Pharmaceutical composition comprising bispecific antibody constructs

Abstract

The present invention provides novel and stable pharmaceutical compositions comprising bispecific single chain antibody constructs, cyclodextrins and a buffer.

1 . A pharmaceutical composition comprising a bispecific single chain antibody construct that binds to target cell surface antigen CD19 via a first binding domain and to the T cell surface antigen CD3 via a second binding domain, a β-cyclodextrin and a buffer,
 wherein the binding domains have pairs of VH regions and VL regions in the format of a single chain antibody (scFv), 
 wherein the composition is characterized by a reduction or prevention of the formation of protein aqqregates (high molecular weight species (HMWS)), and 
 wherein the β-cyclodextrin is not hydroxypropyl-β-cyclodextrin. 
 
     
     
         2 . The composition according to  claim 1 , wherein the β-cyclodextrin is selected from the group consisting of β-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, ethyl-β-cyclodextrin, butyl-β-cyclodextrin Succinyl-(2-hydroxypropyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, β-cyclodextrin phosphate sodium salt, β-cyclodextrin sulphate sodium salt, triacetyl-β-cyclodextrin, heptakis(6-O-sulfo)-β-cyclodextrin heptasodium salt, carboxymethyl-β-cyclodextrin sodium salt, sulfobutylether-β-cyclodextrin sodium salt, and 6-O-p-toluenesulfonyl-β-cyclodextrin. 
     
     
         3 . The composition according to  claim 1 , wherein the β-cyclodextrin is present in a concentration in the range of 0.1% to 20% (w/v). 
     
     
         4 . The composition according to  claim 1 , wherein the β-cyclodextrin is sulfobutylether-β-cyclodextrin sodium salt. 
     
     
         5 . The composition according to  claim 1 , wherein the bispecific single chain antibody construct is present in a concentration range of 0.1-5 mg/ml. 
     
     
         6 . The composition according to  claim 1 , wherein the buffer is selected from the group consisting of potassium phosphate, acetic acid/sodium acetate, citric acid/sodium citrate, succinic acid/sodium succinate, tartaric acid/sodium tartrate, histidine/histidine HCl, glycine, Tris, glutamate, acetate and mixtures thereof. 
     
     
         7 . The composition according to  claim 6 , wherein the buffer is selected from the group consisting of potassium phosphate, citric acid/sodium citrate, succinic acid, histidine, glutamate, acetate and combinations thereof. 
     
     
         8 . The composition according to  claim 1 , wherein the pH of the composition is in the range of 4-7.5. 
     
     
         9 . The composition according to  claim 1 , further comprising one or more excipients selected from the group consisting of sucrose, trehalose, mannitol, sorbitol, arginine, lysine, polysorbate 20, polysorbate 80, poloxamer 188, pluronic and combinations thereof. 
     
     
         10 . The composition according to  claim 1 , further comprising one or more preservatives. 
     
     
         11 . The composition according to  claim 10 , wherein the one or more preservative is selected from the group consisting of benzyl alcohol, chlorobutanol, phenol, meta-cresol, methylparaben, phenoxyethanol, propylparaben and thiomerosal. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The composition according to  claim 3 , wherein the β-cyclodextrin is present in a concentration in the range of 0.5% to 2% (w/v). 
     
     
         16 . The composition according to  claim 15 , wherein the β-cyclodextrin is present in a concentration in the range of 0.8% to 1.5% (w/v). 
     
     
         17 . The composition according to  claim 5 , wherein the bispecific single chain antibody construct is present in a concentration range of 0.2-2.5 mg/ml. 
     
     
         18 . The composition according to  claim 17 , wherein the bispecific single chain antibody construct is present in a concentration range of 0.25-1.0 mg/ml. 
     
     
         19 . The composition according to  claim 1 , wherein the amino acid sequence of the bispecific single chain antibody construct is SEQ ID NO: 174. 
     
     
         20 . The composition according to  claim 19 , wherein the cyclodextrin is sulfobutylether-β-cyclodextrin sodium salt in a concentration of about 1% (w/v) and the buffer is potassium phosphate in concentration of about 10 mM, and wherein the composition further comprises mannitol in a concentration of about 4%, sucrose in a concentration of about 2% (w/v), and polysorbate 80 in concentration of about 0.01% (w/v) at a pH of about 6.0.