM to 75 mM arginine-HCL, and v) 1% w/v+ -0.2% to 5% w/v+ -1% w/v proline, wherein the liquid pharmaceutical formulation has a pH of 6.0+ -0.3, and wherein the antibody or antigen binding fragment thereof comprises three heavy chain complementarity determining regions HCDR, i.e., HCDR1 having an amino acid sequence as shown in SEQ ID NO:68, HCDR2 having an amino acid sequence as shown in SEQ ID NO:70, HCDR3 having an amino acid sequence as shown in SEQ ID NO:72, and three light chain complementarity determining regions LCDR, i.e.g., amino acid sequence LCDR 76 and amino acid sequence of LCDR 80 as shown in SEQ ID NO: 70.
  2. 2. The liquid pharmaceutical formulation of claim 1, wherein the histidine concentration is 10mM ± 2mM, wherein the polysorbate concentration is 0.1% w/v ± 0.05%, wherein the arginine-HCl concentration is about 70 mM, and wherein the proline concentration is 3% w/v ± 0.6%.
  3. 3. The liquid pharmaceutical formulation of any one of claims 1-2, wherein the viscosity of the liquid pharmaceutical formulation is less than about 20 cP.
  4. 4. The liquid pharmaceutical formulation of any one of claims 1-2, wherein at least about 95% of the antibody or antigen-binding fragment thereof has a native conformation after 21 days at 45 ℃.
  5. 5. The liquid pharmaceutical formulation of any one of claims 1-2, wherein at least about 45% of the antibody or antigen-binding fragment thereof is the predominant charge variant of the antibody or antigen-binding fragment thereof after 21 days at 45 ℃.
  6. 6. The liquid pharmaceutical formulation of any one of claims 1-2, wherein at least about 98% of the antibody or antigen-binding fragment thereof has a native conformation after 36 months at 5 ℃.
  7. 7. The liquid pharmaceutical formulation of any one of claims 1-2, wherein at least about 55% of the antibody or antigen-binding fragment thereof is the predominant charge variant of the antibody or antigen-binding fragment thereof after 36 months at 5 ℃.
  8. 8. The liquid pharmaceutical formulation of any one of claims 1-2, wherein at least about 98% of the antibody or antigen-binding fragment thereof has a native conformation after 36 months at-30 ℃.
  9. 9. The liquid pharmaceutical formulation of any one of claims 1-2, wherein at least about 57% of the antibody or antigen-binding fragment thereof is the predominant charge variant of the antibody or antigen-binding fragment thereof after 36 months at-30 ℃.
  10. 10. The liquid pharmaceutical formulation of any one of claims 1-2, wherein the antibody or antigen-binding fragment thereof comprises a Heavy Chain Variable Region (HCVR) having the amino acid sequence shown in SEQ ID No. 66 and a Light Chain Variable Region (LCVR) having the amino acid sequence shown in SEQ ID No. 74.
  11. 11. The liquid pharmaceutical formulation of any one of claims 1-2, wherein the liquid pharmaceutical formulation is in a prefilled syringe or an auto-injector.
  12. 12. The liquid pharmaceutical formulation of any one of claims 1-2, wherein the liquid pharmaceutical formulation is in a glass vial.
  13. 13. A kit comprising the liquid pharmaceutical formulation of any one of claims 1-12, a container, and instructions.
  14. 14. The kit of claim 13, wherein the container is a prefilled syringe or an auto-injector.
  15. 15. Use of a liquid pharmaceutical formulation according to any one of claims 1-12 for the manufacture of a medicament for the treatment of familial hypercholesterolemia in a subject.
  16. 16. The use of claim 15, wherein the liquid pharmaceutical formulation is administered subcutaneously to the subject.

Description

Stable formulations containing anti-ANGPTL 3 antibodies Cross Reference to Related Applications The present application was filed 24 at 5.2020 as PCT international patent application and claims priority from U.S. provisional patent application No. 62/852,643 filed 24 at 5.2019, the entire contents of which are incorporated herein by reference. Technical 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 human antibodies that specifically bind to human angiopoietin-like (protein) 3 (ANGPTL 3). Background Therapeutic macromolecules (e.g., antibodies) must be formulated in such a way that not only renders the molecules suitable for administration to a patient, but also maintains their stability during storage and subsequent use. For example, therapeutic antibodies in liquid solutions are prone to degradation, aggregation, or unwanted chemical modification unless the solution is properly formulated. The stability of antibodies in liquid formulations depends not only on the type of excipient used in the formulation, but also on the amount and ratio of excipients relative to each other. In addition, in the preparation of liquid antibody formulations, other factors must be considered in addition to stability. Examples of such other considerations include the viscosity of the solution and the concentration of antibody that a given formulation can accommodate, as well as the visual quality or appeal of the formulation. Thus, great care must be taken in formulating therapeutic antibodies to obtain a formulation that remains stable, contains sufficient concentration of antibody, and has suitable viscosity and other characteristics that allow the formulation to be conveniently administered to a patient. Antibodies to angiopoietin-like protein 3 (ANGPTL 3) are one example of a therapeutically relevant macromolecule that needs to be properly formulated. anti-ANGPTL 3 antibodies are clinically useful for treating diseases or disorders associated with lipid metabolism, cardiovascular diseases or disorders, and diseases or disorders associated with angiogenesis. The amino acid and nucleotide sequences of human ANGPTL3 are shown in SEQ ID NOS 161 and 162, respectively. Exemplary anti-ANGPTL 3 antibodies are described, for example, in US 9,018,356B2, WO2008/073300, and US 7,935,796. Although anti-ANGPTL 3 antibodies are known, there remains a need in the art for novel pharmaceutical formulations comprising such antibodies that are sufficiently stable and suitable for administration to patients. Summary of The Invention For many commercial monoclonal antibodies, the presentation form of the final product depends on the method of administration. One such method is based on patient preference for self-administration and less frequent administration. Subcutaneous self-administration is a preferred mode of administration for parenteral products developed for the long-term treatment of many diseases. Subcutaneous (SC) injection is required to be administered in a total volume of 2mL or less, preferably 1mL or less. Less frequent dosing requires a higher drug concentration per dose and, correspondingly, a higher protein concentration formulation. Thus, to enable less frequent dosing, it is desirable that a high concentration of drug (150 mg per dose) can be delivered in 1 mL. High concentration formulations can also achieve smaller dosing volumes. For example, to deliver 15mg/kg of drug to a 100kg patient, i.e., 1500mg of drug, 150mL of a 10mg/mL formulation is required, whereas only 10mL of a 150mg/mL formulation is required. Thus, high concentration formulations are preferred because they enable small injection volumes. It is important to consider the stability and viscosity of such higher protein concentration formulations. Because of the exponential relationship between protein concentration and viscosity, small differences in protein concentration can have a large impact on viscosity and affect the ability of a patient to deliver a drug. The steepness of the curve describing viscosity (y-axis) versus protein concentration (x-axis) can be affected by the addition of excipients, especially those that increase (e.g., sugar) or decrease (e.g., salt) viscosity, and temperature. In addition, viscosity is directly related to the ability to deliver a drug through a syringe. The maintenance force (sustaining force) is the force required to continuously dispense the prefilled syringe contents. Can be measured using a syringe thrust tester (Instron). The relationship between holding force and viscosity is linear. Self-administration using a prefilled syringe or an auto-injector requires that the formulation have a low viscosity (typically less than about 20 centipoise). Thus, there is a need to identify viscosity-reducing excipients and evaluate their effect on the rheological properties and stability