High concentration antibody and protein formulations

Abstract

The present application relates to highly concentrated antibody and protein formulations with reduced viscosity that are stable, relatively isotonic and are of low turbidity. The formulations are particularly suitable for subcutaneous administration. The application further describes articles of manufacture containing such formulations and method for using them to treat disorders treatable by the formulated antibody or protein.

1 . A stable, liquid formulation of low turbidity comprising (a) a protein or antibody in an amount of 100 to 260 mg/ml, (b) arginine-HCl in an amount of 50 to 200 mM, (c) histidine in an amount of 10 to 100 mM, (d) polysorbate in an amount of 0.01 to 0.1%, where the formulation further has a pH ranging from 5.5 to 7.0, a kinematic viscosity of about 50 cs or less and osmolarity ranging from 200 mOsm/kg to 450 mOsm/kg. 
     
     
         2 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 120 mg/ml to 260 mg/ml. 
     
     
         3 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 150 mg/ml to 260 mg/ml. 
     
     
         4 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 180 mg/ml to 260 mg/ml. 
     
     
         5 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 200 mg/ml to 260 mg/ml. 
     
     
         6 . The formulation of  claim 1 , wherein the concentration of protein or antibody is about 150 mg/ml. 
     
     
         7 . The formulation of  claim 1 , wherein the osmolarity ranges from 250 mOsm/kg to 350 mOsm/kg. 
     
     
         8 . The formulation of  claim 1 , wherein the concentration of arginine-HCl ranges from 100 mg/ml to 200 mg/ml. 
     
     
         9 . A stable, liquid formulation of low turbidity comprising (a) an anti-IgE monoclonal antibody in an amount of 100 to 260 mg/ml, (b) arginine-HCl in an amount of 50 to 200 mM, (c) histidine in an amount of 10 to 100 mM, (d) polysorbate in an amount of 0.01 to 0.1%, where the formulation further has a pH ranging from 5.5 to 7.0, a kinematic viscosity of about 50 cs or less and osmolarity ranging from 200 mOsm/kg to 450 mOsm/kg. 
     
     
         10 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 120 mg/ml to 260 mg/ml. 
     
     
         11 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 150 mg/ml to 260 mg/ml. 
     
     
         12 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 180 mg/ml to 260 mg/ml. 
     
     
         13 . The formulation of  claim 1 , wherein the concentration of protein or antibody ranges from 200 mg/ml to 260 mg/ml. 
     
     
         14 . The formulation of  claim 1 , wherein the concentration of protein or antibody is about 150 mg/ml. 
     
     
         15 . The formulation of  claim 1 , wherein the osmolarity ranges from 250 mOsm/kg to 350 mOsm/kg. 
     
     
         16 . The formulation of  claim 1 , where the anti-IgE antibody is selected from the group consisting of rhuMAbE25, rhuMAbE26 and Hu-901. 
     
     
         17 . The formulation of  claim 1 , wherein the anti-IgE antibody is rhuMAbE25. 
     
     
         18 . The formulation of  claim 1 , wherein the anti-IgE antibody is rhuMAbE26. 
     
     
         19 . The formulation of  claim 1 , wherein the anti-IgE antibody is Hu-901. 
     
     
         20 . A stable, liquid formulation of low turbidity comprising (a) an anti-IgE antibody in an amount of about 150 mg/ml, (b) arginine-HCl in an amount of 200 mM, (c) histidine in an amount of 20 mM, (d) polysorbate in an amount of 0.02%, where the formulation further has a pH of 6.0. 
     
     
         21 . The formulation of  claim 20 , wherein the anti-IgE antibody is E25. 
     
     
         22 . An article of manufacture comprising a container enclosing the formulation of  claim 1 . 
     
     
         23 . The article of manufacture of  claim 22 , wherein the container is a syringe. 
     
     
         24 . The article of manufacture of  claim 23 , wherein the syringe is further contained within an injection device. 
     
     
         25 . The article of manufacture of  claim 24 , wherein the injection device is an auto-injector. 
     
     
         26 . The formulation of  claim 1 , wherein said formulation is reconstituted. 
     
     
         27 . The formulation of  claim 26 , wherein the protein or antibody concentration in said reconstituted formulation is about 240 times greater than the concentration prior to lyophilization. 
     
     
         28 . A method of treating an IgE-mediated disorder comprising administrating to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20 . 
     
     
         29 . The method of  claim 28 , wherein the IgE-mediated disorder is selected from the group consisting of allergic rhinitis, asthma, allergic asthma, non-allergic asthma, atopic dermatitis and gastroenteropathy. 
     
     
         30 . The method of  claim 28 , wherein the IgE-mediated disorder is allergic rhinitis. 
     
     
         31 . The method of  claim 28 , wherein the IgE-mediated disorder is allergic asthma. 
     
     
         32 . The method of  claim 28 , wherein the IgE-mediated disorder is asthma. 
     
     
         33 . The method of  claim 28 , wherein the IgE-mediated disorder is atopic dermatitis. 
     
     
         34 . The method of  claim 28 , wherein the IgE-mediated disorder is selected from the group consisting of hypersensitivity, allergic bronchopulmonary aspergillosis, parasitic diseases, interstitial cystitis, hyper-IgE syndrome, ataxia-telangiectasia, Wiskott-Akdrich syndrome, thymic alymphoplasia, IgE myeloma and graft-versus-host reaction. 
     
     
         35 . The method of  claim 28  wherein the IgE-mediated disorder is hypersensitivity. 
     
     
         36 . The method of  claim 35 , wherein the hypersensitivity disorder is selected from the group consisting of anaphylaxis, urticaria and food allergy. 
     
     
         37 . The method of  claim 36 , wherein hypersensitivity disorder is food allergy. 
     
     
         38 . The method of  claim 37 , wherein the food allergy results from exposure to a legume. 
     
     
         39 . The method of  claim 38 , wherein the legume is a peanut. 
     
     
         40 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with an antihistamine. 
     
     
         41 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with the administration of an antihistamine. 
     
     
         42 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with a bronchodialator. 
     
     
         43 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with the administration of a bronchodialator. 
     
     
         44 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with a glucocorticoid. 
     
     
         45 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with the administration of a glucocorticoid. 
     
     
         46 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with a glucocorticoid. 
     
     
         47 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with the administration of a glucocorticoid. 
     
     
         48 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with the administration of allergen desensitization. 
     
     
         49 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with an NSAID. 
     
     
         50 . A method of treating an IgE-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of  claim 20  in combination with the administration of an NSAID.