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filingDate 1991-03-13-04:00^^<http://www.w3.org/2001/XMLSchema#date>
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publicationDate 1991-10-31-04:00^^<http://www.w3.org/2001/XMLSchema#date>
publicationNumber WO-9116069-A1
titleOfInvention Selective cytotoxic reagents comprising toxic moieties derived from mammalian proteins
abstract Pancreatic ribonuclease A coupled to human transferrin via a disulfide bond resulted in a hybrid protein that was cytotoxic to mammalian cells in vitro. In measuring protein synthesis capacity of K562 human erythroleukemia cells the IC50 for different preparations of transferrin-RNase ranged from 8 x 10-9 to 8 x 10-8 M whereas the IC¿50? of RNase or SPDP RNase alone was 1000-10,000 times higher. In a clonogenic assay 1 x 10?-6¿ M of the transferrin RNase conjugate killed 6 logs of cells whereas 7 x 10-5 M of the SPDP modified RNase had no significant effect. The inhibition of protein synthesis by transferrin-RNase was blocked by excess transferrin or ribonuclease inhibitors in the medium demonstrating that cytotoxicity was dependent on both components of the conjugate. Human serum RNase may also exhibit receptor mediated toxicities providing a new approach to selective cell killing possibly with less systemic toxicity and, importantly, less immunogenicity than the currently employed antibody-toxin conjugates.
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