ANTIBODY-ENZYME CONJUGATES FOR CANCER-THERAPY

The use of antibody-enzyme conjugates directed at tumor-associated ant igens to achieve site-specific activation of prodrugs to potent cytoto xic species, termed ''antibody-directed enzyme prodrug therapy'' (ADEP T), has attracted considerable interest since the concept was first de scribed in 1987. Prodrug forms of both clinically used anticancer agen ts and novel cytotoxic compounds have been developed to take advantage of potential prodrug-generating technology employing a variety of enz ymes with widely differing substrate specificities. A particular advan tage of the ADEPT approach is that it may allow the use of extremely p otent agents such as nitrogen mustards and palytoxin, which are too to xic to be readily used in conventional chemotherapy. Preliminary studi es using an antibody-enzyme conjugate constructed with a bacterial enz yme and a murine monoclonal antibody not only have established the val ue of the ADEPT technique, but also have highlighted the potential pro blem of immunogenicity of proteins of nonhuman origin. This problem ha s been tackled in the first instance by the use of immunosuppressive a gents, but long-term solutions are being investigated in the developme nt of second-generation ADEPT systems, including the development of hu man antibody-human enzyme fusion proteins and catalytic antibodies. Su ch improvements, coupled with further refinement of the prodrug-drug e lement of the system and the wide variety of antibody-enzyme-drug comb inations available, should mean that ADEPT-based approaches will form an important element of the search for the anticancer drugs of the fut ure.