HIGH CONCENTRATION ANTI-TNFalpha ANTIBODY FORMULATION

Abstract

The invention provides a liquid aqueous pharmaceutical formulation comprising a human anti-TNFa antibody, or antigen-binding portion thereof, which reduces pain associated with injection in a subject by at least about 50% when compared to injecting an otherwise identical formulation comprising at least one salt and/or at least one buffer. The invention also provides a liquid aqueous pharmaceutical formulation comprising a human anti-TNFa antibody, or antigen-binding portion thereof, having increased bioavailability upon subcutaneous administration into a subject. The formulation may comprise a therapeutic protein, such as a human anti-TNF-alpha antibody, or an antigen-binding portion thereof, or a biosimilar thereof.

What is claimed: 
     
         1 . A liquid aqueous formulation comprising:
 (1) an isolated human anti-TNFα antibody, or an antigen-binding portion thereof;   (2) a surfactant; and,   (3) less than 50 mg/ml of a polyol;   wherein the formulation has a pH of 4.7 to 5.7 and does not contain a buffer or a salt, and wherein injection of the formulation into a human subject results in a Pain Visual Analog Scale (VAS) score of less than 1.0.   
     
     
         2 . The formulation of  claim 1 , wherein the polyol is mannitol or sorbitol. 
     
     
         3 . The formulation of  claim 2 , comprising about 38-46 mg/ml of mannitol. 
     
     
         4 . The formulation of  claim 1 , wherein the surfactant is a polysorbate. 
     
     
         5 . The formulation of  claim 1 , wherein the concentration of the anti-TNFα antibody, or antigen-binding portion thereof, is 95-105 mg/ml. 
     
     
         6 . The formulation of  claim 1 , wherein is the antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, 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, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11, 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. 
     
     
         7 . The formulation of  claim 1 , wherein the antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         8 . The formulation of  claim 1 , wherein the antibody, or an antigen-binding portion thereof, is adalimumab. 
     
     
         9 . A liquid aqueous formulation consisting essentially of
 (1) a concentration of 90-110 mg/ml of an isolated human anti-TNFα antibody, or an antigen-binding portion thereof, having a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, 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 having a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11, 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;   (2) a polysorbate; and,   (3) about 38-46 mg/ml of mannitol.   
     
     
         10 . The formulation of  claim 9 , wherein the antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         11 . The formulation of  claim 9 , wherein the antibody, or an antigen-binding portion thereof, is adalimumab. 
     
     
         12 . The formulation of  claim 9 , comprising about 30-90 mg of the antibody, or antigen binding portion thereof. 
     
     
         13 . A method of treating a disorder associated with detrimental TNFα activity in a patient, comprising administering to the patient the formulation of  claim 1 . 
     
     
         14 . A method of improving the bioavailability of an isolated human anti-TNFα antibody, or an antigen-binding portion thereof, in a human subject, said method comprising administering a formulation comprising a surfactant and an effective amount of the antibody, or antigen-binding portion thereof, to the subject such that the bioavailability of the antibody, or antigen-binding portion thereof, is improved, wherein the formulation does not contain a buffer, a polyol, or a salt. 
     
     
         15 . The method of  claim 14 , wherein the effective amount of the antibody, or antigen-binding portion thereof, is 30-90 mg. 
     
     
         16 . The method of  claim 14 , wherein the concentration of the antibody, or antigen-binding portion thereof, in the pharmaceutical formulation is 90-110 mg/ml. 
     
     
         17 . The method of  claim 14 , wherein the bioavailability of the antibody, or antigen-binding portion thereof, is an AUC 0-360  greater than 1300 μg*hr/ml when subcutaneously injected into the human subject. 
     
     
         18 . The method of  claim 14 , wherein the surfactant is a polysorbate. 
     
     
         19 . The method of  claim 14 , wherein is the antibody, or an antigen-binding portion thereof, is selected from the group consisting of
 a) an antibody, or an antigen-binding portion thereof, comprising a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, 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, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11, 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;   b) an antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2; and   c) adalimumab.   
     
     
         20 . A pre-filled syringe or autoinjector device, comprising the formulation of  claim 1 .