Subcutaneous anti-HER2 Antibody Formulations and Uses Thereof

• US 20160166689A1
• Filed: 02/25/2016
• Published: 06/16/2016
• Est. Priority Date: 07/31/2009
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Adler, Michael, Grauschopf, Ulla, Mahler, Hanns-Christian, Stauch, Oliver Boris
• Granted Patent: US 9,968,676 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C12Y 302/01035 Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase

Abstract

The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody, such as e.g. Trastuzumab (HERCEPTIN™), Pertuzumab or T-DM1, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-HER2 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. α,α-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.

Claims

1. A highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody comprising:

a. about 50 to 350 mg/ml anti-HER2 antibody;

b. about 1 to 100 mM of a buffering agent providing a pH of 5.5±

2.0;

c. about 1 to 500 mM of a stabilizer or a mixture of two or more stabilizers;

d. about 0.01 to 0.08% of a nonionic surfactant; and

e. an effective amount of at least one hyaluronidase enzyme.

2. The formulation according to claim 1, wherein the anti-HER2 antibody concentration is about 100 to 150 mg/ml.

3. The formulation according to claim 2, wherein the anti-HER2 antibody concentration is 120±

18 mg/ml.

4. The formulation according to claim 1, comprising more than 150 to about 16,000 U/ml of a hyaluronidase enzyme.

5. The formulation according to claim 4, comprising about 2,000 U/ml to about 12,000 U/ml of a hyaluronidase enzyme.

6. The formulation according to claim 1, wherein the buffering agent is at a concentration of 1 to 50 mM.

7. The formulation according to claim 6, wherein said buffering agent is a histidine buffer.

8. The formulation according to claim 1, wherein the formulation includes α

,α

-trehalose dihydrate or sucrose as a stabilizer.

9. The formulation according to claim 1, wherein the stabilizer is at a concentration of 15 to 250 mM.

10. The formulation according to claim 8, wherein methionine is used as a second stabilizer in a concentration of 5 to 25 mM.

11. The formulation according to claim 1, wherein the nonionic surfactant is a polysorbate selected from the group consisting of polysorbate 20, polysorbate 80, and polyethylene-polypropylene copolymer.

12. The formulation according to claim 11, wherein the concentration of the polysorbate is 0.02% (w/v), 0.04% (w/v) or 0.06% (w/v), respectively.

13. The formulation according to claim 1, wherein the anti-HER2 antibody is selected from the group of Trastuzumab, Pertuzumab and T-DM1 or a combination of such antibodies.

14. The formulation according to claim 1 which is stable upon freezing and thawing.

15. The formulation according to claim 1, wherein the hyaluronidase enzyme is rHuPH20.

16. The formulation according to claim 1, wherein the buffering agent provides a pH of 5.5±

0.5.

17. The formulation according to claim 1 for subcutaneous or intramuscular administration.

18. The formulation according to claim 1 in liquid form.

19. The formulation according to claim 1 in lyophilized form.

21. The formulation according to claim 1 for the treatment of a disease or disorder amenable to treatment with an anti-HER2 antibody.

22. An injection device comprising a highly concentrated, stable pharmaceutical anti-HER2 antibody formulation according to claim 1.

23. The injection device according to claim 22 wherein the formulation is co-administered concomitantly or sequentially with a chemotherapeutic agent.

24. A method of treating a disease or disorder which is amenable to treatment with an anti-HER2 antibody such as cancer or a non-malignant disease in a subject comprising administering a formulation according to claim 1 to a subject in an amount effective to treat the said disease or disorder.

25. The method of claim 24 wherein said disease is cancer.

26. A kit comprising one or more vials containing the formulation according to claim 1 and instructions for subcutaneous administration of the formulation to a patient.

27. The kit according to claim 26 further comprising an injection device for subcutaneous administration of the formulation to a patient.

20. A highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody comprising:

a. about 50 to 350 mg/ml anti-HER2 antibody;

b. about 1 to 100 mM of a buffering agent providing a pH of 5.5±

2.0;

c. about 1 to 500 mM of a stabilizer or a mixture of two or more stabilizers; and

d. about 0.01 to 0.08% of a nonionic surfactant.