Stabilized formulations containing anti-PCSK9 antibodies
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.
1. A pre-filled syringe composition comprising a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises:
(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) 10±1.5 mM histidine (pH 6.0±0.3);
(c) 0.01±0.0015% w/v polysorbate 20; and
(d) 10±1.5% sucrose;
wherein said liquid pharmaceutical formulation is contained within a syringe.
2. The pre-filled syringe composition of claim 1 , wherein the syringe is a normal tungsten syringe.
3. The pre-filled syringe composition of claim 1 , wherein the syringe is a low tungsten syringe.
4. The pre-filled syringe composition of claim 1 , wherein the syringe comprises a coated plunger.
5. The pre-filled syringe composition of claim 4 , wherein the coated plunger is coated with a fluorocarbon film.
6. The pre-filled syringe composition of claim 1 , wherein the syringe is a low tungsten syringe, and wherein the syringe comprises a coated plunger.
7. The pre-filled syringe composition of claim 1 , wherein the syringe is a 1 mL long glass syringe comprising a 27 gauge thin wall needle, a fluorocarbon coated rubber plunger, and a rubber needle shield.
8. The pre-filled syringe composition 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.
9. The pre-filled syringe composition of claim 1 , wherein: over 90% of the antibodies have a molecular weight of 155 kDa±1 kDa; over 50% of the antibodies have an isoelectric point of about 8.5; and from 75% to 90% of the antibodies are fucosylated.
10. The pre-filled syringe composition of claim 1 , wherein at least 91% of the antibody has native conformation after 28 days at 45° C.
11. The pre-filled syringe composition of claim 1 , wherein at least 35% of the antibody is the main charge variant of the antibody after 28 days at 45° C.
12. The pre-filled syringe composition of claim 1 , wherein at least 94% of the antibody has native conformation after six months at 25° C.
13. The pre-filled syringe composition of claim 1 , wherein at least 45% of the antibody is the main charge variant of the antibody after six months at 25° C.
14. The pre-filled syringe composition of claim 1 , wherein at least 96% of the antibody has native conformation after six months at 5° C.
15. The pre-filled syringe composition of claim 1 , wherein at least 58% of the antibody is the main charge variant of the antibody after six months at 5° C.
16. The pre-filled syringe composition of claim 1 , wherein at least 96% of the antibody is the main charge variant of the antibody after three months at −20° C., −30° C., or −80° C.
17. The pre-filled syringe composition of claim 1 , wherein at least 56% of the antibody is the main charge variant of the antibody after three months at −20° C., −30° C., or −80° C.
18. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 175 mg/mL of the antibody.
19. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 150 mg/mL of the antibody.
20. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 100 mg/mL of the antibody.
21. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 75 mg/mL of the antibody.
22. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 50 mg/mL of the antibody.