Self-buffering protein formulations

Abstract

The invention herein described, provides, among other things, self-buffering protein formulations. Particularly, the invention provides self-buffering pharmaceutical protein formulations that arc suitable for veterinary and human medical use, The self-buffering protein formulations are substantially free of other buffering agents, stably maintain pH for the extended time periods involved in the distribution and storage of pharmaceutical proteins for veterinary and human medical use. The invention further provides methods for designing, making, and using the formulation. In addition to other advantages, the formulations avoid the disadvantages associated with the buffering agents conventionally used in current formulations of proteins for pharmaceutical use. The invention in these and other respects can be productively applied to a wide variety of proteins and is particularly useful for making and using self-buffering formulations of pharmaceutical proteins for veterinary and medical use, especially, in particular, for the treatment of diseases in human subjects.

1 . (canceled) 
     
     
         2 . An aqueous pharmaceutical formulation consisting essentially of:
 (a) an anti-tumor necrosis factor alpha antibody comprising a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:5, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:8, wherein the concentration of the antibody is 50 to 200 mg/ml; and   (b) water.   
     
     
         3 . The formulation of  claim 2 , wherein the antibody comprises a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, and a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 
     
     
         4 . The formulation of  claim 3 , wherein the antibody is adalimumab, 
     
     
         5 . The formulation of  claim 2 , wherein the pH of the formulation is from 4 to 8. 
     
     
         6 . The formulation of  claim 4 , wherein the pH of the formulation is from 4 to 8. 
     
     
         7 . An aqueous pharmaceutical formulation comprising:
 (a) an anti-tumor necrosis factor alpha antibody comprising a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:5, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:8, wherein the concentration of the antibody is 50 to 200 mg/ml; and   (b) water; wherein the formulation does not comprise a tonicity modifier.   
     
     
         8 . The formulation of  claim 7 , wherein the antibody comprises a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, and a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2. 
     
     
         9 . The formulation of  claim 8 , wherein the antibody is adalimumab, 
     
     
         10 . The formulation of  claim 7 , wherein the pH of the formulation is from 4 to 8. 
     
     
         11 . The formulation of  claim 7 , wherein the pH of the formulation is from 4 to 6. 
     
     
         12 . The formulation of  claim 7 , wherein the pH of the formulation is from 5 to 6. 
     
     
         13 . The formulation of  claim 9 , wherein the pH of the formulation is from 4 to 8. 
     
     
         14 . The formulation of  claim 9 , wherein the pH of the formulation is from 4 to 6. 
     
     
         15 . The formulation of  claim 9 , wherein the pH of the formulation is from 5 to 6. 
     
     
         16 . The formulation of  claim 9 , wherein the pH of the formulation is 5. 
     
     
         17 . An aqueous pharmaceutical formulation comprising:
 (a) an anti-tumor necrosis factor alpha antibody comprising a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:5, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:8, wherein the concentration of the antibody is 50 to 200 mg/ml; and   (b) water; wherein the formulation does not comprise a buffering system.   
     
     
         18 . The formulation of  claim 17 , wherein the antibody comprises a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, and a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2. 
     
     
         19 . The formulation of  claim 18 , wherein the antibody is adalimumab. 
     
     
         20 . The formulation of  claim 17 , wherein the formulation further comprises a non-ionizable excipient. 
     
     
         21 . The formulation of  claim 17 , wherein the formulation further comprises a polyol, 
     
     
         22 . The formulation of  claim 21 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and sucrose, 
     
     
         23 . The formulation of  claim 17 , wherein the formulation further comprises a surfactant. 
     
     
         24 . The formulation of  claim 23 , wherein the surfactant is selected from the group consisting of polysorbate 80 and polysorbate 20. 
     
     
         25 . The formulation of  claim 17 , wherein the pH of the formulation is from 4 to 8. 
     
     
         26 . The formulation of  claim 17 , wherein the pH of the formulation is from 4 to 6. 
     
     
         27 . The formulation of  claim 17 , wherein the pH of the formulation is from 5 to 6. 
     
     
         28 . The formulation of  claim 19 , wherein the pH of the formulation is from 4 to 8. 
     
     
         29 . The formulation of  claim 19 , wherein the pH of the formulation is from 4 to 6. 
     
     
         30 . The formulation of  claim 19 , wherein the pH of the formulation is from 5 to 6. 
     
     
         31 . The formulation of  claim 19 , wherein the pH of the formulation is 5.