Stabilized anti-respiratory syncytial virus (rsv) antibody formulations

Abstract

The present invention provides liquid formulations of antibodies or fragments thereof that immunospecifically bind to a respiratory syncytial virus (RSV) antigen, which formulations exhibit stability, low to undetectable levels of aggregation, and very little to no loss of the biological activities of the antibodies or antibody fragments, even during long periods of storage. In particular, the present invention provides liquid formulations of antibodies or fragments thereof that immunospecifically bind to a RSV antigen, which formulations are substantially free of surfactant, inorganic salts, and/or other common excipients. Furthermore, the invention provides methods of preventing, treating or ameliorating one or more symptoms associated with RSV infection utilizing the liquid formulations of the present invention.

1 .- 57 . (canceled) 
     
     
         58 . A process for the preparation of a high concentration stable aqueous antibody formulation, comprising diafiltering about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, or about 150 mg/ml of an antibody that immunospecifically binds to a respiratory syncytial virus (RSV) F antigen into a formulation buffer comprising about 1 mM to about 100 mM of histidine, wherein the antibody comprises:
 a. a variable heavy (VH) complementarity determining region (CDR) 1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a variable light (VL) CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:5, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6;   b. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:50, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6;   c. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:77, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6;   d. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:11;   e. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:11;   f. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:49;   g. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:49;   h. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:76; or   i. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:76;   
       and wherein the antibody is in an aqueous phase during the preparation of the high concentration stable aqueous antibody formulation. 
     
     
         59 . The process of  claim 58 , wherein the formulation buffer comprises about 10 mM to about 50 mM of histidine, about 20 mM to about 30 mM of histidine, about 23 mM to about 27 mM of histidine, or about 25 mM of histidine. 
     
     
         60 . The process of  claim 58 , wherein the formulation buffer comprises less than 100 mM glycine, less than 3.0 mM glycine, less than 2.0 mM glycine, or 1.6 mM glycine. 
     
     
         61 . The process of  claim 58 , wherein the high concentration stable aqueous antibody formulation has a pH of about 5.0 to about 7.0, about 5.5 to about 6.5, about 5.8 to about 6.2, or about 6.0. 
     
     
         62 . The process of  claim 58 , wherein the process further comprises sterilization of the high concentration stable aqueous antibody formulation. 
     
     
         63 . The process of  claim 58 , wherein the process comprises purification of the antibody from conditioned medium and concentration of the antibody before diafiltering the antibody into the formulation buffer. 
     
     
         64 . The process of  claim 58 , wherein the high concentration stable aqueous antibody formulation is substantially free of other excipients. 
     
     
         65 . The process of  claim 58 , wherein the high concentration stable aqueous antibody formulation does not comprise mannitol. 
     
     
         66 . The process of  claim 58 , wherein the high concentration stable aqueous antibody formulation is stable at 2° C. to 8° C. for at least 15 months or at least 3 years as assessed by high performance size exclusion chromatography (HPSEC). 
     
     
         67 . The process of  claim 58 , wherein the high concentration stable aqueous antibody formulation is stable at 38° C. to 42° C. for at least 60 days as assessed by HPSEC. 
     
     
         68 . A high concentration stable aqueous antibody formulation comprising, in an aqueous carrier at least 65 mg/ml of antibody that immunospecifically binds to a RSV F antigen, and histidine at a concentration of about 1 mM to about 100 mM, wherein the antibody of the formulation is stable at 2° C. to 8° C. for 15 months as determined by HPSEC, and wherein the antibody comprises:
 a. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:5, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6; 
 b. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:50, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6; 
 c. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:77, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6; 
 d. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:11; 
 e. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:11; 
 f. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:49; 
 g. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:49; 
 h. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:76; or 
 i. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:76. 
 
     
     
         69 . A method for preventing one or more symptoms of a RSV infenction or a respiratory condition associated with a RSV infection, comprising administering to a human subject in need thereof a prophylactically effective amount of a high concentration stable aqueous antibody formulation comprising, in an aqueous carrier at least 65 mg/ml of antibody that immunospecifically binds to a RSV F antigen, and histidine at a concentration of about 1 mM to about 100 mM, wherein the antibody of the formulation is stable at 2° C. to 8 C for 15 months as determined by HPSEC, and wherein the antibody comprises:
 a. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:5, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6; 
 b. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:50, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6; 
 c. a VH CDR1 having the amino acid sequence of SEQ ID NO:10, a VH CDR2 having the amino acid sequence of SEQ ID NO:19, a VH CDR3 having the amino acid of SEQ ID NO:20, a VL CDR1 having the amino acid sequence of SEQ ID NO:39, a VL CDR2 having the amino acid sequence of SEQ ID NO:77, and a VL CDR3 having the amino acid sequence of SEQ ID NO:6; 
 d. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:11; 
 e. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:11; 
 f. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:49; 
 g. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:49; 
 h. a VH domain having the amino acid sequence of SEQ ID NO:48 and a VL domain having the amino acid sequence of SEQ ID NO:76; or 
 i. a VH domain having the amino acid sequence of SEQ ID NO:48 or a VL domain having the amino acid sequence of SEQ ID NO:76. 
 
     
     
         70 . The antibody formulation of  claim 68 , wherein the histidine is at a concentration of about 10 mM to about 50 mM, about 20 mM to about 30 mM, or about 25 mM. 
     
     
         71 . The method of  claim 69 , wherein the histidine is at a concentration of about 10 mM to about 50 mM, about 20 mM to about 30 mM, or about 25 mM. 
     
     
         72 . The antibody formulation of  claim 68 , wherein the formulation has a pH of about 5.0 to about 7.0, about 5.5 to about 6.5, or about 6.0. 
     
     
         73 . The method of  claim 69 , wherein the formulation has a pH of about 5.0 to about 7.0, about 5.5 to about 6.5, or about 6.0. 
     
     
         74 . The antibody formulation of  claim 68 , wherein the formulation is substantially free of surfactants and inorganic salts. 
     
     
         75 . The method of  claim 69 , wherein the formulation is substantially free of surfactants and inorganic salts. 
     
     
         76 . The antibody formulation of  claim 68 , wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 
     
     
         77 . The method of  claim 69 , wherein the formulation is substantially free of surfactants, inorganic salts and other excipients.