Stabilized Formulations Containing Anti-PCSK9 Antibodies

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human proprotein convertase subtilisin/kexin type 9 (PCSK9). The formulations may contain, in addition to an anti-PCSK9 antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

What is claimed is: 
     
         1 . A liquid pharmaceutical formulation comprising:
 (a) 50±7.5 mg/mL to 250±37.5 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:2, an HCDR2 of SEQ ID NO:3, an HCDR3 of SEQ ID NO:4, a light chain complementarity determining region (LCDR) 1 of SEQ ID NO:6, an LCDR2 of SEQ ID NO:7, and an LCDR3 of SEQ ID NO:8;   (b) 5±0.75 mM to 50±7.5 mM histidine (pH 6.0±0.3);   (c) 0.01±0.0015% w/v polysorbate 20; and   (d) 10±1.5% w/v sucrose.   
     
     
         2 . The liquid pharmaceutical formulation of  claim 1 , wherein the histidine concentration is selected from the group consisting of:
 (i) 5±0.75 mM to 15±2.25 mM;   (ii) 6±0.9 mM to 14±2.1 mM;   (iii) 7±1.05 mM to 13±1.95 mM;   (iv) 8±1.2 mM to 12±1.8 mM;   (v) 9±1.35 mM to 11±1.65 mM; and   (vi) 10±1.5 mM.   
     
     
         3 . The liquid pharmaceutical formulation of  claim 1 , wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5. 
     
     
         4 . The liquid pharmaceutical formulation of  claim 2 , wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5. 
     
     
         5 . The liquid pharmaceutical formulation of  claim 1 , wherein the formulation comprises about 175 mg/mL of the antibody or antigen-binding fragment thereof. 
     
     
         6 . The liquid pharmaceutical formulation of  claim 1 , wherein the formulation comprises about 150 mg/mL of the antibody or antigen-binding fragment thereof. 
     
     
         7 . The liquid pharmaceutical formulation of  claim 1 , wherein the formulation comprises about 100 mg/mL of the antibody or antigen-binding fragment thereof. 
     
     
         8 . The liquid pharmaceutical formulation of  claim 1 , wherein the formulation comprises about 75 mg/mL of the antibody or antigen-binding fragment thereof. 
     
     
         9 . The liquid pharmaceutical formulation of  claim 1 , wherein the formulation comprises about 50 mg/mL of the antibody or antigen-binding fragment thereof. 
     
     
         10 . A liquid pharmaceutical formulation comprising:
 (a) 75 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:2, an HCDR2 of SEQ ID NO:3, an HCDR3 of SEQ ID NO:4, a light chain complementarity determining region (LCDR) 1 of SEQ ID NO:6, an LCDR2 of SEQ ID NO:7, and an LCDR3 of SEQ ID NO:8;   (b) histidine (pH 6.0±0.3), at a concentration selected from the group consisting of:
 (i) 5±0.75 mM to 15±2.25 mM; 
 (ii) 6±0.9 mM to 14±2.1 mM; 
 (iii) 7±1.05 mM to 13±1.95 mM; 
 (iv) 8±1.2 mM to 12±1.8 mM; 
 (v) 9±1.35 mM to 11±1.65 mM; and 
 (vi) 10±1.5 mM; 
   (c) 0.01±0.0015% w/v polysorbate 20; and   (d) 10±1.5% w/v sucrose.   
     
     
         11 . The liquid pharmaceutical formulation of  claim 10 , wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5. 
     
     
         12 . The liquid pharmaceutical formulation of  claim 10 , wherein the histidine concentration is 8±1.2 mM. 
     
     
         13 . A liquid pharmaceutical formulation comprising:
 (a) 150 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:2, an HCDR2 of SEQ ID NO:3, an HCDR3 of SEQ ID NO:4, a light chain complementarity determining region (LCDR) 1 of SEQ ID NO:6, an LCDR2 of SEQ ID NO:7, and an LCDR3 of SEQ ID NO:8;   (b) histidine (pH 6.0±0.3), at a concentration selected from the group consisting of:
 (i) 5±0.75 mM to 15±2.25 mM; 
 (ii) 6±0.9 mM to 14±2.1 mM; 
 (iii) 7±1.05 mM to 13±1.95 mM; 
 (iv) 8±1.2 mM to 12±1.8 mM; 
 (v) 9±1.35 mM to 11±1.65 mM; and 
 (vi) 10±1.5 mM; 
   (c) 0.01±0.0015% w/v polysorbate 20; and   (d) 10±1.5% w/v sucrose.   
     
     
         14 . The liquid pharmaceutical formulation of  claim 13 , wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5. 
     
     
         15 . The liquid pharmaceutical formulation of  claim 13 , wherein the histidine concentration is 6±0.9 mM. 
     
     
         16 . A liquid pharmaceutical formulation comprising:
 (a) 75 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5;   (b) histidine (pH 6.0±0.3), at a concentration selected from the group consisting of:
 (i) 5±0.75 mM to 15±2.25 mM; 
 (ii) 6±0.9 mM to 14±2.1 mM; 
 (iii) 7±1.05 mM to 13±1.95 mM; 
 (iv) 8±1.2 mM to 12±1.8 mM; 
 (v) 9±1.35 mM to 11±1.65 mM; and 
 (vi) 10±1.5 mM; 
   (c) 0.01±0.0015% w/v polysorbate 20; and   (d) 10±1.5% w/v sucrose.   
     
     
         17 . The liquid pharmaceutical formulation of  claim 16 , wherein the histidine concentration is 8±1.2 mM. 
     
     
         18 . A liquid pharmaceutical formulation comprising:
 (a) 150 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5;   (b) histidine (pH 6.0±0.3), at a concentration selected from the group consisting of:
 (i) 5±0.75 mM to 15±2.25 mM; 
 (ii) 6±0.9 mM to 14±2.1 mM; 
 (iii) 7±1.05 mM to 13±1.95 mM; 
 (iv) 8±1.2 mM to 12±1.8 mM; 
 (v) 9±1.35 mM to 11±1.65 mM; and 
 (vi) 10±1.5 mM; 
   (c) 0.01±0.0015% w/v polysorbate 20; and   (d) 10±1.5% w/v sucrose.   
     
     
         19 . The liquid pharmaceutical formulation of  claim 13 , wherein the histidine concentration is 6±0.9 mM.