Enhancement of tumor uptakes by stabilized Fab homo-oligomers of a chimeric monoclonal antibody against carcinoembryonic antigen

We investigated the effect of stabilized Fab oligomerization by disuccinimi dyl suberate on tumor uptake in a pancreatic carcinoma xenograft model in n ude mice. Recombinant mouse/human chimeric Fab of the anti-carcinoembryonic antigen (CEA) monoclonal antibody A10, which was previously shown to react specifically with gastrointestinal cancers was used in this study. Fab hom o-oligomers (dimers and trimers) chemically linked with ethylene bonds (C-C oligomers) were produced by linkage of chimeric Fab. Oligomers with C-C bo nds had similar immunoreactivity against human CEA to parental Fab monomer. In biodistribution studies in animals bearing pancreatic carcinoma xenogra fts, at 12 and 24 h after infusion, C-C oligomers showed significantly grea ter uptakes in tumors than Fab or F(ab')(2) but lower than IgG. However, ol igomers with C-C bonds maintained higher tumor to normal tissue specificity ratios than IgG 24 h post-infusion. In conclusion, turner uptake was enhan ced by Fab oligomerization with C-C bonds, compared to Fab or F(ab'),, perh aps due to the larger molecular size. It was also shown that C-C Fab oligom ers could have a potency to deliver high-dose radionuclides with reduced ra dio-uptakes in normal tissues for the radioimmunotherapy of gastrointestina l carcinomas.