Pharmaceutical products and stable liquid compositions of IL-17 antibodies
The disclosure is directed to pharmaceutical products and stable liquid compositions of IL-17 antibodies and antigen-binding fragments thereof, e.g., AIN457 (secukinumab), and processes of making these pharmaceutical products and compositions. The disclosure is also directed to the use of these pharmaceutical products and liquid compositions (e.g., as part of a kit having instructions for use) for the treatment of various IL-17-mediated disorders (e.g., autoimmune disorders, such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis).
1. A pharmaceutical product comprising:
a. a container having a headspace, wherein the oxygen content in the headspace is less than 12%, and
b. a stable ready-to-use liquid pharmaceutical composition having a pH of about 5.2 to about 6.2 disposed within said container, said composition comprising:
i. about 75 mg/mL mg/ml to about 175 mg/ml secukinumab; and
ii. about 2.5 to about 20 mM L-methionine.
2. The pharmaceutical product according to claim 1 , wherein the concentration of methionine is about 2.5 mM, about 5 mM, about 10 mM or about 20 mM.
3. The pharmaceutical product according to claim 1 , wherein the oxygen content in the headspace is less than 10%, less than 8%, or less than 6%.
4. The pharmaceutical product according to claim 1 , wherein the liquid pharmaceutical composition has a pH of about 5.8.
5. The pharmaceutical product according to claim 1 , wherein the concentration of secukinumab is about 150 mg/ml.
6. A pharmaceutical product comprising
a. a container having a headspace, wherein the oxygen content in the headspace is less than 6%; and
b. a stable ready-to-use liquid pharmaceutical composition disposed within said container, said composition comprising about 75 mg/mL to about 175 mg/mL secukinumab, about 10 mM to about 30 mM histidine pH 5.2-6.2, about 200 mM to about 225 mM trehalose, about 0.01% to about 0.04% polysorbate, and about 2.5 mM to about 20 mM methionine.
7. The pharmaceutical product according to claim 6 , comprising about 150 mg/ml secukinumab and about 200 mM trehalose.
8. The pharmaceutical product according to claim 1 , wherein the liquid composition maintains:
a. at least 86% purity by reverse phase high performance liquid chromatography RP-HPLC upon storage at 2-8° C. for 6 months, at least 76% purity by RP-HPLC upon storage at 25° C./60% relative humidity (RH) for 6 months, and/or at least 60% purity by RP-HPLC upon storage at 30° C./75% RH for 6 months;
b. at least 77% purity by cation exchange chromatography (CEX) upon storage at 2-8° C. for 6 months, at least 62% purity by CEX upon storage at 25° C./60% RH for 6 months, and/or at least 50% purity by CEX upon storage at 30° C./75% RH for 6 months;
c. at least 98% purity by size exclusion chromatography (SEC) upon storage at 2-8° C. for 6 months, at least 96% purity by SEC upon storage at 25° C./60% RH for 6 months, and/or at least 94% purity by SEC upon storage at 30° C./75% RH for 6 months;
d. at least 97% purity by non-reducing capillary electrophoresis sodium dodecyl sulfate (CE-SDS) upon storage at 2-8° C. for 6 months, at least 95% purity by non-reducing CE-SDS upon storage at 25° C./60% RH for 6 months, and/or at least 94% purity by non-reducing CE-SDS upon storage at 30° C./75% RH for 6 months;
e. less than 0.57% impurity by reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) upon storage at 2-8° C. for 6 months, less than 1.1% impurity by reducing SDS-PAGE (reducing conditions) upon storage at 25° C./60% RH for 6 months, and/or less than 1.9% impurity by reducing SDS-PAGE upon storage at 30° C./75% RH for 6 months; and/or
f. at least 88% relative biological activity by inhibition of IL-6 release from C-20/A4 chondrocytes upon storage at 2-8° C. for 18 months, at least 94% relative biological activity by inhibition of IL-6 release from chondrocytes upon storage at 25° C./60% RH for 6 months, and/or at least 85% relative biological activity by inhibition of IL-6 release from chondrocytes upon storage at 30° C./75% RH for 6 months.
9. The pharmaceutical product according to according to claim 1 , wherein the liquid composition maintains:
a. at least 84% purity by RP-HPLC upon storage at 2-8° C. for 24 months;
b. at least 73% purity by CEX upon storage at 2-8° C. for 24 months;
c. at least 97% purity by SEC upon storage at 2-8° C. for 24 months;
d. at least 97% purity by non-reducing CE-SDS upon storage at 2-8° C. for 24 months; and/or
e. less than 0.91% impurity by reducing SDS-PAGE upon storage at 2-8° C. for 24 months.
10. A stable ready-to-use liquid pharmaceutical composition comprising, 75 mg/mL to about 150 mg/mL secukinumab, about 10 mM to about 30 mM histidine pH 5.2-6.2, about 200 mM to about 225 mM trehalose, about 0.01% to about 0.04% polysorbate, and about 2.5 mM to about 20 mM methionine.
11. The ready-to-use liquid pharmaceutical composition according to claim 10 , wherein after 13 months storage at 25° C., aggregate formation as measured by SEC is ≤3.5%.
12. The ready-to-use liquid pharmaceutical composition according to claim 10 , wherein after 13 months storage at 25° C., degradation products by RP-HPLC are ≤39.4%.
13. The ready-to-use liquid pharmaceutical composition according to claim 12 , wherein the liquid composition maintains:
a. at least 87.3% purity by RP-HPLC upon storage at 2-8° C. for 24 months;
b. at least 76.5% purity by CEX upon storage at 2-8° C. for 24 months;
c. at least 97.9% purity by SEC upon storage at 2-8° C. for 24 months;
d. at least 97.2% purity by non-reducing CE-SDS upon storage at 2-8° C. for 24 months; and/or
e. less than 0.61% impurity by reducing SDS-PAGE upon storage at 2-8° C. for 24 months.
14. The ready-to-use liquid pharmaceutical composition according to claim 13 , wherein after 13 months storage at 25° C., aggregate formation as measured by SEC is ≤3.5%.
15. The ready-to-use liquid pharmaceutical composition according to claim 13 , wherein after 13 months storage at 25° C., degradation products by RP-HPLC are ≤39.4%.
16. A ready-to-use liquid pharmaceutical composition comprising, about 150 mg/ml secukinumab, about 20 mM histidine pH 5.8, about 200 mM trehalose, about 0.02% polysorbate 80, and about 5 mM L-methionine.
17. The ready-to-use liquid pharmaceutical composition according to claim 16 , wherein after 13 months storage at 25° C., aggregate formation as measured by SEC is ≤ 3.5%.
18. The pharmaceutical product according to claim 1 , wherein after 13 months storage at 25° C., aggregate formation as measured by SEC is ≤3.5%.
19. The pharmaceutical product according to claim 1 , wherein the composition further comprises a surfactant.
20. The pharmaceutical product according to claim 19 , wherein the surfactant is selected from the group consisting of a poloxamer and a polysorbate.
21. The pharmaceutical product according to claim 20 , wherein the surfactant is polysorbate.
22. The pharmaceutical product according to claim 20 , wherein the surfactant is polysorbate 80 at a concentration of about 0.01% (w/v) to about 0.04% (w/v).