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JP-7854782-B2 - B7-H4 antibody preparation

JP7854782B2JP 7854782 B2JP7854782 B2JP 7854782B2JP-7854782-B2

Inventors

  • チュアン， ヨン
  • フアン， チン－イー
  • ガンダ， ハルジート シン

Assignees

  • ファイヴ プライム セラピューティクス インク

Dates

Publication Date
20260507
Application Date
20190221
Priority Date
20180221

Claims (16)

  1. A pharmaceutical composition comprising (i) an IgG1 antibody that specifically binds to human B7-H4 and includes VH containing the amino acid sequence shown in SEQ ID NO: 11 and VL containing the amino acid sequence shown in SEQ ID NO: 12; (ii) a buffer; (iii) a sugar selected from sucrose, trehalose, and sorbitol ; (iv) a polysorbate ; and (v) a pH of about 4.5 to about 6.
  2. The composition according to claim 1, wherein the composition contains approximately 30% to approximately 40% of the acidic variant of the antibody after 6 months at 5°C.
  3. The composition according to claim 1 or claim 2, wherein the composition contains approximately 10% to approximately 17% of the basic variant of the antibody after 6 months at 5°C.
  4. The composition according to any one of claims 1 to 3, wherein the composition contains 55% or less of acidic and basic variants of the antibody after 6 months at 5°C.
  5. The composition according to any one of claims 1 to 4, wherein the concentration of the buffer solution is approximately 15 to approximately 25 mM.
  6. The composition according to any one of claims 1 to 5, wherein the concentration of the antibody is approximately 5 mg/mL to approximately 30 mg/mL.
  7. A composition according to any one of claims 1 to 6, comprising approximately 20 mM acetate, approximately 270 mM sucrose, approximately 20 mg/mL of the antibody, and approximately 0.05% polysorbate 20, wherein the pH is approximately 5.0.
  8. A composition according to any one of claims 1 to 7, comprising approximately 20 mM citrate, approximately 270 mM sucrose, approximately 20 mg/mL of the antibody, and approximately 0.05% polysorbate 20, wherein the pH is approximately 5.5.
  9. The composition according to claim 8, wherein the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO: 21 and a light chain containing the amino acid sequence shown in SEQ ID NO: 22.
  10. The composition according to any one of claims 1 to 9, wherein at least 95% of the antibody in the composition is non-fucosylated.
  11. A pharmaceutical composition comprising: (i) an antibody comprising a heavy chain containing the amino acid sequence shown in SEQ ID NO: 21 and a light chain containing the amino acid sequence shown in SEQ ID NO: 22; (ii) about 20 mM acetate; (iii) about 270 mM sucrose; and (iv) about 0.05 wt/vol% polysorbate 20, wherein the pH of the composition is about 5.0.
  12. A pharmaceutical composition comprising: (i) an antibody comprising a heavy chain containing the amino acid sequence shown in SEQ ID NO: 21 and a light chain containing the amino acid sequence shown in SEQ ID NO: 22; (ii) about 20 mM citrate; (iii) about 270 mM sucrose; and (iv) about 0.05 wt/vol% polysorbate 20, wherein the pH of the composition is about 5.5.
  13. A syringe or vial comprising the pharmaceutical composition described in any one of claims 1 to 12.
  14. A pharmaceutical composition according to any one of claims 1 to 12, for treating cancer expressing B7-H4 in the target organism.
  15. The pharmaceutical composition according to claim 14, wherein the cancer is selected from the group consisting of breast cancer, ductal carcinoma, endometrial cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancer, kidney cancer, and bladder cancer.
  16. The pharmaceutical composition according to claim 14 or claim 15, wherein the pharmaceutical composition is administered parenterally or intravenously.

Description

1. A pharmaceutical composition containing a B7-H4 antibody and a method for using such a preparation are provided. 2. B7-H4 (also known as B7x, B7-S1, and VTCN1) is an immunomodulatory molecule that shares homology with other B7 family members, including PD-L1. It is a type I transmembrane protein composed of extracellular domains of both IgV and IgC. While B7-H4 expression is relatively limited at the protein level in healthy tissues, it is expressed in several solid tumors, such as gynecological cancers of the breast, ovary, and endometrium. B7-H4 expression in tumors tends to correlate with poor prognosis. The receptor for B7-H4 is unknown, but it is thought to be expressed on T cells. B7-H4 is thought to directly inhibit T cell activity. Considering the expression and function of B7-H4, therapeutic approaches involving the regulation of B7-H4, such as antibodies that specifically bind to B7-H4 for the treatment of cancer, have been developed. Therefore, there is a need for pharmaceutical compositions containing B7-H4 antibodies and their antigen-binding fragments for the administration of such therapies. This figure shows the unfolding temperature (Tm1) of the B7-H4 antibody "20502" (non-fucosylated) under various pH conditions, as measured by the UNit system. (See Example 3)This figure shows the effect of buffer pH on aggregate formation of the B7-H4 antibody "20502" (non-fucosylated) at 40°C, as measured by size exclusion high-performance liquid chromatography (SE-HPLC). Table 13 shows the formulations for each pH. The proportion of high molecular weight (HMW) was approximately 0 at T0 for all pH levels examined. (See Example 3)This figure shows the effect of buffer pH on fragment formation at 40°C as measured by SE-HPLC. Table 13 shows the formulations for each pH. The proportion of low molecular weight (LMW) was approximately 0 at T0 for all pH levels examined. (See Example 3)This figure shows the effect of buffer pH on aggregate formation (measured by SE-HPLC) at 40°C in a formulation containing 20 mM citric acid, 270 mM sucrose, and 0.05% polysorbate 20 (PS20). (See Example 4)This figure shows the effect of buffer pH on fragmentation at 40°C (measured by SE-HPLC) in a formulation containing 20 mM citrate, 270 mM sucrose, and 0.05% PS20. The LMW ratio was approximately 0 at T0 for all pH levels examined. (See Example 4)This figure shows the effect of buffer pH on acidic mutants at 40°C (measured by imaging capillary isoelectric focusing (iCE)). (See Example 4)This figure shows the effect of buffer type on aggregate formation at 40°C (measured by SE-HPLC). (See Example 5)This figure shows the effect of buffer type on fragment formation at 40°C (measured by SE-HPLC). (See Example 5)This figure shows the effect of buffer type on acidic mutant formation at 40°C (measured by iCE). (See Example 5)This figure shows the effect of buffer type on basic mutant formation at 40°C (measured by iCE). (See Example 5)This figure shows the effect of excipients on aggregate formation at 40°C (measured by SE-HPLC). (See Example 6)This figure shows the effect of excipients on fragment formation at 40°C (measured by SE-HPLC). (See Example 6)This figure shows the effect of excipients on acidic mutants at 40°C (measured by iCE). (See Example 6)This figure shows the effect of excipients on basic mutants (measured by iCE) at 40°C. (See Example 6)This figure shows the differential scanning calorimetry (DSC) profile of 20502 (non-fucosylated) in the selected formulation. (See Example 6) 5. Provided herein are pharmaceutical compositions comprising an antibody or its antigen-binding fragment that specifically binds to human B7-H4. The pharmaceutical compositions can be stable, for example, under long-term storage conditions, after repeated freeze-thaw cycles (e.g., at least five cycles) and/or after stirring. As provided herein, a pharmaceutical composition comprising a B7-H4 antibody or its antigen-binding fragment may have a pH of about 4.5 to about 6, a B7-H4 antibody or its antigen-binding fragment (e.g., at a concentration of about 5 to about 25 mg/ml), a buffer (including, but not limited to, acetate or citrate), an excipient (including, but not limited to, sucrose, trehalose, and sorbitol), and/or a surfactant (including, but not limited to, polysorbate, e.g., polysorbate 20 (PS20)). In a specific embodiment, a liquid aqueous pharmaceutical composition containing 20 mM acetate, 270 mM sucrose, and 20 mg/mL of anti-B7-H4 antibody (e.g., non-fucosylated antibody 20502) at pH 5.0 is provided herein. In another specific embodiment, a liquid aqueous pharmaceutical composition containing 20 mM citrate, 270 mM sucrose, and 20 mg/mL of anti-B7-H4 antibody (e.g., non-fucosylated antibody 20502) at pH 5.5 is provided herein. The pharmaceutical compositions provided herein may be useful in treating conditions such as cancer. 5.1 Terminology As used herein, the term “B7-H4” refers to mammalian B7-H4 polypeptides, including but not