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 liquid antibody formulation comprising, in an aqueous carrier: (a) at least 40 mg/ml of antibody that immunospecifically binds to a respiratory syncytial virus (RSV) F antigen, wherein the antibody is not palivizumab or an antigen-binding fragment thereof; and (b) histidine. 
     
     
         59 . A liquid antibody formulation comprising at least 40 mg/ml of an antibody that immunospecifically binds to a RSV antigen in an aqueous carrier, the formulation (i) having been prepared by a process in which, for each step of said process, said antibody is in an aqueous phase; and (ii) being suitable for injection in a human subject, and wherein the antibody is not palivizumab or an antigen-binding fragment thereof. 
     
     
         60 . The liquid formulation of  claim 58 , wherein histidine is at a concentration of about 1 mM to about 100 mM. 
     
     
         61 . The liquid antibody formulation of  claim 58 , wherein the histidine is at a concentration of about 10 mM to about 50 mM. 
     
     
         62 . The liquid antibody formulation of  claim 58 , wherein the histidine is at a concentration of about 20 mM to about 30 mM. 
     
     
         63 . The liquid antibody formulation of  claim 58 , wherein the histidine is at a concentration of about 25 mM. 
     
     
         64 . The liquid antibody formulation of  claim 58 , wherein the antibody is at a concentration of at least 50 mg/ml, at least 55 mg/ml, at least 60 mg/ml, at least 65 mg/ml, at least 70 mg/ml, at least 75 mg/ml, at least 80 mg/ml, at least 85 mg/ml, at least 90 mg/ml, at least 95 mg/ml or at least 100 mg/ml. 
     
     
         65 . The liquid antibody formulation of  claim 63 , wherein the antibody is at a concentration of at least 80 mg/ml. 
     
     
         66 . The liquid antibody formulation of  claim 58 , wherein the formulation has a pH of about 5.5 to about 7.0. 
     
     
         67 . The liquid antibody formulation of  claim 58 , wherein the formulation has a pH of about 6.0. 
     
     
         68 . The liquid antibody formulation of  claim 63 , wherein the formulation has a pH of about 6.0. 
     
     
         69 . The liquid antibody formulation of  claim 65 , wherein the formulation has a pH of about 6.0. 
     
     
         70 . The liquid antibody formulation of  claim 58 , wherein the formulation is substantially free of surfactants and inorganic salts. 
     
     
         71 . The liquid antibody formulation of  claim 58 , wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 
     
     
         72 . The liquid antibody formulation of  claim 58 , wherein the formulation further comprises an excipient. 
     
     
         73 . The liquid antibody formulation of  claim 72 , wherein the excipient is glycine, a saccharide, or a polyol. 
     
     
         74 . The liquid antibody formulation of  claim 58 , wherein the aqueous carrier is distilled water. 
     
     
         75 . The liquid antibody formulation of  claim 69 , wherein the aqueous carrier is distilled water. 
     
     
         76 . The liquid antibody formulation of  claim 58 , wherein the formulation is sterile. 
     
     
         77 . The liquid antibody formulation of  claim 69 , wherein the formulation is sterile. 
     
     
         78 . The liquid antibody formulation of  claim 75 , wherein the formulation is sterile. 
     
     
         79 . The liquid antibody formulation of  claim 58 , wherein the formulation is stable at 40° C. for at least 100 days as determined by high performance size exclusion chromatography (HPSEC). 
     
     
         80 . The liquid antibody formulation of  claim 69 , wherein the formulation is stable at 40° C. for at least 100 days as determined by HPSEC. 
     
     
         81 . The liquid antibody formulation of  claim 58 , wherein the formulation is stable at 4° C. for at least 3 years as determined by HPSEC. 
     
     
         82 . The liquid antibody formulation of  claim 69 , wherein the formulation is stable at 4° C. for at least 3 years as determined by HPSEC. 
     
     
         83 . The liquid antibody formulation of  claim 58  which has been prepared by a process in which, for each step of the process, the antibody is in an aqueous phase. 
     
     
         84 . The liquid antibody formulation of  claim 69  which has been prepared by a process in which, for each step of the process, the antibody is in an aqueous phase. 
     
     
         85 . The liquid antibody formulation of  claim 58 , wherein the antibody comprises:
 a. a variable heavy (VH) domain having the amino acid sequence of SEQ ID NO: 9, 17, 24, 28, 33, 36, 40, 44, 48, 51, 55, 67, 70 or 78;   b. a variable light (VL) domain having the amino acid sequence of SEQ ID NO: 11, 13, 21, 26, 30, 34, 38, 42, 46, 49, 52, 54, 56, 58, 60, 62, 64, 65, 68, 71, 74 or 76;   c. a VH domain having the amino acid sequence of SEQ ID NO: 9, 17, 24, 28, 33, 36, 40, 44, 48, 51, 55, 67, 70 or 78 and a VL domain having the amino acid sequence of SEQ ID NO: 11, 13, 21, 26, 30, 34, 38, 42, 46, 49, 52, 54, 56, 58, 60, 62, 64, 65, 68, 71, 74 or 76;   d. a VH complementarity determining region (CDR) having the amino acid sequence of SEQ ID NO: 1, 2, 3, 10, 12, 18, 19, 20, 25, 29, 37, 41, 45 or 79;   e. a variable light (VL) CDR having the amino acid sequence of SEQ ID NO: 4, 5, 6, 14, 15, 16, 22, 23, 26, 27, 31, 32, 35, 39, 43, 47, 53, 57, 59, 61, 63, 66, 69, 72, 73, 75 or 77;   f. a VH CDR having the amino acid sequence of SEQ ID NO: 1, 2, 3, 10, 12, 18, 19, 20, 25, 29, 37, 41, 45 or 79 and a VL CDR having the amino acid sequence of SEQ ID NO: 4, 5, 6, 14, 15, 16, 22, 23, 26, 27, 31, 32, 35, 39, 43, 47, 53, 57, 59, 61, 63, 66, 69, 72, 73, 75 or 77;   g. a VH CDR having the amino acid sequence of a VH CDR in Table 1 or Table 2;   h. a VL CDR having the amino acid sequence of a VL CDR in Table 1 or Table 2; or   i. a VH CDR having the amino acid sequence of a VH CDR in Table 1 or Table 2 and a VL CDR having the amino acid sequence of a VL CDR in Table 1 or Table 2.   
     
     
         86 . The liquid antibody formulation of  claim 69 , wherein the antibody comprises:
 a. a variable heavy (VH) domain having the amino acid sequence of SEQ ID NO: 9, 17, 24, 28, 33, 36, 40, 44, 48, 51, 55, 67, 70 or 78;   b. a variable light (VL) domain having the amino acid sequence of SEQ ID NO: 11, 13, 21, 26, 30, 34, 38, 42, 46, 49, 52, 54, 56, 58, 60, 62, 64, 65, 68, 71, 74 or 76;   c. a VH domain having the amino acid sequence of SEQ ID NO: 9, 17, 24, 28, 33, 36, 40, 44, 48, 51, 55, 67, 70 or 78 and a VL domain having the amino acid sequence of SEQ ID NO: 11, 13, 21, 26, 30, 34, 38, 42, 46, 49, 52, 54, 56, 58, 60, 62, 64, 65, 68, 71, 74 or 76;   d. a VH complementarity determining region (CDR) having the amino acid sequence of SEQ ID NO: 1, 2, 3, 10, 12, 18, 19, 20, 25, 29, 37, 41, 45 or 79;   e. a variable light (VL) CDR having the amino acid sequence of SEQ ID NO: 4, 5, 6, 14, 15, 16, 22, 23, 26, 27, 31, 32, 35, 39, 43, 47, 53, 57, 59, 61, 63, 66, 69, 72, 73, 75 or 77;   f. a VH CDR having the amino acid sequence of SEQ ID NO: 1, 2, 3, 10, 12, 18, 19, 20, 25, 29, 37, 41, 45 or 79 and a VL CDR having the amino acid sequence of SEQ ID NO: 4, 5, 6, 14, 15, 16, 22, 23, 26, 27, 31, 32, 35, 39, 43, 47, 53, 57, 59, 61, 63, 66, 69, 72, 73, 75 or 77;   g. a VH CDR having the amino acid sequence of a VH CDR in Table 1 or Table 2;   h. a VL CDR having the amino acid sequence of a VL CDR in Table 1 or Table 2; or   i. a VH CDR having the amino acid sequence of a VH CDR in Table 1 or Table 2 and a VL CDR having the amino acid sequence of a VL CDR in Table 1 or Table 2.   
     
     
         87 . The liquid antibody formulation of  claim 58 , wherein the antibody is conjugated to a therapeutic moiety, a drug moiety, a diagnostic agent or a detectable agent. 
     
     
         88 . The liquid antibody formulation of  claim 59 , wherein the formulation comprises histidine. 
     
     
         89 . The liquid antibody formulation of  claim 88 , wherein the histidine is at a concentration of about 10 mM to about 50 mM. 
     
     
         90 . The liquid antibody formulation of  claim 59 , wherein the antibody is at a concentration of at least 50 mg/ml, at least 55 mg/ml, at least 60 mg/ml, at least 65 mg/ml, at least 70 mg/ml, at least 75 mg/ml, at least 80 mg/ml, at least 85 mg/ml, at least 90 mg/ml, at least 95 mg/ml or at least 100 mg/ml. 
     
     
         91 . The liquid antibody formulation of  claim 59 , wherein the formulation is at a pH of about 5.5 to about 7.0. 
     
     
         92 . The liquid antibody formulation of  claim 59 , wherein the formulation is substantially free of surfactants, inorganic salts and other excipients. 
     
     
         93 . The liquid antibody formulation of  claim 59 , wherein the formulation is stable at 40° C. for at least 100 days as determined by HPSEC. 
     
     
         94 . The liquid antibody formulation of  claim 59 , wherein the formulation is stable at 4° C. for at least 3 years as determined by HPSEC. 
     
     
         95 . The liquid antibody formulation of  claim 59 , wherein the antibody comprises:
 a. a variable heavy (VH) domain having the amino acid sequence of SEQ ID NO: 9, 17, 24, 28, 33, 36, 40, 44, 48, 51, 55, 67, 70 or 78;   b. a variable light (VL) domain having the amino acid sequence of SEQ ID NO: 11, 13, 21, 26, 30, 34, 38, 42, 46, 49, 52, 54, 56, 58, 60, 62, 64, 65, 68, 71, 74 or 76;   c. a VH domain having the amino acid sequence of SEQ ID NO: 9, 17, 24, 28, 33, 36, 40, 44, 48, 51, 55, 67, 70 or 78 and a VL domain having the amino acid sequence of SEQ ID NO: 11, 13, 21, 26, 30, 34, 38, 42, 46, 49, 52, 54, 56, 58, 60, 62, 64, 65, 68, 71, 74 or 76;   d. a VH complementarity determining region (CDR) having the amino acid sequence of SEQ ID NO: 1, 2, 3, 10, 12, 18, 19, 20, 25, 29, 37, 41, 45 or 79;   e. a variable light (VL) CDR having the amino acid sequence of SEQ ID NO: 4, 5, 6, 14, 15, 16, 22, 23, 26, 27, 31, 32, 35, 39, 43, 47, 53, 57, 59, 61, 63, 66, 69, 72, 73, 75 or 77;   f. a VH CDR having the amino acid sequence of SEQ ID NO: 1, 2, 3, 10, 12, 18, 19, 20, 25, 29, 37, 41, 45 or 79 and a VL CDR having the amino acid sequence of SEQ ID NO: 4, 5, 6, 14, 15, 16, 22, 23, 26, 27, 31, 32, 35, 39, 43, 47, 53, 57, 59, 61, 63, 66, 69, 72, 73, 75 or 77;   g. a VH CDR having the amino acid sequence of a VH CDR in Table 1 or Table 2;   h. a VL CDR having the amino acid sequence of a VL CDR in Table 1 or Table 2; or   i. a VH CDR having the amino acid sequence of a VH CDR in Table 1 or Table 2 and a VL CDR having the amino acid sequence of a VL CDR in Table 1 or Table 2.   
     
     
         96 . The liquid antibody formulation of  claim 59 , wherein the antibody is conjugated a therapeutic moiety, a drug moiety, a diagnostic agent or a detectable agent. 
     
     
         97 . A pharmaceutical unit dosage form comprising the formulation of  claim 58 , which dosage form is suitable for administration to a human and is in a suitable container. 
     
     
         98 . A pharmaceutical unit dosage form comprising the formulation of  claim 69 , which dosage form is suitable for administration to a human and is in a suitable container. 
     
     
         99 . A pharmaceutical unit dosage form comprising the formulation of  claim 59 , which dosage form is suitable for administration to a human and is in a suitable container. 
     
     
         100 . The pharmaceutical unit dosage of  claim 98 , wherein the antibody has a concentration of at least 80 mg/ml in a volume of 1.2 ml. 
     
     
         101 . A method for preventing, treating or managing a RSV infection, comprising administering to a subject a prophylactically or therapeutically effective amount of the formulation of  claim 58 . 
     
     
         102 . A method for preventing, treating or managing a RSV infection, comprising administering to a subject a prophylactically or therapeutically effective amount of the formulation of  claim 69 . 
     
     
         103 . A method for preventing, treating or managing a RSV infection, comprising administering to a subject a prophylactically or therapeutically effective amount of the formulation of  claim 59 .