Anti-c-met antibody formulations

Abstract

Provided herein are pharmaceutical formulations comprising a one-armed, anti-c-met antibody and uses of the same.

1 . A pharmaceutical formulation comprising:
 (a) an anti-c-met antibody, wherein the anti-c-met antibody comprises a HVR-L1 comprising sequence KSSQSLLYTSSQKNYLA (SEQ ID NO:1), a HVR-L2 comprising sequence WASTRES (SEQ ID NO:2), a HVR-L3 comprising sequence QQYYAYPWT (SEQ ID NO:3), a HVR-H1 comprising sequence GYTFTSYWLH (SEQ ID NO:4), a HVR-H2 comprising sequence GMIDPSNSDTRFNPNFKD (SEQ ID NO:5), and a HVR-H3 comprising sequence ATYRSYVTPLDY (SEQ ID NO:6) and wherein the anti-c-met antibody comprises a single antigen binding arm and comprises a Fc region, wherein the Fc region comprises a first and a second Fc polypeptide, and wherein the first and second Fc polypeptides are present in a complex;   (b) a histidine buffer at pH 5.0-5.4;   (c) a saccharide; and   (d) a polysorbate, wherein the polysorbate is present at greater than 0.02% w/v.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the anti-c-met antibody comprises (a) a heavy chain variable domain comprising the sequence: EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDT RFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTV SS (SEQ ID NO:19) and (b) a light chain variable domain comprising the sequence: DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTR ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIKR (SEQ ID NO:20). 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the first and second Fc polypeptides form a Fc region that increases stability of said antibody fragment compared to a Fab molecule comprising said antigen binding arm. 
     
     
         4 . The pharmaceutical formulation of any one of  claim 1 - 3 , wherein the anti-c-met antibody comprises (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO:19, a CH1 sequence, and a first Fc polypeptide and (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO:20 and CL1 sequence. 
     
     
         5 . The pharmaceutical formulation of  claim 4 , wherein the anti-c-met antibody further comprises (c) a third polypeptide comprising a second Fc polypeptide. 
     
     
         6 . The pharmaceutical formulation of any one of  claims 1 - 5 , wherein the first Fc polypeptide comprises the Fc sequence depicted in  FIG. 2  (SEQ ID NO: 17) and the second Fc polypeptide comprises the Fc sequence depicted in  FIG. 3  (SEQ ID NO: 18). 
     
     
         7 . The pharmaceutical formulation of any one of  claims 1 - 6 , wherein the anti-c-met antibody is onartuzumab. 
     
     
         8 . The pharmaceutical formulation of any one of  claims 1 - 7 , wherein the anti-c-met antibody binds the same epitope as onartuzumab. 
     
     
         9 . The pharmaceutical formulation of any one of  claims 1 - 8 , wherein the anti-c-met antibody is present at a concentration between about 10 mg/mL and about 100 mg/mL (e.g. about 15 mg/mL and about 75 mg/mL). 
     
     
         10 . The pharmaceutical formulation of  claim 9 , wherein the anti-c-met antibody is present at a concentration of about 60 mg/mL. 
     
     
         11 . The pharmaceutical formulation of any one of  claims 1 - 10 , wherein the saccharide is present at a concentration of about 75 mM to about 200 mM (e.g., about 100 mM to about 150 mM). 
     
     
         12 . The pharmaceutical formulation of  claim 11 , wherein the saccharide is present at a concentration of about 120 mM. 
     
     
         13 . The pharmaceutical formulation of any one of  claims 1 - 12 , wherein the saccharide is a disaccharide. 
     
     
         14 . The pharmaceutical formulation of  claim 13 , wherein the disaccharide is trehalose. 
     
     
         15 . The pharmaceutical formulation of  claim 13 , wherein the disaccharide is sucrose. 
     
     
         16 . The pharmaceutical formulation of any one of  claims 1 - 15 , wherein the histidine buffer is at a concentration of about 1 mM to about 50 mM (e.g. about 1 mM to about 25 mM). 
     
     
         17 . The pharmaceutical formulation of  claim 16 , wherein the histidine buffer is at a concentration of about 10 mM. 
     
     
         18 . The pharmaceutical formulation of any one of  claims 1 - 17 , wherein the histidine buffer is histidine acetate. 
     
     
         19 . The pharmaceutical formulation of any one of  claims 1 - 18 , wherein the polysorbate is present at a concentration greater than 0.02% and less than about 0.1%. 
     
     
         20 . The pharmaceutical formulation of  claim 19 , wherein the polysorbate is present at a concentration of about 0.04%. 
     
     
         21 . The pharmaceutical formulation of any one of  claims 1 - 20 , wherein the polysorbate is polysorbate 20. 
     
     
         22 . The pharmaceutical formulation of any one of  claims 1 - 21 , wherein the formulation is diluted with a diluent (e.g., 0.9% NaCl). 
     
     
         23 . The pharmaceutical formulation of  claim 22 , wherein the anti-c-met antibody is present at a concentration of about 1 mg/mL. 
     
     
         24 . A method of inhibiting c-met activated cell proliferation, said method comprising contacting a cell or tissue with an effective amount of the pharmaceutical formulation of any one of  claims 1 - 23 . 
     
     
         25 . A method of modulating a disease associated with dysregulation of the HGF/c-met signaling axis, said method comprising administering to a subject an effective amount of the pharmaceutical formulation of any one of  claims 1 - 23 . 
     
     
         26 . A method of treating a subject having a proliferative disorder, said method comprising administering to the subject an effective amount of the pharmaceutical formulation of any one of  claims 1 - 23 . 
     
     
         27 . The method of  claim 26 , wherein the proliferative disorder is cancer. 
     
     
         28 . The method of  claim 27 , wherein the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC)), glioblastoma, pancreatic cancer, sarcoma, renal cell carcinoma, hepatocellular carcinoma, gastric cancer, colorectal cancer, and/or breast cancer. 
     
     
         29 . The method of any one of  claims 24 - 28 , further comprising a second therapeutic agent. 
     
     
         30 . A method of making a pharmaceutical formulation of any one of  claims 1 - 23 . 
     
     
         31 . An article of manufacture comprising a container with the pharmaceutical formulation of any one of  claims 1 - 23  contained therein. 
     
     
         32 . A method of making the article of manufacture of  claim 31 .