Drug conjugate composition

Abstract

The invention provides a liquid composition and a lyophilized composition comprising a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid. The invention further provides a method for killing a cell in a human comprising administering to the human either of the compositions such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed.

1 . A composition comprising (i) a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, and a histidine buffer, (iii) a first excipient selected from the group consisting of glycerol, dimethyl sufoxide, polyethylene glycol, dextran, glucose, trehalose, and sucrose, (iv) a second excipient selected from the group consisting of glycine, mannitol, and dextran, (v) a surfactant, and (vi) water, wherein the composition has a pH of about 5-6. 
     
     
         2 . The composition of  claim 1 , wherein the first excipient is sucrose. 
     
     
         3 . The composition of  claim 2 , wherein the concentration of sucrose is about 0.1% to about 1% wt./vol. of the total volume of the composition. 
     
     
         4 . The composition of  claim 1 , wherein the second excipient is glycine. 
     
     
         5 . The composition of  claim 1 , wherein the second excipient is mannitol. 
     
     
         6 . The composition of  claim 1 , wherein the concentration of the second excipient is about 50 mM to about 500 mM. 
     
     
         7 . The composition of  claim 1 , wherein the surfactant is polysorbate 80. 
     
     
         8 . The composition of  claim 1 , wherein the surfactant is polysorbate 20. 
     
     
         9 . The composition of  claim 1 , wherein the concentration of the surfactant is about 0.002% to about 0.1% wt./vol. of the total volume of the composition. 
     
     
         10 . The composition of  claim 1 , wherein the composition comprises a succinate buffer. 
     
     
         11 . The composition of  claim 1 , wherein the concentration of the buffering agent is about 2 mM to about 50 mM. 
     
     
         12 . The composition of  claim 1 , wherein the concentration of the buffering agent is about 2 mM to about 15 mM. 
     
     
         13 . The composition of  claim 1 , wherein the concentration of the conjugate is about 0.1 mg/ml to about 5 mg/ml. 
     
     
         14 . The composition of  claim 1 , wherein the concentration of the conjugate is about 1 mg/mL. 
     
     
         15 . The composition of  claim 1 , wherein the concentration of the conjugate is about 5 mg/mL. 
     
     
         16 . The composition of  claim 1 , wherein the pH of the composition is about 5.5. 
     
     
         17 . The composition of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         18 . The composition of  claim 17 , wherein the antibody is a humanized monoclonal antibody. 
     
     
         19 . The composition of  claim 17 , wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab. 
     
     
         20 . The composition of  claim 17 , wherein the antibody binds to an antigen selected from the group consisting of NCAM/CD56, CD33, CD19, GD3, CanAg, PSMA, alpha-folate receptor, Her2/neu, CD44v6, fetoacinar pancreatic (FAP) antigen, Cripto-1, CA6, CD20, CA55.1, MN/CA IX, and chondroitin sulfate proteoglycan. 
     
     
         21 . The composition of  claim 1 , wherein the maytansinoid is N 2′ -deacetyl-N 2′ -(3-mercapto-1-oxopropyl)-maytansine (DM1). 
     
     
         22 . The composition of  claim 1 , wherein the maytansinoid is N 2′ -deacetyl-N 2′ -(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         23 . The composition of  claim 1 , wherein the antibody is chemically coupled to the maytansinoid via chemical bonds selected from the group consisting of disulfide bonds, acid labile bonds, photolabile bonds, peptidase labile bonds, thioether bonds, and esterase labile bonds. 
     
     
         24 . The composition of  claim 23 , wherein the antibody is chemically coupled to the maytansinoid via a linker molecule selected from the group consisting of N-succinimidyl-4-(2-pyridyldithio)butanoate (SPDB), N-succinimdyl-4-(2-pyridyldithio)pentanoate (SPP), and N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). 
     
     
         25 . The composition of  claim 1 , wherein the composition comprises (i) 1 mg/ml huN901 chemically coupled to N 2 ′-deacetyl-N 2′ -(3-mercapto-1-oxopropyl)-maytansine (DM1), (ii) 10 mM sodium citrate, (iii) 0.5% wt./vol. sucrose, (iv) 250 mM glycine, (v) 0.01% wt./vol. polysorbate 20, and (vi) water, wherein the composition has a pH of 5.5. 
     
     
         26 . A lyophilized composition of the composition of  claim 1 . 
     
     
         27 . A packaged composition comprising a sealed container and dispersed therein the composition of  claim 1  and an inert gas overlay. 
     
     
         28 . A packaged composition comprising a sealed container and dispersed therein the composition of  claim 26  and an inert gas overlay. 
     
     
         29 . A method for killing a cell in a human comprising administering the composition of  claim 1  to the human, such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed. 
     
     
         30 . A method for killing a cell in a human comprising (a) providing the lyophilized composition of  claim 26 , (b) adding water to the lyophilized composition to provide a reconstituted composition, and (c) administering the reconstituted composition to the human, such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed.