Stable antibody formulation
The present invention provides stable pharmaceutical formulations comprising a human antibody that specifically binds to human programmed death-1 protein (PD-1). In certain embodiments, the formulations contain, in addition to an anti-PD-1 antibody, a buffer, an amino acid, a non-ionic surfactant, and a sugar. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability upon stress and storage.
1. A stable liquid pharmaceutical formulation, comprising:
(a) 5 mg/mL ±0.75 mg/mL to 250 mg/mL ±37.5 mg/mL of an antibody that binds specifically to human programmed death-1 (PD-1), wherein the antibody comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2;
(b) 10 mM ±2 mM histidine buffer,
(c) 0.2% ±0.1% w/v polysorbate,
(d) 5% ±1% w/v sucrose, and
(e) 1.5% ±0.3% w/v proline,
in water at pH 6.0±0.3.
2. The pharmaceutical formulation of claim 1 , wherein the antibody concentration is 25 mg/mL ±3.75 mg/mL.
3. The pharmaceutical formulation of claim 1 , wherein the antibody concentration is 50 mg/mL ±7.5 mg/mL.
4. The pharmaceutical formulation of claim 1 , wherein the antibody concentration is 150 mg/mL ±22.5 mg/mL.
5. The pharmaceutical formulation of claim 1 , wherein the antibody concentration is 175 mg/mL ±26.25 mg/mL.
6. The pharmaceutical formulation of claim 1 , wherein the histidine buffer is prepared from L-histidine and L-histidine monohydrochloride monohydrate.
7. The pharmaceutical formulation of claim 1 , wherein the histidine buffer is prepared from 4.8 mM ±0.96 mM L-histidine and 5.2 mM ±1.04 mM L-histidine monohydrochloride monohydrate.
8. The pharmaceutical formulation of claim 2 , wherein the histidine buffer is prepared from 4.8 mM ±0.96 mM L-histidine and 5.2 mM ±1.04 mM L-histidine monohydrochloride monohydrate.
9. The pharmaceutical formulation of claim 3 , wherein the histidine buffer is prepared from 4.8 mM ±0.96 mM L-histidine and 5.2 mM ±1.04 mM L-histidine monohydrochloride monohydrate.
10. The pharmaceutical formulation of claim 4 , wherein the histidine buffer is prepared from 4.8 mM ±0.96 mM L-histidine and 5.2 mM ±1.04 mM L-histidine monohydrochloride monohydrate.
11. The pharmaceutical formulation of claim 5 , wherein the histidine buffer is prepared from 4.8 mM ±0.96 mM L-histidine and 5.2 mM ±1.04 mM L-histidine monohydrochloride monohydrate.
12. The pharmaceutical formulation of claim 1 , wherein the polysorbate is polysorbate 80.
13. The pharmaceutical formulation of claim 1 , wherein the formulation has a viscosity of less than 20 cP at 25° C.
14. The pharmaceutical formulation of claim 3 , wherein the formulation has a viscosity of less than 10 cP at 25° C.
15. The pharmaceutical formulation of claim 1 , wherein the antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
16. The pharmaceutical formulation of claim 1 , wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.
17. The pharmaceutical formulation of claim 1 , wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from SEQ ID NOs: 9 and 11.
18. The pharmaceutical formulation of claim 1 , wherein the antibody comprises a heavy chain and a light chain, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 10.
19. The pharmaceutical formulation of claim 1 , wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 9, and the light chain comprises the amino acid sequence of SEQ ID NO: 10.
20. The pharmaceutical formulation of claim 1 , wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, and the light chain comprises the amino acid sequence of SEQ ID NO: 10.
21. The pharmaceutical formulation of claim 1 , comprising:
(a) 25 mg/mL of the antibody,
(b) 0.74 mg/mL of L-histidine,
(c) 1.1 mg/mL of L-histidine monohydrochloride monohydrate,
(d) 2 mg/mL of polysorbate 80,
(e) 50 mg/mL of sucrose, and
(f) 15 mg/mL of proline.
22. The pharmaceutical formulation of claim 1 , comprising:
(a) 50 mg/mL of the antibody,
(b) 0.74 mg/mL of L-histidine,
(c) 1.1 mg/mL of L-histidine monohydrochloride monohydrate,
(d) 2 mg/mL of polysorbate 80,
(e) 50 mg/mL of sucrose, and
(f) 15 mg/mL of proline.
23. The pharmaceutical formulation of claim 1 , comprising:
(a) 150 mg/mL of the antibody,
(b) 0.74 mg/mL of L-histidine,
(c) 1.1 mg/mL of L-histidine monohydrochloride monohydrate,
(d) 2 mg/mL of polysorbate 80,
(e) 50 mg/mL of sucrose, and
(f) 15 mg/mL of proline.
24. The pharmaceutical formulation of claim 1 , comprising:
(a) 175 mg/mL of the antibody,
(b) 0.74 mg/mL of L-histidine,
(c) 1.1 mg/mL of L-histidine monohydrochloride monohydrate,
(d) 2 mg/mL of polysorbate 80,
(e) 50 mg/mL of sucrose, and
(f) 15 mg/mL of proline.