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EP-4739710-A1 - STABILIZED FORMULATIONS CONTAINING ANTI-BCMA X ANTI-CD3 BISPECIFIC ANTIBODIES

EP4739710A1EP 4739710 A1EP4739710 A1EP 4739710A1EP-4739710-A1

Abstract

The present invention provides stable liquid pharmaceutical formulations comprising a human bispecific antibody that specifically binds to human BCMA and human CD3. In certain embodiments, the formulations contain, in addition to the bispecific antibody, a buffer, a surfactant, and a sugar. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability upon stress and storage.

Inventors

  • GRAHAM, KENNETH S.
  • WADHWA, SAURABH
  • KAMEN, DOUGLAS

Assignees

  • Regeneron Pharmaceuticals, Inc.

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. What is claimed is: 1. A stable liquid pharmaceutical formulation comprising: (a) a bispecific antibody comprising a first antigen-binding domain that binds specifically to human BCMA and a second antigen-binding domain that binds specifically to human CD3, wherein the first antigen-binding domain comprises three heavy chain complementarity determining regions (CDRs) (A1-HCDR1, A1-HCDR2 and A1-HCDR3) contained in a heavy chain variable region (HCVR) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR), and the second antigen-binding domain comprises three heavy chain CDRs (A2-HCDR1, A2-HCDR2 and A2-HCDR3) contained in a heavy chain variable region (HCVR) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR), wherein A1- HCDR1, A1-HCDR2 and A1-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 2, 3 and 4, A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 10, 11 and 12, and LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 6, 7 and 8; (b) a buffer comprising histidine; (c) an organic co-solvent comprising polysorbate; and (d) a stabilizer comprising a sugar; wherein the formulation has a pH of 6.0 ± 0.3.
  2. 2. The pharmaceutical formulation of claim 1, wherein the antibody concentration is from 1 mg/ml ± 0.1 mg/ml to 200 mg/ml ± 20 mg/ml.
  3. 3. The pharmaceutical formulation of claim 2, wherein the antibody concentration is from 2 mg/ml ± 0.2 mg/ml to 125 mg/ml ± 12.5 mg/ml.
  4. 4. The pharmaceutical formulation of claim 3, wherein the antibody concentration is 2 mg/ml ± 0.2 mg/ml.
  5. 5. The pharmaceutical formulation of claim 3, wherein the antibody concentration is 10 mg/ml ± 1 mg/ml.
  6. 6. The pharmaceutical formulation of claim 3, wherein the antibody concentration is 20 mg/ml ± 2 mg/ml.
  7. 7. The pharmaceutical formulation of claim 3, wherein the antibody concentration is 120 mg/ml ± 12.0 mg/ml.
  8. 8. The pharmaceutical formulation of any one of claims 1 to 7, wherein the histidine buffer concentration is from 2 mM ± 0.4 mM to 20 mM ± 4 mM.
  9. 9. The pharmaceutical formulation of claim 8, wherein the histidine buffer concentration is from 5 mM ± 1 mM to 15 mM ± 3 mM.
  10. 10. The pharmaceutical formulation of claim 8, wherein the histidine buffer concentration is from 8 mM to 12 mM.
  11. 11. The pharmaceutical formulation of claim 8, wherein the histidine buffer concentration is 10 mM ± 2 mM.
  12. 12. The pharmaceutical formulation of any one of claims 1 to 11, wherein the polysorbate concentration is from 0.01% ± 0.005% to 0.5% ± 0.25% w/v.
  13. 13. The pharmaceutical formulation of claim 12, wherein the polysorbate concentration is from 0.05% ± 0.025% to 0.15% ± 0.025% w/v.
  14. 14. The pharmaceutical formulation of claim 12, wherein the polysorbate concentration if from 0.05% to 0.15% w/v.
  15. 15. The pharmaceutical formulation of claim 12, wherein the polysorbate concentration is 0.1% ± 0.05% w/v.
  16. 16. The pharmaceutical formulation of any one of claims 1 to 15, wherein the polysorbate is polysorbate 80.
  17. 17. The pharmaceutical formulation of any one of claims 1 to 16, wherein the sugar is sucrose.
  18. 18. The pharmaceutical formulation of claim 17, wherein the sucrose concentration is from 5% ± 1% to 20% ± 4% w/v.
  19. 19. The pharmaceutical formulation of claim 18, wherein the sucrose concentration is from 7% ± 0.5% to 12% ± 0.5% w/v.
  20. 20. The pharmaceutical formulation of claim 18, wherein the sucrose concentration is from 8% to 12% w/v.

Description

STABILIZED FORMULATIONS CONTAINING ANTI-BCMA X ANTI-CD3 BISPECIFIC ANTIBODIES REFERENCE TO A SEQUENCE LISTING [0001] This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 10853WO01_Sequence, created on July 5, 2024 and containing 27,595 bytes. FIELD OF THE INVENTION [0002] 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 bispecific antibody that specifically binds to human BCMA and human CD3. BACKGROUND [0003] 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 and/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 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 other properties which enable the formulation to be conveniently administered to patients. [0004] B-cell maturation antigen (BCMA), also known as TNFRSF17, or CD269, is a type III transmembrane protein lacking a signal peptide and containing a cysteine-rich extracellular domain. BCMA, along with closely related proteins, promotes B-cell survival at distinct stages of development. BCMA is expressed exclusively in B-cell lineage cells, particularly in the interfollicular region of the germinal center as well as on plasmablasts and differentiated plasma cells. BCMA is selectively induced during plasma cell differentiation, and is required for optimal survival of long-lived plasma cells in the bone marrow. In multiple myeloma, BCMA is widely expressed on malignant plasma cells at elevated levels, and BCMA expression is increased with progression from normal cells to active multiple myeloma. BCMA is also expressed in other B-cell malignancies, including Waldenström’s macroglobulinemia, Burkitt lymphoma, and Diffuse Large B-Cell Lymphoma. CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex (TCR) and is required for T cell activation. [0005] Bispecific antibodies to human BCMA and human CD3 are one example of therapeutically relevant macromolecules that require proper formulation. Such antibodies are clinically useful for, e.g., the treatment of cancer (e.g., BCMA-expressing cancers, multiple myeloma). [0006] Although anti-BCMA x anti-CD3 bispecific antibodies are known in the art (see, e.g., WO 2020/018820), there remains a need for pharmaceutical formulations comprising anti- BCMA x anti-CD3 bispecific antibodies that are sufficiently stable and suitable for administration to patients. BRIEF SUMMARY OF THE INVENTION [0007] Stable liquid pharmaceutical formulations comprising a bispecific anti-BCMA x anti- CD3 antibody and one or more excipients, as well as kits, unit dosage forms, and containers comprising such formulations and uses thereof, are provided. [0008] In one aspect, the present invention provides a stable liquid pharmaceutical formulation comprising: (a) a bispecific antibody comprising a first antigen-binding domain that binds specifically to human BCMA and a second antigen-binding domain that binds specifically to human CD3, wherein the first antigen-binding domain comprises three heavy chain complementarity determining regions (CDRs) (A1-HCDR1, A1-HCDR2 and A1- HCDR3) contained in a heavy chain variable region (HCVR) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR), and the second antigen-binding domain comprises three heavy chain CDRs (A2-HCDR1, A2-HCDR2 and A2-HCDR3) contained in a heavy chain variable region (HCVR) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR), wherein A1-HCDR1, A1-HCDR2 and A1-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 2, 3 and 4, A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 10, 11 and 12, and LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 6, 7 and 8; (b) a buffer comprising histidine; (c) an organic co-solvent comp