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,   (iv) a surfactant, and optionally   (v) an amino acid.   
     
     
         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,   (iv) polysorbate 20 as a surfactant, and optionally   (v) an amino acid selected from arginine, methionine and glycine.   
     
     
         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,   (iv) up to 0.2% polysorbate 20 as a surfactant, and optionally   (v) 2-80 mM arginine, methionine or glycine.   
     
     
         4 . The lyophilised formulation as claimed in  claim 3 , 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.   
     
     
         5 . The lyophilised formulation as claimed in  claim 3 , 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 3 , 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 pharmaceutical 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 pharmaceutical composition of  claim 8 , wherein the reconstitution factor is 1:3. 
     
     
         9 . An aqueous pharmaceutical 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,   (iv) a surfactant, and optionally   (v) an amino acid.   
     
     
         10 . The aqueous pharmaceutical 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, 
 (iv) polysorbate 20 as a surfactant, and optionally 
 (v) an amino acid selected from arginine, methionine or glycine. 
 
     
     
         11 . The aqueous pharmaceutical 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, 
 (iv) up to 0.2% polysorbate 20 as a surfactant, and optionally 
 (v) 10-80 mM arginine, methionine or glycine. 
 
     
     
         12 . The aqueous pharmaceutical composition of  claim 10 , 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 pharmaceutical composition of  claim 11 , 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 pharmaceutical 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 lyophilised formulation of  claim 1 , wherein the anti-CD40 antibody comprises a heavy chain region of SEQ ID NO: 9 and a light chain region of SEQ ID NO: 10. 
     
     
         17 . The lyophilised formulation of  claim 1 , wherein the anti-CD40 antibody comprises a heavy chain region of SEQ ID NO: 13 and a light chain region of SEQ ID NO: 14. 
     
     
         18 . The lyophilised formulation of  claim 1 , wherein the anti-CD40 antibody comprises a heavy chain region of SEQ ID NO: 17 and a light chain region of SEQ ID NO: 18. 
     
     
         19 . A delivery device including the aqueous pharmaceutical composition of  claim 9 . 
     
     
         20 . A pre-filled syringe including the aqueous pharmaceutical 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 pharmaceutical composition as claimed in  claim 9 . 
     
     
         22 . A method of treating a disease or disorder that is mediated by CD40 comprising administering to a patient in need thereof a lyophilised formulation of  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the disease or disorder that is mediated by CD40 is an autoimmune disease. 
     
     
         24 . The method of  claim 22 , wherein the disease or disorder is multiple sclerosis, Sjögren's syndrome, transplant rejection, graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, or Pemphigus vulgaris. 
     
     
         25 . The aqueous pharmaceutical 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. 
     
     
         26 . The aqueous pharmaceutical composition of  claim 9 , wherein the anti-CD40 antibody comprises a heavy chain region of SEQ ID NO: 9 and a light chain region of SEQ ID NO: 10. 
     
     
         27 . The aqueous pharmaceutical composition of  claim 9 , wherein the anti-CD40 antibody comprises a heavy chain region of SEQ ID NO: 13 and a light chain region of SEQ ID NO: 14. 
     
     
         28 . The aqueous pharmaceutical composition of  claim 9 , wherein the anti-CD40 antibody comprises a heavy chain region of SEQ ID NO: 17 and a light chain region of SEQ ID NO: 18. 
     
     
         29 . A method for delivering an anti-CD40 antibody to a mammal, comprising a step of administering to the mammal an aqueous pharmaceutical composition as claimed  claim 9 . 
     
     
         30 . A method of treating a disease or disorder that is mediated by CD40 comprising administering to a patient in need thereof an aqueous pharmaceutical composition according to  claim 9 . 
     
     
         31 . The method according to  claim 30 , wherein the disease or disorder is an autoimmune disease. 
     
     
         32 . The method according to  claim 31 , wherein the disease or disorder is multiple sclerosis, Sjögren's syndrome, transplant rejection, graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, or Pemphigus vulgaris.