Antibody formulation

Abstract

Anti-CD40 antibodies are formulated as lyophilisate or liquid formulation. The lyophilisates can be reconstituted to give a solution with a high concentration of the antibody active ingredient for delivery to a patient without high levels of antibody aggregation. The lyophilisate can be reconstituted with an aqueous reconstituent to provide an aqueous composition in which the antibody has a concentration of at least 50 mg/ml. The lyophilisate or aqueous pharmaceutical composition may include one or more of a sugar, a buffering agent, a surfactant, and/or a free amino acid.

1 . A lyophilised formulation prepared by lyophilising an aqueous formulation having a pH of 5.0-7.0 and comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of 20-150 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) a stabiliser,   (iii) a buffering agent, and   (iv) a surfactant.   
     
     
         2 . The lyophilised formulation of  claim 1 , wherein said formulation is prepared from an aqueous formulation having a pH of 5.0-7.0 and comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of 20-150 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) sucrose or trehalose as a stabiliser,   (iii) histidine as a buffering agent, and   (iv) polysorbate 20 as a surfactant.   
     
     
         3 . The lyophilised formulation of  claim 2 , wherein said formulation is prepared from an aqueous formulation having a pH of 5.0-7.0 and comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of 20-150 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) 3-300 mM sucrose or trehalose as a stabiliser,   (iii) 1-60 mM histidine as a buffering agent, and   (iv) up to 0.2% polysorbate 20 as a surfactant.   
     
     
         4 . The lyophilised formulation as claimed in  claim 1 , wherein said formulation is prepared from an aqueous formulation having a pH of 6.0 and comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) 90 mM sucrose as a stabiliser,   (iii) 10 mM histidine as a buffering agent, and   (iv) 0.02% polysorbate 20 as a surfactant.   
     
     
         5 . The lyophilised formulation as claimed in  claim 1 , wherein said formulation is prepared from an aqueous formulation having a pH of 6.0 and comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) 90 mM sucrose as a stabiliser,   (iii) 10 mM histidine as a buffering agent,   (iv) 0.02% polysorbate 20 as a surfactant, and   (v) 17 mM arginine.   
     
     
         6 . The lyophilised formulation as claimed in  claim 1 , wherein said formulation is prepared from an aqueous formulation having a pH of 6.0 and comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of 150 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) 270 mM sucrose as a stabiliser,   (iii) 30 mM histidine as a buffering agent, and   (iv) 0.06% polysorbate 20 as a surfactant.   
     
     
         7 . An aqueous composition obtained by reconstituting a lyophilised formulation of  claim 1 , wherein the reconstitution factor is between 1:0.5 to 1:6. 
     
     
         8 . The aqueous composition of  claim 7 , wherein the reconstitution factor is 1:3. 
     
     
         9 . An aqueous composition having a pH of 5.0 to 7.0 comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of at least 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) a stabiliser,   (iii) a buffering agent, and   (iv) a surfactant.   
     
     
         10 . The aqueous composition of  claim 9  comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of at least 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8, 
 (ii) sucrose or trehalose as a stabiliser, 
 (iii) histidine as a buffering agent, and 
 (iv) polysorbate 20 as a surfactant. 
 
     
     
         11 . The aqueous composition of  claim 10  comprising
 (i) an anti-CD40 antibody wherein the antibody has a concentration of at least 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8, 
 (ii) 200-300 mM sucrose as a stabiliser, 
 (iii) 25-35 mM histidine as a buffering agent, and 
 (iv) up to 0.2% polysorbate 20 as a surfactant 
 
     
     
         12 . The aqueous composition of  claim 9 , wherein the composition has a pH of 6.0 and comprises
 (i) an anti-CD40 antibody wherein the antibody has a concentration of at least 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) 270 mM sucrose as a stabiliser,   (iii) 30 mM histidine as a buffering agent, and   (iv) 0.06% polysorbate 20 as a surfactant.   
     
     
         13 . The aqueous composition of  claim 9 , wherein the composition has a pH of 6.0 and comprises
 (i) an anti-CD40 antibody wherein the antibody has a concentration of at least 50 mg/ml, and wherein said anti-CD40 antibody includes heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs 3, 4 and 5 respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8,   (ii) 270 mM sucrose as a stabiliser,   (iii) 30 mM histidine as a buffering agent,   (iv) 0.06% polysorbate 20 as a surfactant, and   (v) 51 mM arginine.   
     
     
         14 . The aqueous composition of  claim 9 , wherein the anti-CD40 antibody has a concentration of 150 mg/ml. 
     
     
         15 . The lyophilised formulation of  claim 1 , wherein the anti-CD40 antibody comprises a V H  domain having the amino acid sequence of SEQ ID NO: 1 and a V L  domain having the amino acid sequence of SEQ ID NO: 2. 
     
     
         16 . The aqueous composition of  claim 9 , wherein the anti-CD40 antibody comprises a V H  domain having the amino acid sequence of SEQ ID NO: 1 and a V L  domain having the amino acid sequence of SEQ ID NO: 2. 
     
     
         17 . The lyophilised formulation of  claim 1 , wherein the anti-CD40 antibody comprises a heavy chain region and a light chain region having the amino acid sequence selected from the group consisting of: a) SEQ ID NO: 9 and SEQ ID NO: 10, respectively; b) SEQ ID NO: 13 and SEQ ID NO: 14, respectively; and c) SEQ ID NO: 17 and SEQ ID NO: 18, respectively. 
     
     
         18 . The aqueous composition of  claim 9 , wherein the anti-CD40 antibody comprises a heavy chain region and a light chain region having the amino acid sequence selected from the group consisting of: a) SEQ ID NO: 9 and SEQ ID NO: 10, respectively; b) SEQ ID NO: 13 and SEQ ID NO: 14, respectively; and c) SEQ ID NO: 17 and SEQ ID NO: 18, respectively. 
     
     
         19 . A delivery device including the aqueous composition of  claim 9 . 
     
     
         20 . A pre-filled syringe including the aqueous composition of  claim 9 . 
     
     
         21 . A method for delivering an anti-CD40 antibody to a mammal, comprising a step of administering to the mammal an aqueous composition as claimed  claim 9 . 
     
     
         22 . A method of treating a disease or disorder that is mediated by CD40, comprising a step of administering the aqueous composition of  claim 9  to a subject. 
     
     
         23 . The method of  claim 22  wherein the disease or disorder is an autoimmune disease. 
     
     
         24 . The method of  claim 23  wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or Pemphigus vulgaris. 
     
     
         25 . The formulation of  claim 1  further comprising and amino acid. 
     
     
         26 . The formulation of  claim 25 , where in the amino acid is arginine, methionine or glycine. 
     
     
         27 . The aqueous composition of  claim 9  further comprising an amino acid. 
     
     
         28 . The aqueous composition of  claim 27 , wherein the amino acid is arginine, methionine or glycine.