STABLE FORMULATIONS OF PROGRAMMED DEATH RECEPTOR 1 (PD-1) ANTIBODIES AND METHODS OF USE THEREOF
The invention relates to stable formulations of antibodies against human programmed death receptor PD-1, or antigen binding fragments thereof. In some embodiments the formulations of the invention comprise between 5-250 mg/mL anti-PD-1 antibody, or antigen binding fragment thereof, a buffer, a stabilizer, a surfactant, and an antioxidant in the amounts specified herein. In particular embodiments, the anti-PD-1 antibody is pembrolizumab. The invention further provides methods for treating various cancers with stable formulations of the invention. In some embodiments of the methods of the invention, the formulations are administered to a subject by intravenous or subcutaneous administration.
1 . An anti-human PD-1 antibody formulation, comprising:
a) 5 mg/mL to 250 mg/mL of an anti-human programmed death receptor 1 (PD-1) antibody;
b) 5 mM to 20 mM buffer;
c) a stabilizer selected from the group consisting of:
i) about 6% to about 8% weight/volume (w/v) sucrose or trehalose;
ii) about 3% to about 5% w/v sorbitol, L-arginine, L-proline, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline;
iii) about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof;
iv) about 1.5% to about 1.9% w/v L-proline, or a pharmaceutically acceptable salt of L-proline; and
v) about 1.9% to about 3.3% w/v L-arginine, or a pharmaceutically acceptable salt of L-arginine; and
d) about 0.005% w/v to about 0.60% w/v non-ionic surfactant, which is selected from the group consisting of: polysorbate 20 (PS20), polysorbate 80 (PS80), poloxamer 338 (P338), and poloxamer 407 (P407);
e) about 1 mM to about 30 mM anti-oxidant, wherein the anti-oxidant is L-methionine, or a pharmaceutically acceptable salt thereof; and
wherein the anti-human PD-1 antibody is pembrolizumab.
2 . The anti-human PD-1 antibody formulation of claim 1 , wherein the stabilizer is about 1.5% to 1.9% w/v L-proline, or a pharmaceutically acceptable salt of L-proline.
3 . The anti-human PD-1 antibody formulation of claim 1 , wherein the stabilizer is about 3% to 5% w/v L-proline, or a pharmaceutically acceptable salt of L-proline.
4 . The anti-human PD-1 antibody formulation of claim 3 , comprising greater than 200 mg/mL of the anti-human PD-1 antibody.
5 . The anti-human PD-1 antibody formulation of claim 1 , wherein the surfactant is about 0.01% to about 0.04% PS20 or 0.01% to about 0.04% PS80.
6 . The anti-human PD-1 antibody formulation of claim 1 , wherein the surfactant is about 0.01% to about 0.03% w/v poloxamer 407 (P407) or 0.01% to about 0.03% w/v poloxamer 338 (P338).
7 . The anti-human PD-1 antibody formulation of claim 1 , wherein the buffer is a histidine buffer or an acetate buffer.
8 . The anti-human PD-1 antibody formulation of claim 1 , wherein the L-methionine is present at a concentration of about 1 mM to about 20 mM.
9 . The anti-human PD-1 antibody formulation of claim 1 , wherein the viscosity of the formulation is <60 centipoise at 20° C.
10 . The anti-human PD-1 antibody formulation of claim 1 , wherein the concentration of anti-human PD-1 antibody is from about 75 mg/mL to about 250 mg/mL and the viscosity reducing agent is L-arginine or a pharmaceutically acceptable salt thereof.
11 . The anti-human PD-1 antibody formulation of claim 1 , wherein the formulation has a pH between 4.5 and 6.5.
12 . The anti-human PD-1 antibody formulation of claim 1 , wherein the formulation has a pH between 5.0 and 6.0.
13 . The anti-human PD-1 antibody formulation of claim 1 , wherein the stabilizer is sucrose or trehalose.
14 . The anti-human PD-1 antibody formulation of claim 1 , wherein the formulation is stable for at least 10 days at 50° C.
15 . The anti-human PD-1 antibody formulation of claim 1 , wherein the buffer is a histidine buffer, which is present at a concentration of about 8 mM to about 12 mM.
16 . The anti-human PD-1 antibody formulation of claim 1 , wherein the L-methionine or a pharmaceutically acceptable salt thereof is present at a concentration of about 10 mM.
17 . The anti-human PD-1 antibody formulation of claim 1 , wherein the stabilizer is sucrose which is present at a weight ratio of about 7% w/v.
18 . The anti-human PD-1 antibody formulation of claim 1 , comprising:
a) about 125 to about 250 mg/mL of pembrolizumab;
b) about 10 mM histidine or acetate buffer;
c) about 0.005% w/v to about 0.60% PS20;
d) about 7% w/v sucrose; and
e) about 10 mM L-methionine HCl.
19 . The anti-human PD-1 antibody formulation of claim 1 , comprising:
a) about 25 to about 250 mg/mL of pembrolizumab;
b) about 10 mM histidine buffer;
c) about 0.005% w/v to about 0.60% PS80;
d) about 3% to about 5% w/v L-arginine; and
e) about 30 mM L-methionine HCl.
20 . A method of treating cancer in a human patient in need thereof, the method comprising administering an effective amount of the anti-human PD-1 antibody formulation of claim 1 to the patient.
21 . A method of treating cancer in a human patient in need thereof, the method comprising administering an effective amount of the anti-human PD-1 antibody formulation of claim 18 to the patient.
22 . A method of treating cancer in a human patient in need thereof, the method comprising administering an effective amount of the anti-human PD-1 antibody formulation of claim 19 to the patient.