Subcutaneous anti-HER2 antibody formulations and uses thereof
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.
1 . A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising:
a. 120±18 mg/mL anti-HER2 antibody, wherein the antibody is Trastuzumab;
b. 1 to 50±5% mM of a buffering agent providing a pH of 5.5±0.6;
c. 150 to 250±5% mM of α,α-trehalose dihydrate or sucrose as a first stabilizer and
5 to 15±5% mM methionine as a second stabilizer;
d. 0.01 to 0.1%±5% of a nonionic surfactant; and
e. 1,000 to 16,000±5% U/mL of at least one hyaluronidase enzyme.
2 . The formulation according to claim 1 , wherein the anti-HER2 antibody concentration is 110 mg/mL, 120 mg/mL, or 130 mg/mL.
3 . The formulation according to claim 1 , comprising 2,000 U/mL to 12,000 U/mL of a hyaluronidase enzyme.
4 . The formulation according to claim 1 , wherein the buffering agent is a histidine buffer.
5 . The formulation according to claim 1 , wherein the first stabilizer is α,α-trehalose dihydrate.
6 . 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.
7 . The formulation according to claim 6 , wherein the concentration of the polysorbate is 0.02%, 0.04%, or 0.06%.
8 . The formulation according to claim 1 , which is stable upon freezing and thawing.
9 . The formulation according to claim 1 , wherein the hyaluronidase enzyme is recombinant humanized PH20 (rHuPH20).
10 . The formulation according to claim 1 , for the treatment of a disease or disorder amenable to treatment with an anti-HER2 antibody.
11 . An injection device comprising a highly concentrated, stable, liquid pharmaceutical anti-HER2 antibody formulation according to claim 1 .
12 . The injection device according to claim 11 wherein the formulation is co-administered concomitantly or sequentially with a chemotherapeutic agent.
13 . A method of treating cancer cells expressing HER2 receptor in a subject comprising administering a formulation according to claim 1 to the subject in an amount effective to treat the cancer cells.
14 . 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.
15 . The kit according to claim 14 further comprising an injection device for subcutaneous administration of the formulation to a patient.
16 . A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising:
a. 100 to 150 mg/mL anti-HER2 antibody, wherein the antibody is Trastuzumab;
b. 1 to 50 mM of a buffering agent providing a pH of 5.5±0.6;
c. 150 to 250 mM of α,α-trehalose dihydrate or sucrose as a first stabilizer and 5 to 15 mM methionine as a second stabilizer;
d. 0.01 to 0.1% of a nonionic surfactant; and
e. 1,000 to 16,000 U/mL of at least one hyaluronidase enzyme.
17 . The formulation according to claim 16 , wherein the anti-HER2 antibody concentration is 110 mg/mL, 120 mg/mL, or 130 mg/mL.
18 . The formulation according to claim 16 , comprising 2,000 U/mL to 12,000 U/mL of a hyaluronidase enzyme.
19 . The formulation according to claim 16 , wherein the buffering agent is a histidine buffer.
20 . The formulation according to claim 16 , wherein the first stabilizer is α,α-trehalose dihydrate.
21 . The formulation according to claim 16 , wherein the nonionic surfactant is a polysorbate selected from the group consisting of polysorbate 20, polysorbate 80, and polyethylene-polypropylene copolymer.
22 . The formulation according to claim 21 , wherein the concentration of the polysorbate is 0.02%, 0.04%, or 0.06%.
23 . The formulation according to claim 16 , which is stable upon freezing and thawing.
24 . The formulation according to claim 16 , wherein the hyaluronidase enzyme is recombinant humanized PH20 (rHuPH20).
25 . The formulation according to claim 16 , for the treatment of a disease or disorder amenable to treatment with an anti-HER2 antibody.
26 . An injection device comprising a highly concentrated, stable, liquid pharmaceutical anti-HER2 antibody formulation according to claim 16 .
27 . A method of treating cancer cells expressing HER2 receptor in a subject comprising administering a formulation according to claim 16 to the subject in an amount effective to treat the cancer cells.
28 . A kit comprising one or more vials containing the formulation according to claim 16 and instructions for subcutaneous administration of the formulation to a patient.
29 . A highly concentrated, stable liquid pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising:
a. 120±18 mg/mL anti-HER2 antibody, wherein the antibody is Trastuzumab;
b. 10 to 30 mM of a histidine buffer;
c. 150 to 250 mM±2% of α,α-trehalose dihydrate or sucrose as a first stabilizer and
5 to 15 mM methionine as a second stabilizer;
d. 0.01 to 0.1% of a nonionic surfactant; and
e. 1,000 to 16,000±2% U/mL of at least one hyaluronidase enzyme.
30 . The formulation according to claim 29 , wherein the pH of the formulation is 5.5±0.6.