Preparation of four daunomycin‐monoclonal antibody 79IT/36 conjugates with anti‐tumour activity

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Abstract
As an approach to developing more specific anti-tumor therapeutic agents, daunomycin was covalently linked to murine monoclonal antibody 791T/36. Four procedures for coupling drug to antibody were investigated. The sugar amino group of daunomycin was modified by reaction with succinic anhydride or cis-aconitic anhydride and these derivatives were linked to antibody, a carbodiimide reagent being used to produce stable peptide bonding. Alternatively, 14-bromo daunomycin was linked directly to antibody or antibody containing free thiol groups introduced by means of the heterobifunctional reagent SPDP [N-succinimidyl-3 (2-pyridyldithio) propionate] thus producing a thioether linkage. Each of the conjugates, with drug-antibody ratios of 3 to 4:1, retained a proportion of drug activity although the succinic anhydride derivative was the least cytotoxic. The 3 other conjugates specifically bound to [human] tumor cells expressing the 791T/36 antibody defined antigen. In short-term assays in which tumor cells were briefly exposed to conjugates and then washed to remove non-bound conjugate, it was determined that the conjugate with the cis aconityl linkage displayed the greatest selective cytotoxicity against tumor cells reactive with 791T/36 antibody. These studies illustrate the feasibility of preparing chemically defined drug-antibody conjugates retaining cytotoxicity and selectivity of action against tumor cells.

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