High concentration antibody formulations
The present disclosure relates to, inter alia, stable aqueous solutions comprising a high concentration of an antibody that binds to human complement component C5 and methods for preparing the solutions. The disclosure also provides methods for treating or preventing complement-associated disorders (for example, age-related macular degeneration or rheumatoid arthritis) using the solutions. Also featured are therapeutic kits containing one or more of the solutions and a means for administering the solutions to a patient in need such a treatment.
1. A method for producing a stable concentrated antibody solution comprising eculizumab at a concentration of 100 mg/mL to 150 mg/mL, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, the method comprising:
i) providing a first aqueous solution comprising eculizumab, the first aqueous solution having a first formulation and comprising no more than 50 mg/mL of eculizumab;
ii) subjecting the first aqueous solution to diafiltration into a formulation comprising 20 mkt histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, at pH 7.0 to thereby produce a second aqueous solution, wherein the second aqueous solution has a second formulation as a result of the diafiltration; and
iii) concentrating the second aqueous solution to produce a stable concentrated antibody solution comprising 100 mg/mL to 150 mg/mL of eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol.
2. The method of claim 1 , wherein eculizumab is not lyophilized prior to or following the diafiltration or concentrating.
3. The method of claim 1 , wherein the concentrating comprises tangential flow filtration.
4. The method of claim 1 , wherein eculizumab remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC.
5. The method of claim 1 , wherein the stable concentrated antibody solution comprises 105 mg/mL of eculizumab.
6. The method of claim 1 , wherein the pH of the stable concentrated antibody solution is 7.0.
7. A method for producing a stable concentrated antibody solution consisting of eculizumab at a concentration of 100 mg/mL to 150 mg/mL, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, the method comprising:
i) providing a first aqueous solution comprising eculizumab, the first aqueous solution having a first formulation and comprising no more than 50 mg/mL of eculizumab;
ii) subjecting the first aqueous solution to diafiltration into a formulation comprising 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, at pH 7.0 to thereby produce a second aqueous solution, wherein the second aqueous solution has a second formulation as a result of the diafiltration, and
iii) concentrating the second aqueous solution to produce a stable concentrated antibody solution consisting of 100 mg/mL to 150 mg/mL of eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol.
8. The method of claim 7 , wherein eculizumab is not lyophilized prior to or following the diafiltration or concentrating.
9. The method of claim 7 , wherein the concentrating comprises tangential flow filtration.
10. The method of claim 7 , wherein eculizumab remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC.
11. The method of claim 7 , wherein the pH of the stable concentrated antibody solution is 7.0.
12. A method for producing a stable concentrated antibody solution comprising 105 mg/mL eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, the method comprising:
i) providing a first aqueous solution comprising eculizumab, the first aqueous solution having a first formulation and comprising no more than 50 mg/mL of eculizumab;
ii) subjecting the first aqueous solution to diafiltration into a formulation comprising 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, at pH 7.0 to thereby produce a second aqueous solution, wherein the second aqueous solution has a second formulation as a result of the diafiltration; and
iii) concentrating the second aqueous solution to produce a stable concentrated antibody solution comprising 105 mg/mL of eculizumab.
13. The method of claim 12 , wherein eculizumab is not lyophilized prior to or following the diafiltration or concentrating.
14. The method of claim 12 , wherein the concentrating comprises tangential flow filtration.
15. The method of claim 12 , wherein eculizumab remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC.
16. The method of claim 12 , wherein the pH of the stable concentrated antibody solution is 7.0.
17. A method for producing a stable concentrated antibody solution consisting of 105 mg/mL eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, the method comprising:
i) providing a first aqueous solution comprising eculizumab, the first aqueous solution having a first formulation and comprising no more than 50 mg/mL of eculizumab;
ii) subjecting the first aqueous solution to diafiltration into a formulation consisting of 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, at pH 7.0 to thereby produce a second aqueous solution, wherein the second aqueous solution has a second formulation as a result of the diafiltration; and
iii) concentrating the second aqueous solution to produce a stable concentrated antibody solution consisting of 105 mg/mL eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol.
18. The method of claim 17 , wherein eculizumab is not lyophilized prior to or following the diafiltration or concentrating.
19. The method of claim 17 , wherein the concentrating comprises tangential flow filtration.
20. The method of claim 17 , wherein eculizumab remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC.
21. The method of claim 17 , wherein the pH of the stable concentrated antibody solution is 7.0.
22. A method for producing a stable concentrated antibody solution consisting of 105 mg/mL eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, wherein eculizumab remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC, and wherein the pH of the stable concentrated antibody solution is 7.0, the method comprising:
i) providing a first aqueous solution comprising eculizumab, the first aqueous solution having a first formulation and comprising no more than 50 mg/mL of eculizumab;
ii) subjecting the first aqueous solution to diafiltration into a formulation consisting of 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol, at pH 7.0 to thereby produce a second aqueous solution, wherein the second aqueous solution has a second formulation as a result of the diafiltration; and
iii) concentrating the second aqueous solution to produce a stable concentrated antibody solution consisting of 105 mg/mL eculizumab, 20 mM histidine, 50 mM serine, 3% sorbitol, and 1.5% mannitol.