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JP-7856672-B2 - antibody composition

JP7856672B2JP 7856672 B2JP7856672 B2JP 7856672B2JP-7856672-B2

Inventors

  • バッケル，アレクサンデル・ベルトルト・ヘンドリック
  • ヘンドリクス，リンダ・ヨハンナ・アレイダ
  • ドルンボス，ロベルト・パウル
  • アルヴィンテ，チューダー
  • ダーピン，ギヨーム・デジレ
  • ポワリエ，エミリー・ブリジット

Assignees

  • メルス・ナムローゼ・フェンノートシャップ

Dates

Publication Date
20260511
Application Date
20211216
Priority Date
20201218

Claims (20)

  1. A human bispecific IgG antibody comprising a first binding domain that binds to EGFR and a second binding domain that binds to LGR5, wherein the antibody comprises the VH amino acid sequence of MF3755 shown in SEQ ID NO: 5 , the VH amino acid sequence of MF5816 shown in SEQ ID NO: 41 , and the VL amino acid sequence shown in SEQ ID NO: 53. Histidine buffer and/or citrate buffer, Sucrose and polysorbate 80 A pharmaceutical composition comprising the above.
  2. The pharmaceutical composition according to claim 1, wherein the composition comprises a histidine buffer and the composition has a pH of 5 to 7.
  3. The pharmaceutical composition according to claim 1 , wherein the composition comprises a citrate buffer and the composition has a pH of 6.2 to 7.8.
  4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the antibody is present at a concentration of 0.5 to 150 mg/mL.
  5. The sucrose is present at a concentration of 200 to 400 mM, or the molar concentration ratio of sucrose to antibody is 250:1 to 60,000:1. A pharmaceutical composition according to any one of claims 1 to 4.
  6. Polysorbate 80 is present at a concentration of 0.01 to 2 mg/mL, or the molar concentration ratio of polysorbate 80 to antibody is 1:90 to 224:1. A pharmaceutical composition according to any one of claims 1 to 5.
  7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the histidine buffer, citrate buffer, or combination of histidine buffer and citrate buffer is present at a concentration of 2 to 50 mM, or the molar concentration ratio of histidine buffer or citrate buffer (or combination of histidine buffer and citrate buffer) to antibody is 2.9:1 to 7300:1.
  8. The pharmaceutical composition according to any one of claims 1 and 4 to 6 , wherein the composition comprises a histidine buffer or a citrate buffer.
  9. The pharmaceutical composition according to any one of claims 1 and 4 to 6 , wherein the composition comprises only one of either a histidine buffer or a citrate buffer.
  10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition does not contain trehalose.
  11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition does not contain polysorbate 20, and/or sodium chloride, and/or an antioxidant, and/or a chelating agent.
  12. The pharmaceutical composition according to any one of claims 1 to 11 , wherein the antibody comprises a light chain constant region (CL) containing the sequence of Sequence ID No. 57.
  13. The pharmaceutical composition according to any one of claims 1 to 11, wherein the antibody comprises the light chain constant region (CL) sequence shown in SEQ ID NO: 57, the CH1 domain sequence shown in SEQ ID NO: 58, the hinge sequence shown in SEQ ID NO: 59, the CH2 domain sequence shown in SEQ ID NO: 60, the CH3-DE domain sequence shown in SEQ ID NO: 61, and the CH3-KK domain sequence shown in SEQ ID NO: 62 .
  14. The composition is Antibodies in concentrations of 1-30 mg/mL, 3–20 mM histidine buffer and/or citrate buffer, 200–400 mM sucrose and 0.01–2 mg/mL polysorbate 80 an aqueous composition containing The pharmaceutical composition according to any one of claims 1 , 4 to 7, and 10 to 13 , wherein the composition has a pH of 5.4 to 7.4.
  15. The composition is 15-25 mg/mL antibody, 4–12 mM histidine buffer and/or citrate buffer, 250–350 mM sucrose and 0.1–1.5 mg/mL polysorbate 80 an aqueous composition containing The pharmaceutical composition according to any one of claims 1 , 4 to 7, and 10 to 13 , wherein the composition has a pH of 5.4 to 7.4.
  16. 20 mg/mL antibody, 10 mM histidine buffer, 280 mM sucrose, It contains 0.5 mg/mL or 1.0 mg/mL of polysorbate 80, and water. The pharmaceutical composition according to any one of claims 1 , 2, and 4 to 13 , wherein the composition has a pH of 5.8 to 6.0.
  17. i) 20 mg/ml antibody, 5 mM histidine pH 6.3, 290 mM sucrose, 0.1% polysorbate 80, and water, or ii) 20 mg/ml antibody, 10 mM histidine pH 5.9, 280 mM sucrose, 0.05% polysorbate 80, and water, or iii) 20 mg/ml antibody, 10 mM histidine pH 5.9, 280 mM sucrose, 0.1% polysorbate 80, and water, or iv) 20 mg/ml antibody, 10 mM Na-citrate pH 7.0, 280 mM sucrose, 0.05% polysorbate 80, and water, according to any one of claims 1 and 4 to 13 .
  18. The composition is the antibody, Histidine buffer or citrate buffer (or a combination of histidine buffer and citrate buffer) versus antibody molar concentration ratio is 21:1 to 146:1, histidine buffer and/or citrate buffer, Sucrose with a molar concentration ratio of sucrose versus antibody of 1460:1 to 2920:1, and polysorbate 80 with a molar concentration ratio of 1:18 to 11:1. Includes, The pharmaceutical composition according to any one of claims 1 , 4 to 7, and 10 to 13 , wherein the composition has a pH of 5.4 to 7.4.
  19. the antibody, Histidine buffer or citrate buffer (or a combination of histidine buffer and citrate buffer) versus antibody molar concentration ratio is 29:1 to 88:1, histidine buffer and/or citrate buffer, Sucrose with a molar concentration ratio of sucrose versus antibody of 1825:1 to 2555:1, and polysorbate 80 with a molar concentration ratio of 1:2 to 8.5:1. Includes, The pharmaceutical composition according to any one of claims 1 and 4 to 13 , wherein the composition has a pH of 5.4 to 7.4.
  20. the antibody, Histidine buffer with a molar concentration ratio of 73:1 to antibody, Sucrose with a molar concentration ratio of sucrose versus antibody of 2040:1 Polysorbate 80 with a molar concentration ratio of 2.79:1 to antibody, and optionally containing water. The pharmaceutical composition according to any one of claims 1 , 2, and 4 to 13 , wherein the composition has a pH of 5.8 to 6.0.

Description

[introduction] The present invention relates to (bio)pharmaceutical compositions comprising an anti-EGFR/anti-LGR5 bispecific antibody, more particularly to liquid (e.g., aqueous) biopharmaceutical compositions, and more particularly to liquid biopharmaceutical compositions. The present invention also relates, among other things, to methods for producing the compositions, kits containing the compositions, packages containing the compositions, methods for producing the packages, and methods of treatment using the compositions and/or packages, particularly methods of cancer treatment, for example, for the treatment of colorectal cancer. Recently, the applicants developed Biclonics®, characterized by enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) for treating solid tumors, including the potential treatment of colorectal cancer, and which bind to cancer stem cells expressing leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) and epidermal growth factor receptor (EGFR). Antibodies binding to both EGFR and LGR5 are described in detail in International Publication No. 2017069628A2 (MERUS et al.), and their relevant sequences are shown in Figures 1-4. Such antibodies have two distinct mechanisms of action: firstly, by blocking the proliferation and survival pathways of cancer stem cells; and secondly, by recruiting and enhancing immune effector cells to directly kill cancer stem cells that persist in solid tumors and cause recurrence and metastasis. The object of the present invention is to provide viable pharmaceutical compositions of bispecific antibodies that bind to both EGFR and LGR5, and optionally similar variants thereof. The inherent unpredictability in the formulation techniques of biopharmaceuticals, particularly antibodies, has hindered the discovery of such viable pharmaceutical compositions. This is because most formulations of a given biopharmaceutical (if such formulation is arbitrarily selected) are unstable over long periods and/or under stress conditions due to various physical or chemical factors that can affect the biopharmaceutical, particularly aqueous formulations. For example, preventing protein aggregation can be difficult. Furthermore, the pharmaceutical composition should be formulated with the intention of being safe for administration to human subjects, meaning that adverse effects from its administration, e.g., intravenous injection, are minimized. Physical or chemical influences, particularly due to fluctuating stresses (e.g., agitation, heat, frost, light) that different batches of drug products may be exposed to during manufacturing, transport, and storage, can result in either drug products that are unsustainable (potentially unsafe for use in medical procedures) or drug products whose sustainability is volatile and unpredictable. U.S. Patent No. 6,171,586 (Lam et al.) describes a stable aqueous antibody formulation. The F(ab')2rhuMAb CD18 antibody was formulated with sodium acetate and histidine-HCl buffer. A preferred formulation of rhuMAb CD18 was prepared with 10 mM sodium acetate, 8% trehalose, 0.01% Tween® 20, and pH 5.0. Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody and is available in different formulations depending on whether it is lyophilized or liquid. In its dry form, omalizumab is packaged as a sterile, white, preservative-free lyophilized powder in a single-use vial and is administered subcutaneously after reconstitution with sterile water for injection. Each vial contains 202.5 mg of omalizumab, 145.5 mg of sucrose, 2.8 mg of L-histidine hydrochloride monohydrate, 1.8 mg of L-histidine, and 0.5 mg of polysorbate 20, and is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL of sterile water. In its aqueous form, it is available in pre-filled syringes. The injection solution in the syringe contains L-arginine hydrochloride, L-histidine hydrochloride, L-histidine, polysorbate 20, and water. The label accompanying the pre-filled syringe includes instructions for use, including storing the sealed syringe in a refrigerator at 2°C to 8°C (36°F to 46°F) and noting that the product should not be frozen. It also states that the shelf life is 15 months, including potential temperature deviations. This product can be maintained at 25°C for a total of 4 hours, and if necessary, the product can be returned to the refrigerator for later use; however, this should not be done more than once. International Publication No. 2015/130173A1 discloses a bispecific antibody formulated as a pharmaceutical composition containing 25 mM histidine, 220 mM trehalose, 0.2 g/L polysorbate 20, or a combination thereof, most preferably set to pH 6. The present invention suitably addresses one or more of the aforementioned stability problems, thereby providing a pharmaceutical formulation that can maintain its activity for administration to humans. Another object of the present invention is to provide a form