Aqueous pharmaceutical formulation comprising anti-pd-l1 antibody avelumab

Abstract

The present invention relates to a novel anti-PD-L1 antibody formulation. In particular, the invention relates to an aqueous pharmaceutical formulation of the anti-PD-L1 antibody Avelumab.

1 - 42 . (canceled) 
     
     
         43 . A method of treating cancer comprising administering an aqueous pharmaceutical antibody formulation to a patient, wherein the formulation comprises:
 (i) Avelumab in a concentration of 1 milligram/milliliter (mg/mL) to 30 mg/ml, as the antibody;   (ii) acetate or histidine in a concentration of 5 millimolar (mM) to 15 mM as the buffering agent;   (iii) D-mannitol or trehalose in a concentration of 240 mM to 320 mM, or a combination of arginine HCl in a concentration of 50 to 150 mM and glutamic acid in a concentration of 25 mM to 75 mM as a stabiliser; and   (iv) Poloxamer 188 or Polysorbate 20 in a concentration of 0.25 mg/mL to 0.75 mg/mL, as surfactant, or no surfactant;   wherein the formulation does not comprise methionine, and further wherein the formulation has a pH of 5.0 to 6.0.   
     
     
         44 . The method of  claim 43 , wherein the formulation has a pH of 5.0 to 5.6. 
     
     
         45 . The method of  claim 43 , wherein the formulation comprises Avelumab at a concentration of about 10 mg/mL to about 20 mg/mL. 
     
     
         46 . The method of  claim 43 , wherein the formulation comprises acetate or histidine at a concentration of about 10 mM. 
     
     
         47 . The method of  claim 43 , wherein the formulation comprises D-mannitol or trehalose at a concentration of about 280 mM, or for the combination of arginine HCl and glutamic acid, the formulation comprises arginine HCl at a concentration of about 150 mM and glutamic acid at a concentration of about 50 mM. 
     
     
         48 . The method of  claim 43 , wherein the formulation comprises Poloxamer 188 or Polysorbate 20 at a concentration of about 0.5 mg/mL. 
     
     
         49 . The method of  claim 43 , wherein the formulation has a pH of 5.2 (±0.1) to 5.5 (±0.1). 
     
     
         50 . The method of  claim 43 , wherein the formulation comprises acetate in a concentration of about 10 mM, and not comprising any other buffering agent. 
     
     
         51 . The method of  claim 43 , wherein the formulation comprises D-mannitol or trehalose in a concentration of about 280 mM, and not comprising any other stabiliser. 
     
     
         52 . The method of  claim 43 , wherein the formulation comprises Polysorbate 20 or Poloxamer 188 in a concentration of about 0.5 mg/mL and does not comprise any other surfactant. 
     
     
         53 . The method of  claim 51 , wherein the formulation comprises:
 (i) Avelumab in a concentration of 10 mg/mL;   (ii) acetate in a concentration of 10 mM;   (iii) D-mannitol or trehalose in a concentration of 280 mM; and   (iv) Polysorbate 20 or Poloxamer 188 in a concentration of 0.5 mg/mL;   wherein the formulation has a pH of 5.5 (±0.1).   
     
     
         54 . The method of  claim 52 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 10 mg/mL;   (ii) sodium acetate trihydrate in a concentration of 10 mM;   (iii) D-mannitol or trehalose in a concentration of 280 mM;   (iv) Polysorbate 20 or Poloxamer 188 in a concentration of 0.5 mg/mL;   (v) HCl to adjust the pH; and   (vi) water (for injection) as the solvent;   wherein the formulation has a pH of 5.5 (±0.1).   
     
     
         55 . The method of  claim 54 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 10 mg/mL;   (ii) sodium acetate trihydrate in a concentration of 10 mM;   (iii) trehalose dihydrate in a concentration of 280 mM;   (iv) Polysorbate 20 in a concentration of 0.5 mg/mL;   (v) HCl to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.5 (±0.1).   
     
     
         56 . The method of  claim 43 , wherein the formulation comprises:
 (i) Avelumab in a concentration of about 20 mg/mL as the antibody;   (ii) acetate in a concentration of about 10 mM as the buffering agent;   (iii) D-mannitol or trehalose in a concentration of about 280 mM as a stabiliser; and   (iv) Polysorbate 20 or Poloxamer 188 in a concentration of about 0.5 mg/mL as surfactant;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         57 . The method of  claim 56 , wherein the formulation comprises:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetate in a concentration of 10 mM;   (iii) D-mannitol or trehalose in a concentration of 280 mM; and   (iv) Polysorbate 20 or Poloxamer 188 in a concentration of 0.5 mg/mL;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         58 . The method of  claim 43 , wherein the formulation does not comprise an antioxidant. 
     
     
         59 . The method of  claim 56 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 10 mM;   (iii) D-mannitol or trehalose dihydrate in a concentration of 280 mM;   (iv) Polysorbate 20 or Poloxamer 188 in a concentration of 0.5 mg/mL;   (v) sodium acetate to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         60 . The method of  claim 59 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 10 mM;   (iii) D-mannitol in a concentration of 280 mM;   (iv) Polysorbate 20 in a concentration of 0.5 mg/mL;   (v) sodium acetate to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         61 . The method of  claim 59 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 10 mM;   (iii) trehalose dihydrate in a concentration of 280 mM;   (iv) Polysorbate 20 in a concentration of 0.5 mg/mL;   (v) sodium acetate to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         62 . The method of  claim 59 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 10 mM;   (iii) D-mannitol in a concentration of 280 mM;   (iv) Poloxamer 188 in a concentration of 0.5 mg/mL;   (v) sodium acetate to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         63 . The method of  claim 59 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 10 mM;   (iii) trehalose dihydrate in a concentration of 280 mM;   (iv) Poloxamer 188 in a concentration of 0.5 mg/mL;   (v) sodium acetate to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         64 . The method of  claim 56 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 10 mM;   (iii) D-mannitol in a concentration of 280 mM;   (iv) Polysorbate 20 in a concentration of 0.5 mg/mL;   (v) sodium hydroxide in a concentration of 7.5 mM; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.2 (±0.1).   
     
     
         65 . The method of  claim 64 , wherein the formulation is made by combining:
 (i) 20 mg/mL of Avelumab;   (ii) 0.6 mg/mL of glacial acetic acid;   (iii) 51 mg/mL of D-mannitol;   (iv) 0.5 mg/mL of Polysorbate 20;   (v) 0.3 mg/mL of sodium hydroxide; and   (vi) water (for injection) as the diluent.   
     
     
         66 . The method of  claim 44 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 20 mg/mL;   (ii) acetic acid in a concentration of 0.6 mg/mL;   (iii) D-mannitol in a concentration of 51 mg/mL;   (iv) Polysorbate 20 in a concentration of 0.5 mg/mL;   (v) sodium hydroxide in a concentration of 0.3 mg/mL; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.0 to 5.6   
     
     
         67 . The method of  claim 43 , wherein the Avelumab has the heavy chain sequence of either (SEQ ID NO:1) or (SEQ ID NO:2), the light chain sequence of (SEQ ID NO:3), and carries a glycosylation on Asn300 comprising FA2 and FA2G1 as the main glycan species, having a joint share of more than 70% of all glycan species. 
     
     
         68 . The method of  claim 67 , wherein in the Avelumab glycosylation the FA2 has a share of 44% to 54% and the FA2G1 has a share of 25% to 41% of all glycan species. 
     
     
         69 . The method of  claim 68 , wherein in the Avelumab glycosylation the FA2 has a share of 47% to 52% and the FA2G1 has a share of 29% to 37% of all glycan species. 
     
     
         70 . The method of  claim 67 , wherein in the Avelumab glycosylation the FA2 has a share of about 49% and the FA2G1 has a share of about 30% to about 35% of all glycan species. 
     
     
         71 . The method of  claim 67 , wherein the Avelumab glycosylation further comprises as minor glycan species A2 with a share of less than 5%, A2G1 with a share of less than 5%, A2G2 with a share of less than 5% and FA2G2 with a share of less than 7% of all glycan species. 
     
     
         72 . The method of  claim 71 , wherein in the Avelumab glycosylation the A2 has a share of 3% to 5%, the A2G1 has a share of less than 4%, the A2G2 has a share of less than 3% and the FA2G2 has a share of 5% to 6% of all glycan species. 
     
     
         73 . The method of  claim 72 , wherein in the Avelumab glycosylation the A2 has a share of about 3.5% to about 4.5%, the A2G1 has a share of about 0.5% to about 3.5%, the A2G2 has a share of less than 2.5% and the FA2G2 has a share of about 5.5% of all glycan species. 
     
     
         74 . The method of  claim 67 , wherein the Avelumab has the heavy chain sequence of (SEQ ID NO:2). 
     
     
         75 . The method of  claim 43 , wherein the formulation is administered by intravenous (IV) administration. 
     
     
         76 . The method of  claim 43 , wherein the cancer is selected from non-small cell lung cancer, urothelial carcinoma, bladder cancer, mesothelioma, Merkel cell carcinoma, gastric or gastroesophageal junction cancer, ovarian cancer, breast cancer, thymoma, adenocarcinoma of the stomach, adrenocortical carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, melanoma, and/or classical Hodgkin's lymphoma. 
     
     
         77 . A method of treating cancer comprising administering an aqueous pharmaceutical antibody formulation to a patient, wherein the formulation comprises:
 (i) Avelumab in a concentration of about 10 milligram/milliliter (mg/mL) as the antibody;   (ii) acetate in a concentration of about 10 millimolar (mM) as the buffering agent;   (iii) D-mannitol or trehalose in a concentration of about 280 mM as a stabiliser; and   (iv) Polysorbate 20 or Poloxamer 188 in a concentration of about 0.5 mg/mL as surfactant;   wherein the formulation does not comprise methionine, and   further wherein the formulation has a pH of 5.5 (±0.1).   
     
     
         78 . The method of  claim 77 , wherein the formulation consists of:
 (i) Avelumab in a concentration of 10 mg/mL;   (ii) sodium acetate trihydrate in a concentration of 10 mM;   (iii) D-mannitol in a concentration of 280 mM;   (iv) Polysorbate 20 in a concentration of 0.5 mg/mL;   (v) HCl to adjust the pH; and   (vi) water (for injection) as the diluent;   wherein the formulation has a pH of 5.5 (±0.1).   
     
     
         79 . The method of  claim 77 , wherein the formulation is administered by intravenous (IV) administration. 
     
     
         80 . The method of  claim 77 , wherein the cancer is selected from non-small cell lung cancer, urothelial carcinoma, bladder cancer, mesothelioma, Merkel cell carcinoma, gastric or gastroesophageal junction cancer, ovarian cancer, breast cancer, thymoma, adenocarcinoma of the stomach, adrenocortical carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, melanoma, and/or classical Hodgkin's lymphoma. 
     
     
         81 . A method of treating cancer comprising administering an aqueous pharmaceutical antibody formulation to a patient, wherein the formulation consists of Avelumab in a concentration of 20 milligram/milliliter (mg/mL) as the active ingredient; and glacial acetic acid, D-mannitol, Polysorbate 20, sodium hydroxide and water for injection as the excipients; wherein the formulation has a pH of 5.0 to 5.6. 
     
     
         82 . The method of  claim 81 , wherein the formulation has a pH of 5.2 (±0.1). 
     
     
         83 . The method of  claim 81 , wherein the formulation is administered by intravenous (IV) administration. 
     
     
         84 . The method of  claim 81 , wherein the cancer is selected from non-small cell lung cancer, urothelial carcinoma, bladder cancer, mesothelioma, Merkel cell carcinoma, gastric or gastroesophageal junction cancer, ovarian cancer, breast cancer, thymoma, adenocarcinoma of the stomach, adrenocortical carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, melanoma, and/or classical Hodgkin's lymphoma.