Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof

Abstract

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 5-200 mg/mL anti- PD-1 antibody, or antigen binding fragment thereof. 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.

What is claimed is: 
     
         1 . An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
 a) about 100 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody;   b) about 5 mM to about 20 mM buffer;   c) a stabilizer selected from the group consisting of:
 i) about 6% to about 8% weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin; 
 ii) about 3% to about 5% w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and 
 iii) about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof; 
   d) about 0.01 % to about 0.10% non-ionic surfactant; and   e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof;   wherein the anti-human PD-1 antibody comprises three light chain CDRs comprising CDRL1 of SEQ ID NO:1, CDRL2 of SEQ ID NO:2 and CDRL3 of SEQ ID NO:3 and three heavy chain CDRs of CDRH1 of SEQ ID NO:6, CDRH2 of SEQ ID NO:7 and CDRH3 of SEQ ID NO:8.   
     
     
         2 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the formulation has a pH between 5.0 and 6.0. 
     
     
         3 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the buffer is a histidine buffer or an acetate buffer. 
     
     
         4 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the stabilizer is about 6% to about 8% trehalose. 
     
     
         5 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the stabilizer is mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline and wherein the stabilizer is present at a concentration of about 3% to about 5% w/v. 
     
     
         6 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the stabilizer is about 1.8 % to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the stabilizer is about 3% to about 5% w/v L-arginine or L-arginine HC1 and the pH of the formulation is from about 6.0 to about 6.4. 
     
     
         8 . The anti-human PD-1 antibody formulation of  claim 1 , further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The anti-human PD-1 antibody formulation of  claim 1 , further comprising from about 1.25 % to about 2.5 % w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the non-ionic surfactant is polysorbate 20, polysorbate 80 or F127. 
     
     
         11 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the L-methionine is L-methionine HCl. 
     
     
         12 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the formulation further comprises a metal chelator. 
     
     
         13 . The anti-human PD-1 antibody formulation of  claim 12 , wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 µM to about 30 µM. 
     
     
         14 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the anti-human PD-1 antibody comprises a VL region which comprises the amino acid sequence set forth in SEQ ID NO:4, and a VH region which comprises the amino acid sequence set forth in SEQ ID NO:9. 
     
     
         15 . The anti-human PD-1 antibody formulation of  claim 1 , wherein the formulation comprises a light chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO: 10. 
     
     
         16 . An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
 a) about 100 mg/mL to about 200 mg/mL of pembrolizumab;   b) about 5 mM to about 20 mM buffer;   c) a stabilizer selected from the group consisting of:
 i) about 6 % to about 8 % weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin; 
 ii) about 3 % to about 5 % w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and 
 iii) about 1.8 % to about 2.2 % w/v glycine, or a pharmaceutically acceptable salt thereof; 
   d) about 0.01 % to about 0.10 % non-ionic surfactant; and   e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof.   
     
     
         17 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the formulation has a pH between 5.0 and 6.0. 
     
     
         18 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the buffer is a histidine buffer or an acetate buffer. 
     
     
         19 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the stabilizer is about 6% to about 8% trehalose. 
     
     
         20 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the stabilizer is mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline and wherein the stabilizer is present at a concentration of about 3% to about 5% w/v. 
     
     
         21 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the stabilizer is about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the stabilizer is about 3% to about 5% w/v L-arginine or L-arginine HC1 and the pH of the formulation is from about 6.0 to about 6.4. 
     
     
         23 . The anti-human PD-1 antibody formulation of  claim 16 , further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The anti-human PD-1 antibody formulation of  claim 16 , further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the non-ionic surfactant is polysorbate 20, polysorbate 80 or F127. 
     
     
         26 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the L-methionine is L-methionine HCl. 
     
     
         27 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the formulation further comprises a metal chelator. 
     
     
         28 . The anti-human PD-1 antibody formulation of  claim 27 , wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 µM to about 30 µM. 
     
     
         29 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the anti-human PD-1 antibody formulation is administered by subcutaneous administration. 
     
     
         30 . The anti-human PD-1 antibody formulation of  claim 16 , wherein the concentration of pembrolizumab is about 165 mg/mL to about 170 mg/mL. 
     
     
         31 . The anti-human PD-1 antibody formulation of  claim 32 , wherein the formulation is contained in an injection device. 
     
     
         32 . The anti-human PD-1 antibody formulation of  claim 32 , wherein the formulation is contained in a glass vial. 
     
     
         33 . A method of treating cancer in a human patient in need thereof, the method comprising administering to the human patient an effective amount of an anti-human PD-1 antibody formulation comprising:
 a) about 100 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody;   b) about 5 mM to about 20 mM buffer;   c) a stabilizer selected from the group consisting of:
 i) about 6 % to about 8 % weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin; 
 ii) about 3 % to about 5 % w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and 
 iii) about 1.8 % to about 2.2 % w/v glycine, or a pharmaceutically acceptable salt thereof; 
   d) about 0.01% to about 0.10% non-ionic surfactant; and   e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof;   wherein the anti-human PD-1 antibody comprises three light chain CDRs comprising CDRL1 of SEQ ID NO:1, CDRL2 of SEQ ID NO:2 and CDRL3 of SEQ ID NO:3 and three heavy chain CDRs of CDRH1 of SEQ ID NO:6, CDRH2 of SEQ ID NO:7 and CDRH3 of SEQ ID NO:8.   
     
     
         34 . The method of  claim 33 , wherein the formulation has a pH between 5.0 and 6.0. 
     
     
         35 . The method of  claim 33 , wherein the buffer is a histidine buffer or an acetate buffer. 
     
     
         36 . The method of  claim 33 , wherein the stabilizer is about 6% to about 8% trehalose. 
     
     
         37 . The method of  claim 33 , wherein the stabilizer is mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline and wherein the stabilizer is present at a concentration of about 3% to about 5% w/v. 
     
     
         38 . The method of  claim 33 , wherein the stabilizer is about 1.8 % to about 2.2 % w/v glycine, or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The method of  claim 33 , wherein the stabilizer is about 3% to about 5% w/v L-arginine or L-arginine HCl and the pH of the formulation is from about 6.0 to about 6.4. 
     
     
         40 . The method of  claim 33 , further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 33 , further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The method of  claim 33 , wherein the non-ionic surfactant is polysorbate 20, polysorbate 80 or F127. 
     
     
         43 . The method of  claim 33 , wherein the L-methionine is L-methionine HCl. 
     
     
         44 . The method of  claim 33 , wherein the formulation further comprises a metal chelator. 
     
     
         45 . The method of  claim 44 , wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 µM to about 30 µM. 
     
     
         46 . The method of  claim 33 , wherein the anti-human PD-1 antibody comprises a VL region which comprises the amino acid sequence set forth in SEQ ID NO:4, and a VH region which comprises the amino acid sequence set forth in SEQ ID NO:9. 
     
     
         47 . The method of  claim 33 , wherein the formulation comprises a light chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO: 10. 
     
     
         48 . The method of  claim 33 , wherein the anti-human PD-1 antibody formulation is administered by subcutaneous administration. 
     
     
         49 . The method of  claim 33 , wherein the concentration of the anti-human PD-1 antibody is about 165 mg/mL to about 170 mg/mL. 
     
     
         50 . A method of treating cancer in a human patient in need thereof, the method comprising administering to the human patient an effective amount of an anti-human PD-1 antibody formulation comprising:
 a) about 100 mg/mL to about 200 mg/mL of pembrolizumab;   b) about 5 mM to about 20 mM buffer;   c) a stabilizer selected from the group consisting of:
 i) about 6 % to about 8 % weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin; 
 ii) about 3% to about 5% w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and 
 iii) about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof; 
   d) about 0.01 % to about 0.10 % non-ionic surfactant;   e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof.   
     
     
         51 . The method of  claim 50 , wherein the formulation has a pH between 5.0 and 6.0. 
     
     
         52 . The method of  claim 50 , wherein the buffer is a histidine buffer or an acetate buffer. 
     
     
         53 . The method of  claim 50 , wherein the stabilizer is about 6% to about 8% trehalose. 
     
     
         54 . The method of  claim 50 , wherein the stabilizer is mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline and wherein the stabilizer is present at a concentration of about 3% to about 5 % w/v. 
     
     
         55 . The method of  claim 50 , wherein the stabilizer is about 1.8% to about 2.2 % w/v glycine, or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 50 , wherein the stabilizer is about 3% to about 5% w/v L-arginine or L-arginine HCl and the pH of the formulation is from about 6.0 to about 6.4. 
     
     
         57 . The method of  claim 50 , further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The method of  claim 50 , further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 50 , wherein the non-ionic surfactant is polysorbate 20, polysorbate 80 or F127. 
     
     
         60 . The method of  claim 50 , wherein the L-methionine is L-methionine HCl. 
     
     
         61 . The method of  claim 50 , wherein the formulation further comprises a metal chelator. 
     
     
         62 . The method of  claim 61 , wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 µM to about 30 µM. 
     
     
         64 . The method of  claim 50 , wherein the anti-human PD-1 antibody formulation is administered by subcutaneous administration. 
     
     
         65 . The method of  claim 50 , wherein the concentration of pembrolizumab is about 165 mg/mL to about 170 mg/mL.