Formulation of human antibodies for treating TNF-alpha associated disorders

Abstract

A liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.

What is claimed is:  
     
         1 . A pharmaceutical formulation selected frrom the group consisting of: 
 (a) A liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months.    (b) An aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 and having a shelf life of at least 18 months in the liquid state.    (c) A liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between about 4 and 8 which maintains stability following at least 3 freeze/thaw cycles of the formulation.    (d) A liquid aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody in a buffered solution, said formulation having a pH between 4 and 8 and having enhanced stability of at least 12 months at a temperature of 2-8° C.    
     
     
         2 . The formulation of  claim 1 , wherein the antibody is directed to TNFα.  
     
     
         3 . The formulation of  claim 1 , wherein the concentration of the antibody is between about 1-150 mg/ml.  
     
     
         4 . The formulation of  claim 1 , wherein the concentration of the antibody is about 50 mg/ml.  
     
     
         5 . The formulation of  claim 1 , which further is suitable for single use sc injection.  
     
     
         6 . The formulation of  claim 1 , wherein the antibody is an antibody, or an antigen-binding portion thereof, that dissociates from human TNFα with a K d  of 1×10 −8  M or less and a K off  rate constant of 1×10 −3  s −1  or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −7  M or less.  
     
     
         7 . The formulation of  claim 6 , wherein the antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.  
     
     
         8 . The formulation of  claim 1 , wherein the antibody is an the antibody, or antigen-binding portion, thereof which: 
 a) dissociates from human TNFα with a K off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance;    b) has a light chain 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 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;    c) has a heavy chain 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 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.    
     
     
         9 . The formulation of  claim 1 , wherein the antibody, or antigen-binding portion thereof, has 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.  
     
     
         10 . The formulation of  claim 1 , wherein the antibody, or antigen-binding portion thereof, neutralizes the activity of human TNFα, chimpanzee TNFα and at least one additional primate TNFα selected from the group consisting of baboon TNFα, marmoset TNFα, cynomolgus TNFα and rhesus TNFα.  
     
     
         11 . The formulation of  claim 1 , wherein the antibody, or an antigen-binding portion thereof, also neutralizes the activity of mouse TNFα and/or pig TNFα.  
     
     
         12 . The formulation of  claim 1 , wherein the antibody, or antigen-binding portion thereof, binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof.  
     
     
         13 . An aqueous pharmaceutical composition comprising a polyol, a surfactant, and a buffer system comprising citrate and/or phosphate with a pH of about 4 to 8, in amounts sufficient to formulate an antibody for therapeutic use at a concentration of greater than about 45 mg/ml.  
     
     
         14 . The composition of  claim 13 , wherein the polyol is mannitol and the surfactant is polysorbate 80.  
     
     
         15 . The composition of  claim 14 , which contains 5-20 mg/ml of mannitol and 0.1-10 mg/ml of polysorbate 80.  
     
     
         16 . The formulation of  claim 13 , which contains an antibody, or antigen-binding portion thereof, which binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof.  
     
     
         17 . A liquid aqueous pharmaceutical formulation comprising 
 (a) 1-150 mg/ml of antibody,    (b) 5-20 mg/ml of mannitol,    (c) 0.1-10 mg/ml of Tween-80, and    (d) a buffer system comprising citrate and/or phosphate, with a pH of 4 to 8.    
     
     
         18 . The formulation of  claim 17 , wherein the pH is selected from the group consisting of between about 4.5 to about 6.0, between about 4.8 to about 5.5, and between about 5.0 to about 5.2.  
     
     
         19 . The liquid aqueous pharmaceutical formulation of  claim 17 , which contains 
 (a) about 50 mg/ml of antibody,    (b) about 12 mg/ml of mannitol,    (c) about 1 mg/ml of Tween-80, and    
     
     
         20 . The formulation of  claim 17 , wherein the buffer system comprises 
 (a) about 1.3 mg/ml of citric acid,    (b) about 0.3 mg/ml of sodium citrate,    (c) about 1.5 mg/ml of disodium phosphate dihydrate,    (d) about 0.9 mg/ml of sodium dihydrogen phosphate dihydrate, and    (e) about 6.2 mg/ml of sodium chloride    
     
     
         21 . The formulation of  claim 19 , wherein the antibody is directed to TNFα.  
     
     
         22 . The formulation of  claim 19 , wherein the antibody, or antigen-binding portion thereof, binds human TNFα and is the antibody D2E7 or an antigen binding portion thereof.  
     
     
         23 . The formulation of  claim 22 , which is administered to a subject suffering from a disorder in which TNFα activity is detrimental such that TNFα activity in the subject is inhibited