CONJUGATION OF SMALL RIBOSOMAL INHIBITORS TO ANTIBODIES

NEORX CORPORATION PROPOSES A NEW SERIES OF SMALL-MOLECULAR WEIGHT NATURAL PRODUCTS THAT ARE SIMILAR TO HIGHER PLANT TOXINS IN THEIR MECHANISMS OF ACTION-INHIBITING PROTEIN SYNTHESIS AT THE LEVEL OF THE RIBOSOME. ALL INHIBIT IN VIVOTRANSLATION IN CELL-FREE SYSTEMS. SOME ARE CYTOTOXIC TO EUCARYOTIC CELLS AT LOW CONCENTRATIONS (ID50 100PG/ML) AND THUS BEHAVE LIKE THE "INTACT" DIMERIC TOXINS RICIN AND ABRIN; OTHERS ARE NOT CYTOTOXIC AT RELATIVELY HIGH CONCENTRATIONS (10 /ML) AND ARE SIMILAR TO RIBOSOMAL INACTIVATING PROTEINS (RIPS) SUCH AS GELONIN. MONOCLONAL ANTIBODIES (MOARBS) ARE PROPOSED AS VEHICLES TO FACILITATE BINDING AND INTERNALIZATION OF THE NONCYTOTOXIC (RIP-LIKE) MOLECULES AND TO ENHANCE SELECTIVITY OF THE CYTOTOXIC (INTACT TOXIN-LIKE) MOLECULES. TWO OF THE RIP-LIKE MOLECULES, DIFFERING ONLY IN ONE SITE OFACETYLATION, AND ONE TOXIN-LIKE MOLECULE TO AN ANTIMELANOMA MOAB WILL BE CONJUGATED AND TESTED FOR INHIBITION OF PROTEINSYNTHESIS AND OVERALL CYTOTOXICITY AND SELECTIVITY WITH ANTIGEN-POSITIVE AND ANTIGEN-NEGATIVE MELANOMA CELLS. THEIRCONJUGATES MAY HAVE EQUIVALENT POTENCY BUT NOT SUFFER THE POOR DELIVERY CAUSED BY NONSPECIFIC UPTAKE AS OCCURS WITH HIGHER MOLECULAR WEIGHT TOXINS. THEY ARE ALSO NOT LIKELY TOSUFFER FROM DRUG-INDUCED CROSS-RESISTANCE, AS OCCURS WITH DRUGS CURRENTLY USED IN CHEMOTHERAPY. SHOULD EITHER OR BOTHOF THESE APPROACHES PROVE FEASIBLE, IT WILL BE POSSIBLE TO CONSTRUCT SEVERAL GENERATIONS OF A WIDE RANGE OF RELATED ANTITUMOR AGENTS THAT HAVE UNIQUE MECHANISMS OF ACTION AND THAT WILL BE IMPORTANT NEW AGENTS FOR THE TREATMENT OF CANCER.