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US-20260125458-A1 - BISPECIFIC ANTI-VEGF/ANG2 ANTIBODY FORMULATION

US20260125458A1US 20260125458 A1US20260125458 A1US 20260125458A1US-20260125458-A1

Abstract

This invention relates to a pharmaceutical formulation of a bispecific anti-VEGF/ANG2 antibody, and a process for the preparation and uses of the formulation.

Inventors

  • Christian Freichel
  • Claudia Mueller
  • Robert Mueller
  • Piotr Jan Szczesny
  • Martin Worgull
  • Christine Wurth

Assignees

  • HOFFMANN-LA ROCHE INC.

Dates

Publication Date
20260507
Application Date
20251121

Claims (20)

  1. 1 . A liquid pharmaceutical formulation comprising: 120 mg/ml±18 mg/ml of a bispecific antibody against human Angiopoietin-2 and human vascular endothelial growth factor (bispecific anti-VEGF/ANG2 antibody) comprising a constant heavy chain region of human IgG1 subclass, 15 to 35 mM of sodium chloride, 15 to 25 mM of a histidine acetate buffer, at a pH of 5.5±0.5; wherein the bispecific anti-VEGF/ANG2 antibody is bivalent and comprises a first antigen-binding site that specifically binds to human vascular endothelial growth factor (VEGF) and a second antigen-binding site that specifically binds to human Angiopoietin-2 (ANG-2), wherein i) said first antigen-binding site specifically binding to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO:3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:6; and ii) said second antigen-binding site specifically binding to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of, SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A and P329G (numberings according to EU Index of Kabat.
  2. 2 . The pharmaceutical formulation according to claim 1 , wherein the bispecific anti-VEGF/ANG2 antibody is bivalent and comprises a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein i) said first antigen-binding site specifically binding to VEGF comprises as heavy chain variable domain VH an amino acid sequence of SEQ ID NO: 7, and as light chain variable domain VL an amino acid sequence of SEQ ID NO: 8, and ii) said second antigen-binding site specifically binding to ANG-2 comprises as heavy chain variable domain VH an amino acid sequence of SEQ ID NO: 15, and as light chain variable domain VL an amino acid sequence of SEQ ID NO: 16.
  3. 3 . The pharmaceutical formulation according to claim 2 , wherein the bispecific anti-VEGF/ANG2 antibody is bivalent and comprises a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein iv) in the constant heavy chain region a S354C and T366W mutations are comprised in one CH3 domain and Y349C, T366S, L368A and Y407V mutations are comprised the other CH3 domain (numberings according to EU Index of Kabat).
  4. 4 . The pharmaceutical formulation according to any one of claims 1 to 3 , wherein the bispecific anti-VEGF/ANG2 antibody is bivalent and comprises the amino acid sequences of SEQ ID NO: 17, of SEQ ID NO: 18, of SEQ ID NO: 19, and of SEQ ID NO: 20.
  5. 5 . The pharmaceutical formulation according to any one of claims 1 to 3 , wherein the bispecific anti-VEGF/ANG2 antibody is faricimab.
  6. 6 . The pharmaceutical formulation according to any one of claims 1 to 5 for intravitreal administration.
  7. 7 . The pharmaceutical formulation according to any one of claims 1 to 6 , wherein the formulation is essentially free of visible particles.
  8. 8 . The pharmaceutical formulation according to any one of claims 1 to 7 , wherein the formulation further comprises 1 to 20 mM of at least one stabilizer.
  9. 9 . The pharmaceutical formulation according to any one of claims 1 to 7 , wherein the formulation further comprises 7.0 mM±2.0 mM methionine.
  10. 10 . The pharmaceutical formulation according to any one of claims 1 to 9 , wherein the formulation further comprises 0.01-0.07% (w/v) of a surfactant.
  11. 11 . The pharmaceutical formulation according to any one of claims 1 to 9 , wherein the formulation further comprises 0.03% to 0.07% (w/v) polysorbate 20.
  12. 12 . The pharmaceutical formulation according to any one of claims 1 to 11 , wherein the formulation further comprises 50-250 mM of a tonicity agent.
  13. 13 . The pharmaceutical formulation according to any one of claims 1 to 11 , wherein the formulation further comprises 160 mM±24 mM sucrose.
  14. 14 . The pharmaceutical formulation according to any one of claims 1 to 13 , wherein the formulation has a viscosity of 20 mPas or less.
  15. 15 . The pharmaceutical formulation according to any one of claims 1 to 14 , wherein the formulation has a turbidity of 30 FTU or less.
  16. 16 . The pharmaceutical formulation according to any one of claims 1 to 15 , wherein the formulation has an ionic strength between 20 and 50.
  17. 17 . The pharmaceutical formulation according to any one of claims 1 to 16 , wherein formulation is a stable formulation.
  18. 18 . The pharmaceutical formulation according to any one of claims 1 to 17 , wherein the high molecular weight species (HMW) content of the bispecific antibody in the pharmaceutical formulation is below 10% after 8 weeks at 25° C. or after 52 weeks at 25° C.
  19. 19 . The pharmaceutical formulation according to any one of claims 1 to 18 , wherein the osmolality of the formulation is 300±100 mOsm/kg.
  20. 20 . A method of treating an ocular vascular disease comprising administering the pharmaceutical formulation according to any one of claims 1 to 19 .

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a Continuation of U.S. application Ser. No. 17/242,667, filed Apr. 28, 2021, which is a continuation of International Application No. PCT/EP2019/079137, filed Oct. 25, 2019, which claims benefit of priority to EP Application Serial No. 18203104.7 filed Oct. 29, 2018, each of which is incorporated herein by reference in its entirety. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Nov. 12, 2025, is named P35108-US-1_SL.xml and is 33,558 bytes in size. FIELD OF THE INVENTION This invention relates to a liquid pharmaceutical formulation of bispecific antibodies against Angiopoietin-2 (ANG-2) and human vascular endothelial growth factor (VEGF, VEGF-A) (bispecific anti-VEGF/ANG2 antibodies) and a process for the preparation and uses of the formulation. BACKGROUND Bispecific antibodies against Angiopoietin-2 (ANG-2) and human vascular endothelial growth factor (VEGF, VEGF-A) (bispecific anti-VEGF/ANG2 antibodies), are of therapeutic interest, in particular as medicaments for the treatment and prophylaxis of treatment of vascular diseases, including ocular vascular disease. Bispecific anti-VEGF/ANG2 antibodies are for example described in WO2010/040508, WO2011/117329 or WO2014/009465. These antibodies inhibit Vegf binding to the VEGF receptor and at the same time ANG-2 binding to Tie2. Antibody molecules, as part of the group of protein pharmaceuticals, are very susceptible to physical and chemical degradation. Chemical degradation includes any process that involves modification of the protein via bond formation or cleavage, yielding a new chemical entity. A variety of chemical reactions is known to affect proteins. These reactions can involve hydrolysis including cleavage of peptide bonds as well as deamidation, isomerization, oxidation and decomposition. Physical degradation refers to changes in the higher order structure and includes denaturation, adsorption to surfaces, aggregation and precipitation. Protein stability is influenced by the characteristics of the protein itself, e.g. the amino acid sequence, the glycosylation pattern, and by external influences, such as temperature, solvent pH, excipients, interfaces, or shear rates. So, it is important to define the optimal formulation conditions to protect the protein against degradation reactions during manufacturing, storage and administration. (Manning, M. C., et al. (1989), “Stability of protein pharmaceuticals”, Pharm Res 6(11), 903-918; Zheng, J. Y., Janis, L. J. (2005), “Influence of pH, buffer species, and storage temperature on physicochemical stability of a humanized monoclonal antibody LA298”, Int. J. Pharmaceutics 308, 46-51). Stable liquid formulations of therapeutic antibodies are particularly difficult to obtain when the formulation should include antibodies in a high concentration. It is therefore an object of the present invention to provide a liquid, in particular high concentration, formulation of a bispecific VEGF/ANG2 antibody with as few as necessary excipients, which enables the desired dosing and allows convenient intravitreal administration of the bispecific antibody through thin needles to a patient. SUMMARY The present invention relates to a liquid pharmaceutical formulation of a bispecific anti-VEGF/ANG2 antibody, a method for the preparation and uses of the formulation. In particular, the pharmaceutical formulations of the present invention are for use in intravitreal administration for the treatment of ophthalmologic diseases like AMD and DME. In one aspect, the invention refers to a liquid pharmaceutical formulation, comprising: 20 to 150 mg/ml of a bispecific anti-VEGF/ANG2 antibody comprising a constant heavy chain region of human IgG1 subclass15 to 35 mM of sodium chloride15 to 25 mM of a histidine acetate bufferat a pH of 5.5±0.5; whereinthe bispecific anti-VEGF/ANG2 antibody is bivalent and comprises a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, whereini) said first antigen-binding site specifically binding to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR 1H region of SEQ ID NO:3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:6; andii) said second antigen-binding site specifically binding to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of, SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14,and whereiniii) the bispecific antibody comprises a constant heavy chain region of