Subcutaneous anti-HER2 Antibody Formulations and Uses Thereof

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.

What is claimed is: 
     
         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. 
     
     
         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.   
     
     
         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.