High concentration anti-C5 antibody formulations
The present disclosure relates to stable aqueous solutions comprising a high concentration of an anti-C5 antibody (e.g., ravulizumab) and methods for preparing the solutions. The disclosure also provides methods for treating or preventing complement-associated disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), using the solutions. Also featured were 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 stable aqueous solution comprising:
(a) an anti-C5 antibody at a concentration of about 100 mg/mL, wherein the anti-C5 antibody comprises a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:19, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:18, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6;
(b) about 50 mM Phosphate Buffer;
(c) about 5% sucrose; and
(d) about 25 mM Arginine.
2. A stable aqueous solution comprising:
(a) an anti-C5 antibody, wherein the anti-C5 antibody comprises a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:19, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:18, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6;
(b) about 50 mM Phosphate Buffer;
(c) about 5% sucrose;
(d) about 0.05% Polysorbate 80; and
(e) about 25 mM Arginine.
3. The stable aqueous solution of claim 1 , further comprising a surfactant.
4. The stable aqueous solution of claim 3 , wherein the surfactant is about 0.05% Polysorbate 80.
5. The stable aqueous solution of claim 2 , wherein the an anti-C5 antibody is at a concentration of about 100 mg/mL.
6. The stable aqueous solution of claim 1 or 2 , wherein the anti-C5 antibody further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.
7. The stable aqueous solution of claim 1 or 2 , wherein the anti-C5 antibody comprises a heavy chain variable region depicted in SEQ ID NO:12 and a light chain variable region depicted in SEQ ID NO:8.
8. The stable aqueous solution of claim 1 or 2 , wherein the anti-C5 antibody comprises a heavy chain constant region depicted in SEQ ID NO:13.
9. The stable aqueous solution of claim 1 or 2 , wherein the anti-C5 antibody comprises a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 11.
10. The stable aqueous solution of claim 1 or 2 , wherein the anti-C5 antibody is ALXN1210 (ravulizumab).
11. The stable aqueous solution of claim 1 or 2 , wherein the pH of the solution is between 7.2 and 7.6.
12. The stable aqueous solution of claim 11 , wherein the pH of the solution is 7.4.
13. The stable aqueous solution of claim 1 or 2 , wherein the solution is sterile.
14. The stable aqueous solution of claim 1 or 2 , wherein:
(a) the anti-C5 antibody remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC;
(b) less than 3% of the anti-C5 antibody in the solution is aggregated as determined by SEC-HPLC; and/or
(c) during storage at 2° C. to 8° C. for at least six months, the anti-C5 antibody retains at least 90% of its C5-binding activity, as compared to the anti-C5 antibody prior to storage.
15. The stable aqueous solution of claim 1 or 2 , wherein the solution is suitable for subcutaneous or intravenous administration.
16. A method for producing a stable concentrated antibody solution comprising an anti-C5 antibody comprising a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:19, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:18, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6, at a concentration of 100 mg/mL, 50 mM Phosphate Buffer, 5% sucrose; and 25 mM Arginine, the method comprising:
i) providing a first aqueous solution comprising the anti-C5 antibody, the first aqueous solution having a first formulation and comprising no more than 10 mg/mil, of the anti-C5 antibody;
ii) subjecting the first aqueous solution to diafiltration into a formulation comprising 50 mM Phosphate Buffer, 5% sucrose, and 25 mM Arginine, at pH 7.4 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 of the anti-C5 antibody, 50 mM Phosphate Buffer, 5% sucrose; and 25 mM Arginine.
17. A therapeutic kit comprising the stable aqueous solution according to claim 1 .