Stable IGG4 Based Binding Agent Formulations

Abstract

The present invention provides stable pharmaceutical antibody formulations, including liquid drug product formulations and lyophilized drug product formulations, comprising an IgG4 binding agent and a citrate buffer, wherein the pH of the formulation is at or below both pH 6 and the pI of the binding agent. The formulations can be used in the treatment of chronic bowel diseases or rheumatoid arthritis.

1 : A pharmaceutical formulation for intravenous or subcutaneous administration, comprising:
 a humanized or a fully human IgG4 antibody;   about 5 to about 50 mM citrate buffer;   about 0.005% to about 0.1% polysorbate 20;   about 0.1% to about 10% of a tonicity agent;   wherein the pH of the formulation is at or below both about pH 6 and the pI of the antibody.   
     
     
         2 : The formulation of  claim 1 , wherein the antibody concentration is from about 5 to about 280 mg/mL. 
     
     
         3 : The formulation of  claim 1 , wherein the citrate concentration is from about 5 to about 15 mM. 
     
     
         4 : The formulation of  claim 1 , wherein the formulation further comprises about 0.1% to about 5% of an amino acid. 
     
     
         5 : The formulation of  claim 1 , wherein the tonicity agent is at least one of a saccharide and sodium chloride. 
     
     
         6 : The formulation of  claim 5 , wherein the saccharide is mannitol or sucrose. 
     
     
         7 : The formulation of  claim 6 , wherein the formulation comprises about 4% mannitol or about 4% to about 6% sucrose. 
     
     
         8 : The formulation of  claim 5 , wherein the formulation comprises about 0.01% to about 1% sodium chloride. 
     
     
         9 : The formulation of  claim 4 , wherein the amino acid is proline or arginine. 
     
     
         10 : The formulation of  claim 1 , wherein the pI of the antibody is from about 6.8 to about 7.2. 
     
     
         11 : The formulation of  claim 1 , wherein the pI of the antibody is from about 7.6 to about 8.4. 
     
     
         12 : The formulation of  claim 1 , wherein the pH is about pH 5 to about pH 6. 
     
     
         13 : The formulation of  claim 12 , wherein the pH is selected from the group consisting of about pH 5.0, about pH 5.5, and about pH 6.0. 
     
     
         14 : The formulation of  claim 1 , wherein the formulation exhibits a reduced amount of at least one byproduct selected from the group consisting of aggregates, half-molecules, degradation products, low molecular weight proteins, high molecular weight proteins, and rearrangement of acidic/basic/neutral isoforms of the humanized or fully human IgG4 antibody as compared to a reference formulation comprising the humanized or fully human IgG4 antibody in phosphate buffered saline at pH 7.3. 
     
     
         15 : The formulation of  claim 1 , wherein the formulation is a liquid formulation. 
     
     
         16 : The formulation of  claim 1 , wherein the formulation is a lyophilized formulation. 
     
     
         17 : A kit comprising a container comprising: 1) the formulation of  claim 1 , and 2) a label or instructions for the administration and use of the formulation. 
     
     
         18 : A pre-filled container comprising the formulation of  claim 1 . 
     
     
         19 : The formulation of  claim 1 , wherein the formulation is stable for at least 6 months at +5° C. 
     
     
         20 : The formulation of  claim 1 , wherein the formulation is stable for at least 9 months at +5° C.