Anti-pdl1 antibody formulations

Abstract

The invention provides stable aqueous pharmaceutical formulations comprising an anti-PDL1 antibody. The invention also provides methods for making such formulations and methods of using such formulations.

What is claimed is: 
     
         1 . A stable aqueous pharmaceutical formulation, the formulation comprising an anti-PDL1 monoclonal antibody in a concentration of about 40 mg/ml to about 125 mg/ml, histidine acetate or sodium acetate in a concentration of about 15 mM to about 25 mM, sucrose in a concentration of about 60 mM to about 240 mM, polysorbate in a concentration of about 0.005% (w/v) to about 0.06% (w/v), and pH about 5.0 to about 6.3. 
     
     
         2 . The formulation of  claim 1 , wherein said monoclonal antibody in the formulation is about 40 mg/ml to about 80 mg/ml. 
     
     
         3 . The formulation of  claim 1 , wherein said monoclonal antibody in the formulation is about 54 mg/ml to about 66 mg/ml. 
     
     
         4 . The formulation of  claim 1 , wherein said monoclonal antibody in the formulation is about 60 mg/ml. 
     
     
         5 . The formulation of  claim 1 , wherein said monoclonal antibody in the formulation is about 60 mg/ml to about 125 mg/ml. 
     
     
         6 . The formulation of  claim 1 , wherein said monoclonal antibody in the formulation is about 125 mg/ml. 
     
     
         7 . The formulation of any one of  claims 1 - 6 , herein said histidine acetate or sodium acetate is in a concentration of about 17 mM to bout 22 mM. 
     
     
         8 . The formulation of any one of  claims 1 - 6 , wherein said histidine acetate or sodium acetate is in a concentration of about 20 mM. 
     
     
         9 . The formulation of any one of  claims 1 - 8 , wherein said sucrose in the formulation is about 60 mM to about 180 mM. 
     
     
         10 . The formulation of any one of  claims 1 - 8 , wherein said sucrose in the formulation is about 120 mM. 
     
     
         11 . The formulation of any one of  claims 1 - 10 , wherein the formulation has a pH of about 5.5 to about 6.1. 
     
     
         12 . The formulation of any one of  claims 1 - 10 , wherein the formulation has a pH of about 5.5 or about 5.8. 
     
     
         13 . The formulation of any one of  claims 1 - 12 , wherein said polysorbate in the formulation is polysorbate 20. 
     
     
         14 . The formulation of any one of  claims 1 - 13 , wherein said polysorbate in the formulation is about 0.02% to about 0.04%. 
     
     
         15 . The formulation of any one of  claims 1 - 5  and  7 - 14 , wherein said monoclonal antibody in the formulation is about 60 mg/ml, sucrose in the formulation is about 120 mM, and pH is about 5.8. 
     
     
         16 . The formulation of any one of  claims 1 ,  6 - 8 , and  11 - 14 , wherein said monoclonal antibody in the formulation is about 125 mg/ml, sucrose in the formulation is about 240 mM, and pH is about 5.5. 
     
     
         17 . The formulation of any one of  claims 1 - 16 , wherein said monoclonal antibody is not subject to prior lyophilization. 
     
     
         18 . The formulation of any one of  claims 1 - 17 , wherein said monoclonal antibody is a full length antibody. 
     
     
         19 . The formulation of any one of  claims 1 - 18 , wherein said monoclonal antibody is an IgG1, an IgG2, an IgG3 or an IgG4 antibody. 
     
     
         20 . The formulation of any one of  claims 1 - 10 , wherein said monoclonal antibody is a humanized antibody. 
     
     
         21 . The formulation of any one of  claims 1 - 20 , wherein said monoclonal antibody is an antibody fragment comprising an antigen-binding region. 
     
     
         22 . The formulation of  claim 21 , wherein the antibody fragment is a Fab or F(ab′) 2  fragment. 
     
     
         23 . The formulation of any one of  claims 1 - 22 , wherein said monoclonal antibody comprises
 (a) a light chain variable region comprising:
 (1) HVR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO:1); 
 (2) HVR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO:2); 
 (3) HVR-L3 comprising the amino acid sequence QQYLYHPAT (SEQ ID NO:3); and 
   (b) a heavy chain variable region comprising:
 (1) HVR-H1 comprising the amino acid sequence GFTFSDSWIH (SEQ ID NO:4); 
 (2) HVR-H2 comprising the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO:5); 
 (3) HVR-H3 comprising the amino acid sequence RHWPGGFDY (SEQ ID NO:6). 
   
     
     
         24 . The formulation of any one of  claims 1 - 23 , wherein said monoclonal antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8. 
     
     
         25 . The formulation of any one of  claims 1 - 23 , wherein said monoclonal antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:32. 
     
     
         26 . The formulation of  claim 24  or  25 , wherein said monoclonal antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:9, and a heavy comprising the amino acid sequence of SEQ ID NO:10. 
     
     
         27 . The formulation of any one of  claims 1 - 26 , wherein said monoclonal antibody is stored in a glass vial or a metal alloy container. 
     
     
         28 . The formulation of  claim 27 , wherein the metal alloy is 316L stainless steal or hastelloy. 
     
     
         29 . The formulation of any one of  claims 1 - 28 , wherein the formulation is stable at 2-8° C. for at least 6 months, at least 12 months, at least 18 months or at least 24 months. 
     
     
         30 . The formulation of  claim 29 , wherein the antibody in the formulation retains at least about 80% of its biological activity after storage. 
     
     
         31 . The formulation of  claim 30 , wherein the biological activity is measured by antibody binding to PD-L1. 
     
     
         32 . The formulation of any one of  claim 1 - 31  which is sterile. 
     
     
         33 . The formulation of any one of  claim 1 - 32  which is suitable to be administered to a subject. 
     
     
         34 . The formulation of any one of  claim 1 - 33  which is for intravenous (IV) administration. 
     
     
         35 . The formulation of  claim 1 , wherein said monoclonal antibody is in an amount of about 60 mg/mL, said histidine acetate is in a concentration of about 20 mM, said sucrose is in a concentration of shout 120 mM, and said polysorbate is polysorbate 20 in a concentration of 0.04% (w/v), and said formulation has a pH of about 5.8. 
     
     
         36 . The formulation of  claim 1 , wherein said monoclonal antibody is in an amount of about 125 mg/mL, said histidine acetate is in a concentration of about 20 mM, said sucrose is in a concentration of about 240 mM, and said polysorbate is polysorbate 20 in a concentration of 0.02%, and said formulation has a pH of about 5.5. 
     
     
         37 . An article of manufacture comprising a container holding the stable aqueous pharmaceutical formulation of any one of  claims 1 - 36 . 
     
     
         38 . The article of  claim 37 , wherein the container is a glass vial or a metal alloy container. 
     
     
         39 . The article of  claim 38 , wherein the metal alloy is 316L stainless steel or hastelloy. 
     
     
         40 . A method of treating a disease or disorder in a subject comprising administering an effective amount of the formulation of any one of  claims 1 - 36  to the subject, wherein the disease or disorder is selected from the group consisting of infection, cancer, and inflammatory disease. 
     
     
         41 . The formulation of any one of  claims 1 - 36 , wherein the monoclonal antibody comprises a N297A or D265A/N297A substitution in the constant region, numbering of the residue is that of the EU index as in Kabat.