Antibody formulations

Abstract

The present application describes antibody formulations, including monoclonal antibodies formulated in histidine-acetate buffer, as well as a formulation comprising an antibody that binds to domain II of HER2 (for example, Pertuzumab), and a formulation comprising an antibody that binds to DR5 (for example, Apomab).

1 . A stable pharmaceutical formulation comprising a monoclonal antibody in histidine-acetate buffer, pH 5.5 to 6.5.  
     
     
         2 . The formulation of  claim 1  wherein the pH is from 5.8 to 6.2.  
     
     
         3 . The formulation of  claim 1  wherein the histidine-acetate buffer concentration is from about 1 mM to about 200 mM.  
     
     
         4 . The formulation of  claim 3  wherein the histidine-acetate buffer concentration is from about 10 mM to about 40 mM.  
     
     
         5 . The formulation of  claim 1  wherein the antibody concentration is from about 10 mg/mL to about 250 mg/mL.  
     
     
         6 . The formulation of  claim 5  wherein the monoclonal antibody concentration is from about 20 mg/mL to about 40 mg/mL.  
     
     
         7 . The formulation of  claim 5  wherein the monoclonal antibody concentration is from about 80 mg/mL to about 250 mg/mL.  
     
     
         8 . The formulation of  claim 1  further comprising saccharide.  
     
     
         9 . The formulation of  claim 8  wherein the saccharide is a disaccharide.  
     
     
         10 . The formulation of  claim 8  wherein the saccharide is trehalose.  
     
     
         11 . The formulation of  claim 8  wherein the saccharide is sucrose.  
     
     
         12 . The formulation of  claim 8  wherein the saccharide concentration is from about 10 mM to about 1M.  
     
     
         13 . The formulation of  claim 12  wherein the saccharide concentration is from about 60 mM to about 250 mM.  
     
     
         14 . The formulation of  claim 1  further comprising surfactant.  
     
     
         15 . The formulation of  claim 14  wherein the surfactant is polysorbate.  
     
     
         16 . The formulation of  claim 15  wherein the surfactant is polysorbate 20.  
     
     
         17 . The formulation of  claim 14  wherein the surfactant concentration is from about 0.0001% to about 1.0%.  
     
     
         18 . The formulation of  claim 17  wherein the surfactant concentration is from about 0.01% to about 0.1%.  
     
     
         19 . The formulation of  claim 1  wherein the monoclonal antibody is a full length antibody.  
     
     
         20 . The formulation of  claim 19  wherein the monoclonal antibody is an IgG1 antibody.  
     
     
         21 . The formulation of  claim 1  wherein the monoclonal antibody is a humanized antibody.  
     
     
         22 . The formulation of  claim 1  wherein the monoclonal antibody is an antibody fragment comprising an antigen-binding region.  
     
     
         23 . The formulation of  claim 22  wherein the antibody fragment is a Fab or F(ab′)2 fragment.  
     
     
         24 . The formulation of  claim 1  which is sterile.  
     
     
         25 . The formulation of  claim 1  wherein the monoclonal antibody binds an antigen selected from the group consisting of HER2, CD20, DR5, BR3, IgE, and VEGF.  
     
     
         26 . The formulation of  claim 25  wherein the antigen is CD20 and the monoclonal antibody is humanized 2H7.  
     
     
         27 . The formulation of  claim 25  wherein the antigen is VEGF and the monoclonal antibody is Bevacizumab.  
     
     
         28 . The formulation of  claim 1  wherein the monoclonal antibody is susceptible to deamidation or aggregation.  
     
     
         29 . The formulation of  claim 1  which is stable upon storage at about 40° C. for at least 4 weeks  
     
     
         30 . The formulation of  claim 1  which is stable upon storage at about 5° C. or about 15° C. for at least 3 months.  
     
     
         31 . The formulation of  claim 1  which is stable upon storage at about −20° C. for at least 3 months.  
     
     
         32 . The formulation of  claim 1  which is stable upon freezing and thawing.  
     
     
         33 . The formulation of  claim 1  which is aqueous.  
     
     
         34 . The formulation of  claim 1  which is frozen.  
     
     
         35 . The formulation of  claim 1  which is not lyophilized and has not been subjected to prior lyophilization.  
     
     
         36 . The formulation of  claim 35  which is aqueous and is administered to a subject.  
     
     
         37 . The formulation of  claim 36  wherein the formulation is for intravenous (IV), subcutaneous (SQ) or intramuscular (IM) administration.  
     
     
         38 . The formulation of  claim 37  which is for IV administration and the antibody concentration is from about 20 mg/mL to about 40 mg/mL.  
     
     
         39 . The formulation of  claim 37  which is for SQ administration and the antibody concentration is from about 80 mg/mL to about 250 mg/mL.  
     
     
         40 . A vial with a stopper pierceable by a syringe comprising the formulation of  claim 1  inside the vial.  
     
     
         41 . The vial of  claim 40  which is stored at about 2-8° C.  
     
     
         42 . The vial of  claim 40  which is a 20 cc or 50 cc vial.  
     
     
         43 . A stainless steel tank comprising the formulation of  claim 1  inside the tank.  
     
     
         44 . The tank of  claim 43  wherein the formulation therein is frozen.  
     
     
         45 . A method of treating a disease or disorder in a subject comprising administering the formulation of  claim 1  to a subject in an amount effective to treat the disease or disorder.  
     
     
         46 . A pharmaceutical formulation comprising: 
 (a) a full length IgG1 antibody susceptible to deamidation or aggregation in an amount from about 10 mg/mL to about 250 mg/mL;    (b) histidine-acetate buffer, pH 5.5 to 6.5;    (c) saccharide selected from the group consisting of trehalose and sucrose, in an amount from about 60 mM to about 250 M; and    (d) polysorbate 20 in an amount from about 0.01% to about 0.1%.    
     
     
         47 . A method for reducing deamidation or aggregation of a therapeutic monoclonal antibody, comprising formulating the antibody in a histidine-acetate buffer, pH 5.5 to 6.5.  
     
     
         48 . The method of  claim 47  comprising evaluating any antibody deamidation or aggregation before and after the antibody is formulated.  
     
     
         49 . A pharmaceutical formulation comprising an antibody that binds to domain II of HER2 in a histidine buffer at a pH from about 5.5 to about 6.5, a saccharide, and a surfactant.  
     
     
         50 . The formulation of  claim 49  wherein the buffer is histidine-acetate.  
     
     
         51 . The formulation of  claim 49  wherein the HER2 antibody comprises the variable light and variable heavy amino acid sequences in SEQ ID Nos. 3 and 4, respectively.  
     
     
         52 . The formulation of  claim 51  wherein the HER2 antibody comprises a light chain amino acid sequence selected from SEQ ID No. 15 and 23, and a heavy chain amino acid sequence selected from SEQ ID No. 16 and 24.  
     
     
         53 . The formulation of  claim 49  wherein the pH of the formulation is from about 5.8 to about 6.2.  
     
     
         54 . The formulation of  claim 49  wherein the antibody binds to the junction between domains I, II and III of HER2.  
     
     
         55 . The formulation of  claim 49  wherein the antibody is a full length antibody.  
     
     
         56 . The formulation of  claim 49  wherein the antibody concentration is from about 20 mg/mL to about 40 mg/mL.  
     
     
         57 . A pharmaceutical formulation comprising Pertuzumab in an amount from about 20 mg/mL to about 40 mg/mL, histidine-acetate buffer, sucrose, and polysorbate 20, wherein the pH of the formulation is from about 5.5 to about 6.5.  
     
     
         58 . The formulation of  claim 57  comprising about 30 mg/mL Pertuzumab, about 20 mM histidine-acetate, about 120 mM sucrose, and about 0.02% polysorbate 20, wherein the pH of the formulation is about 6.0.  
     
     
         59 . A vial with a stopper pierceable by a syringe comprising the formulation of  claim 49 .  
     
     
         60 . A stainless steel tank comprising the formulation of  claim 49  in the tank.  
     
     
         61 . A method of treating HER2-expressing cancer in a subject, comprising administering the pharmaceutical formulation of  claim 49  to the subject in an amount effective to treat the cancer.  
     
     
         62 . The method of  claim 61  wherein the formulation is administered to the subject intravenously, subcutaneously, or intramuscularly.  
     
     
         63 . A method of making a pharmaceutical formulation comprising: 
 (a) preparing the formulation of  claim 1;  and    (b) evaluating physical stability, chemical stability, or biological activity of the monoclonal antibody in the formulation.    
     
     
         64 . A pharmaceutical formulation comprising a DR5 antibody in a histidine buffer at a pH from about 5.5 to about 6.5, a saccharide, and a surfactant.  
     
     
         65 . The formulation of  claim 64  wherein the buffer is histidine-acetate.  
     
     
         66 . The formulation of  claim 64  wherein the DR5 antibody is an agonist antibody.  
     
     
         67 . The formulation of  claim 64  wherein the DR5 antibody is Apomab.  
     
     
         68 . The formulation of  claim 67  wherein the DR5 antibody comprises the heavy chain amino acid sequence of SEQ ID No. 51, and light chain amino acid sequence of SEQ ID No. 52.  
     
     
         69 . The formulation of  claim 64  wherein the pH of the formulation is from about 5.8 to about 6.2.  
     
     
         70 . The formulation of  claim 64  wherein the antibody is a full length antibody.  
     
     
         71 . The formulation of  claim 64  wherein the antibody concentration is from about 10 mg/mL to about 30 mg/mL.  
     
     
         72 . A pharmaceutical formulation comprising Apomab in an amount from about 10 mg/mL to about 30 mg/mL, histidine-acetate buffer, trehalose, and polysorbate 20, wherein the pH of the formulation is from about 5.5 to about 6.5.  
     
     
         73 . The formulation of  claim 72  comprising about 20 mg/mL Apomab, about 20 mM histidine acetate, about 240 mM trehalose, and about 0.02% polysorbate 20, wherein the pH of the formulation is about 6.0.  
     
     
         74 . A vial with a stopper pierceable by a syringe comprising the formulation of  claim 64 .  
     
     
         75 . A stainless steel tank comprising the formulation of  claim 64  in the tank.  
     
     
         76 . A method of treating cancer in a subject, comprising administering the pharmaceutical formulation of  claim 64  to the subject in an amount effective to treat the cancer.  
     
     
         77 . The method of  claim 76  wherein the cancer is a solid tumor.  
     
     
         78 . The method of  claim 76  wherein the cancer is non-Hodgkin's lymphoma.  
     
     
         79 . The method of  claim 76  wherein the formulation is administered to the subject intravenously, subcutaneously, or intramuscularly.