Misonidazole conjugates of the colorectal tumor associated monoclonal antibody 17-1A

The radiation sensitizer misonidazole has been linked to the monoclonal antibody 17-1A which recognizes a nonshed antigen of a human gastrointestinal tumor. Linkage was accomplished through a hemisuccinate of misonidazole attached by a mixed anhydride coupling and gave a conjugate whose plasma half-life (for drug cleavage) was ca. 70 h. The degree of substitution on the antibody could be precisely regulated by varying the reactant ratios. The binding avidities of the resulting conjugates to the SW1116 colorectal tumor cells decrease logarithmically with increasing drug load. Four to six misonidazoles per antibody represented the optimum drug loading on this system. Enzymatic cleavage of the conjugate-drug union took place at both the ester and the amide linkages with the former scission predominating.