Antibody formulations

Abstract

The invention provides stable aqueous pharmaceutical formulations comprising a therapeutic antibody, trehalose, a buffer, and optional surfactant, and having a pH in the range of about 5.5 to about 7.0. The invention also provides methods for making such formulations and methods of using such formulations.

1 . A stable aqueous pharmaceutical formulation, the formulation comprising a monoclonal antibody, trehalose, and a buffer, wherein the weight ratio of said monoclonal antibody to said trehalose in the formulation is greater than or equal to 0.41 and less than 1.65, wherein the formulation has a pH of about 5.5 to about 7.0, and wherein the monoclonal antibody binds VEGF. 
     
     
         2 . The formulation of  claim 1 , wherein the weight ratio of said monoclonal antibody to said trehalose is 0.49 to 1.47, 0.41 to 0.73, or 0.73 to 1.47. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The formulation of  claim 1 , wherein said monoclonal antibody in the formulation is about 25 mg/mL to about 100 mg/mL, about 45 mg/mL to about 55 mg/mL, or about 35 mg/mL to about 75 mg/mL. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The formulation of  claim 1 , wherein said trehalose in the formulation is about 45 mM to about 634 mM, about 50 mM to about 600 mM, about 150 mM to about 400 mM, about 45 mM to about 135 mM, or about 180 mM to about 634 mM. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The formulation of  claim 1 , wherein said buffer is an amount of greater than 35 mM to about 100 mM. 
     
     
         12 . The formulation of  claim 11 , wherein said buffer comprises histidine or sodium phosphate. 
     
     
         13 . (canceled) 
     
     
         14 . A stable aqueous pharmaceutical formulation, the formulation comprising (a) a monoclonal antibody in an amount of about 25 mg/mL to about 100 mg/mL; (b) trehalose in an amount of about 45 mM to about 634 mM; and (c) sodium phosphate in an amount of greater than 35 mM to about 100 mM, wherein said formulation has a pH of about 5.5 to about 7.0, wherein the weight ratio of said monoclonal antibody to said trehalose in the formulation is greater than or equal to 0.41 and less than 1.65, and wherein the monoclonal antibody binds VEGF. 
     
     
         15 - 25 . (canceled) 
     
     
         26 . The formulation of  claim 1 , further comprising a surfactant. 
     
     
         27 . The formulation of  claim 26 , wherein said surfactant is polysorbate or poloxamer. 
     
     
         28 . The formulation of  claim 26 , wherein said surfactant is polysorbate 20 or poloxamer 188. 
     
     
         29 . (canceled) 
     
     
         30 . The formulation of  claim 26 , wherein said surfactant concentration is about 0.01% to about 0.1%, about 0.01% to about 0.05%, or about 0.04%. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . The formulation of  claim 1 , wherein said formulation has a pH of about 5.9 to about 6.5 or about 6.2 or about 6.0. 
     
     
         34 . (canceled) 
     
     
         35 . The formulation of  claim 1 , wherein said monoclonal antibody is not subject to prior lyophilization. 
     
     
         36 . The formulation of  claim 1 , wherein said monoclonal antibody is a full length antibody or an antibody fragment comprising an antigen-binding region. 
     
     
         37 . (canceled) 
     
     
         38 . The formulation of  claim 36 , wherein said monoclonal antibody is a humanized antibody. 
     
     
         39 - 40 . (canceled) 
     
     
         41 . The formulation of  claim 1 , wherein said antibody is bevacizumab. 
     
     
         42 . The formulation of  claim 1 , wherein said monoclonal antibody is susceptible to aggregation. 
     
     
         43 . The formulation of  claim 1 , wherein the formulation is stable at −20° C. for at least 12 months, at least 18 months or at least 24 months. 
     
     
         44 - 46 . (canceled) 
     
     
         47 . An article of manufacture comprising a container holding the stable aqueous pharmaceutical formulation of  claim 1 . 
     
     
         48 . A method of reducing aggregation of a therapeutic monoclonal antibody, comprising formulating said antibody in a formulation comprising trehalose in an amount of about 45 mM to about 634 mM and sodium phosphate in an amount of greater than 35 mM to about 100 mM, and said formulation having a pH of about 5.5 to about 7.0, wherein said monoclonal antibody is formulated in an amount of about 25 mg/mL to about 100 mg/mL in the formulation, wherein the weight ratio of said monoclonal antibody to said trehalose in the formulation is greater than or equal to 0.41 and less than 1.65, and wherein the monoclonal antibody binds VEGF. 
     
     
         49 - 52 . (canceled) 
     
     
         53 . A method of reducing aggregation of a therapeutic monoclonal antibody, comprising formulating said antibody in a formulation comprising trehalose and a buffer, wherein the weight ratio of said monoclonal antibody to said trehalose in the formulation is greater than or equal to 0.41 and less than 1.65, wherein the formulation has a pH of about 5.5 to about 7.0, and wherein the monoclonal antibody binds VEGF. 
     
     
         54 - 74 . (canceled) 
     
     
         75 . A method of making a pharmaceutical formulation comprising:
 (a) preparing the formulation of  claim 1 ; and   (b) evaluating physical stability, chemical stability, or biological activity of the antibody in the formulation.   
     
     
         76 . A method of treating a disease or disorder in a subject comprising administering the formulation of  claim 1  to a subject in an amount effective to treat the disease or disorder. 
     
     
         77 . A stable aqueous pharmaceutical formulation for intravenous administration, the formulation comprising (a) a monoclonal antibody in an amount of less than or equal to about 100 mg/mL; and (b) trehalose in an amount of about 50 mM to about 600 mM, wherein said formulation has a pH of about 5.5 to about 7.0, and wherein the weight ratio of said monoclonal antibody to said trehalose in the formulation is greater than or equal to 0.41 and less than 1.65. 
     
     
         78 . A stable aqueous pharmaceutical formulation for subcutaneous or intraocular administration, the formulation comprising (a) a monoclonal antibody in an amount of less than or equal to about 100 mg/mL; and (b) trehalose in an amount of about 150 mM to about 400 mM, wherein said formulation has a pH of about 5.5 to about 7.0, and wherein the weight ratio of said monoclonal antibody to said trehalose in the formulation is greater than or equal to 0.41 and less than 1.65.