Formulations of antibody molecules to influenza virus

Abstract

This disclosure relates to formulations of peptide agents, e.g., antibodies and antigen-binding fragments thereof, that bind hemagglutinin protein of influenza viruses, and methods of their use.

1 .- 41 . (canceled) 
     
     
         42 . A formulation comprising 20 mg/mL to 30 mg/mL of an anti-hemagglutinin (HA) antibody molecule, 30 mM to 50 mM citrate-sodium phosphate, 140 mM to 160 mM sodium chloride, and 0.01% to 0.05% polysorbate 80, wherein the formulation has a pH of 6,
 wherein the antibody molecule comprises:   (a) a heavy chain (HC) immunoglobulin variable region segment comprising:   an HC CDR1 comprising the sequence S-Y-A-M-H (SEQ ID NO: 68);   an HC CDR2 comprising the sequence V-V-S-Y-D-G-N-Y-K-Y-Y-A-D-S-V-Q-G (SEQ ID NO: 69); and   an HC CDR3 comprising the sequence D-S-R-L-R-S-L-L-Y-F-E-W-L-S-Q-G-Y-F-N-P (SEQ ID NO: 70); and   (b) a light chain (LC) immunoglobulin variable region segment comprising:   an LC CDR1 comprising the sequence Q-S-I-T-F-D-Y-K-N-Y-L-A (SEQ ID NO: 145);   an LC CDR2 comprising the sequence W-G-S-Y-L-E-S (SEQ ID NO: 72); and   an LC CDR3 comprising the sequence Q-Q-H-Y-R-T-P-P-S (SEQ ID NO: 73), and   wherein the levels of high molecular weight (HMW) species and low molecular weight (LMW) species of the antibody molecule in the formulation are less than or equal to 5%, as determined by size exclusion-high performance liquid chromatography (SEC-HPLC).   
     
     
         43 . The formulation of  claim 42 , comprising 25 mg/mL of the antibody molecule. 
     
     
         44 . The formulation of  claim 42 , wherein the antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, or an amino acid sequence that differs by no more than 1, 2, 3, 4, or 5 amino acids therefrom. 
     
     
         45 . The formulation of  claim 42 , wherein the antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25. 
     
     
         46 . The formulation of  claim 42 , wherein the antibody molecule comprises a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52, or an amino acid sequence that differs by no more than 1, 2, 3, 4, or 5 amino acids therefrom. 
     
     
         47 . The formulation of  claim 42 , wherein the antibody molecule comprises a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52. 
     
     
         48 . The formulation of  claim 42 , wherein the antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, and a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52. 
     
     
         49 . The formulation of  claim 42 , comprising 40 mM citrate-sodium phosphate. 
     
     
         50 . The formulation of  claim 42 , comprising 150 mM sodium chloride. 
     
     
         51 . The formulation of  claim 42 , comprising 0.025% polysorbate 80. 
     
     
         52 . The formulation of  claim 42 , comprising 25 mg/mL of the antibody molecule, 40 mM citrate-sodium phosphate, 150 mM sodium chloride, 0.025% polysorbate 80, wherein the formulation has a pH of 6. 
     
     
         53 . The formulation of  claim 42 , wherein the level of HMW species of the antibody molecule in the formulation is less than 2% after storage for 2 weeks at 4° C. as determined by SEC-HPLC. 
     
     
         54 . The formulation of  claim 42 , wherein the level of HMW species of the antibody molecule in the formulation is less than 5% after storage for 2 weeks at 45° C. as determined by SEC-HPLC. 
     
     
         55 . The formulation of  claim 42 , wherein the level of LMW species of the antibody molecule in the formulation is less than 1% after storage for 2 weeks at 4° C. as determined by SEC-HPLC. 
     
     
         56 . The formulation of  claim 42 , which the level of LMW species of the antibody molecule in the formulation is less than 2% after storage for 2 weeks at 45° C. as determined by SEC-HPLC. 
     
     
         57 . The formulation of  claim 42 , wherein 95% or more of the antibody molecules in the formulation are present as monomers as determined by SEC-HPLC. 
     
     
         58 . The formulation of  claim 42 , wherein 98% or more of the antibody molecules in the formulation are present as monomers after storage for 2 weeks at 4° C. as determined by SEC-HPLC. 
     
     
         59 . The formulation of  claim 42 , wherein 94% or more of the antibody molecules in the formulation are present as monomers after storage for 2 weeks at 45° C. as determined by SEC-HPLC. 
     
     
         60 . The formulation of  claim 42 , wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 4° C. is at least 98% as determined by reduced CE-SDS. 
     
     
         61 . The formulation of  claim 42 , wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 45° C. is at least 95% as determined by reduced CE-SDS. 
     
     
         62 . The formulation of  claim 42 , wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 4° C. is at least 97% as determined by non-reduced CE-SDS. 
     
     
         63 . The formulation of  claim 42 , wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 45° C. is at least 92% as determined by non-reduced CE-SDS. 
     
     
         64 . The formulation of  claim 42 , wherein the activity of the antibody molecule is decreased by less than about 25% after storage for 2 weeks at 45° C. as determined by an HA-binding ELISA. 
     
     
         65 . A formulation comprising 20 mg/mL to 30 mg/mL of an HA antibody molecule, 30 mM to 50 mM citrate-sodium phosphate, 140 mM to 160 mM sodium chloride, and 0.01% to 0.05% polysorbate 80, wherein the formulation has a pH of 6,
 wherein the antibody molecule comprises:   (a) an HC immunoglobulin variable region segment comprising:   an HC CDR1 comprising the sequence S-Y-A-M-H (SEQ ID NO: 68);   an HC CDR2 comprising the sequence V-V-S-Y-D-G-N-Y-K-Y-Y-A-D-S-V-Q-G (SEQ ID NO: 69); and   an HC CDR3 comprising the sequence D-S-R-L-R-S-L-L-Y-F-E-W-L-S-Q-G-Y-F-N-P (SEQ ID NO: 70); and   (b) an LC immunoglobulin variable region segment comprising:   an LC CDR1 comprising the sequence Q-S-I-T-F-D-Y-K-N-Y-L-A (SEQ ID NO: 145);   an LC CDR2 comprising the sequence W-G-S-Y-L-E-S (SEQ ID NO: 72); and   an LC CDR3 comprising the sequence Q-Q-H-Y-R-T-P-P-S (SEQ ID NO: 73), and   wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 45° C. is at least 95% as determined by reduced CE-SDS or is at least 92% as determined by non-reduced CE-SDS.   
     
     
         66 . The formulation of  claim 65 , comprising 25 mg/mL of the antibody molecule, 40 mM citrate-sodium phosphate, 150 mM sodium chloride, 0.025% polysorbate 80, wherein the formulation has a pH of 6. 
     
     
         67 . The formulation of  claim 65 , wherein the antibody molecule comprises:
 (a) a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, or an amino acid sequence that differs by no more than 1, 2, 3, 4, or 5 amino acids therefrom;   (b) a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52, or an amino acid sequence that differs by no more than 1, 2, 3, 4, or 5 amino acids therefrom; or   (c) both (a) and (b).   
     
     
         68 . The formulation of  claim 65 , wherein the antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52, or both. 
     
     
         69 . The formulation of  claim 65 , wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 4° C. is at least 98% as determined by reduced CE-SDS or at least 97% as determined by non-reduced CE-SDS. 
     
     
         70 . A formulation comprising 20 mg/mL to 30 mg/mL of an HA antibody molecule, 30 mM to 50 mM citrate-sodium phosphate, 140 mM to 160 mM sodium chloride, and 0.01% to 0.05% polysorbate 80, wherein the formulation has a pH of 6,
 wherein the antibody molecule comprises:   (a) a heavy chain (HC) immunoglobulin variable region segment comprising:   an HC CDR1 comprising the sequence S-Y-A-M-H (SEQ ID NO: 68);   an HC CDR2 comprising the sequence V-V-S-Y-D-G-N-Y-K-Y-Y-A-D-S-V-Q-G (SEQ ID NO: 69); and   an HC CDR3 comprising the sequence D-S-R-L-R-S-L-L-Y-F-E-W-L-S-Q-G-Y-F-N-P (SEQ ID NO: 70); and   (b) a light chain (LC) immunoglobulin variable region segment comprising:   an LC CDR1 comprising the sequence Q-S-I-T-F-D-Y-K-N-Y-L-A (SEQ ID NO: 145);   an LC CDR2 comprising the sequence W-G-S-Y-L-E-S (SEQ ID NO: 72); and   an LC CDR3 comprising the sequence Q-Q-H-Y-R-T-P-P-S (SEQ ID NO: 73), and   wherein the activity of the antibody molecule is decreased by less than about 25% after storage for 2 weeks at 45° C. as determined by an HA-binding ELISA.   
     
     
         71 . The formulation of  claim 70 , comprising 25 mg/mL of the antibody molecule, 40 mM citrate-sodium phosphate, 150 mM sodium chloride, 0.025% polysorbate 80, wherein the formulation has a pH of 6. 
     
     
         72 . The formulation of  claim 70 , wherein the antibody molecule comprises:
 (a) a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, or an amino acid sequence that differs by no more than 1, 2, 3, 4, or 5 amino acids therefrom;   (b) a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52, or an amino acid sequence that differs by no more than 1, 2, 3, 4, or 5 amino acids therefrom; or   (c) both (a) and (b).   
     
     
         73 . The formulation of  claim 70 , wherein the antibody molecule comprises a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25, a light chain immunoglobulin variable region segment comprising SEQ ID NO: 52, or both. 
     
     
         74 . The formulation of  claim 70 , wherein the purity of the antibody molecule in the formulation after storage for 2 weeks at 4° C. is at least 98% as determined by reduced CE-SDS or at least 97% as determined by non-reduced CE-SDS.