title: Selective chemotherapeutic strategies using catalytic antibodies: a common pro-moiety for antibody-directed abzyme prodrug therapy.
abstract: Prodrug activation by catalytic antibodies (abzymes) conjugated with anti-tumor antibodies, called antibody-directed abzyme prodrug therapy (ADAPT), has been proposed as a strategy for site-specific drug delivery systems for anti-tumor drugs. The delivery of abzymes is achieved by making a bi-specific antibody with a monovalent catalytic antibody and a monovalent binding antibody. To achieve ADAPT, we focused on specific requirements for prodrugs and catalytic antibodies, the stability of the prodrugs against natural enzymes, and the applicability of abzymes for a wide range of prodrugs. Attention was paid to the design of a pro-moiety rather than a parent drug. As a common pro-moiety, we chose vitamin B(6), because the bulky vitamin B(6) esters are relatively stable against hydrolytic enzymes in serum. We have generated catalytic antibodies by immunization of a vitamin B(6) phosphonate transition state analog. The elicited antibodies were found to hydrolyze several anti-cancer and anti-inflammatory prodrugs with the vitamin B(6) pro-moiety. Finally, we evaluated antibody-catalyzed prodrug activation by examining the growth inhibition of human cervical cancer (HeLa) cells with the vitamin B(6) ester of butyric acid. These results suggest that the pro-moiety of vitamin B(6) ester is stable enough to resist natural enzymes in serum and is removed by the tailored catalytic antibodies. The combination of catalytic antibodies and prodrugs masked with vitamin B(6) would allow hydrophobic and highly toxic drugs to be used.
authors.affiliation: Laboratory of Life Science and Bimolecular Engineering, Japan Tobacco Inc., 6-2 Umegaoka, Aoba-ku, Yokohama 227-8512, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kakinuma
authors.forename: Ikuo
authors.initials: I
authors.lastname: Fujii
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Nishi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D017151:Antibodies, Catalytic / Q000378:metabolism* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002699:Chlorambucil / Q000378:metabolism; D006241:Haptens; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007052:Ibuprofen / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009149:Mustard Plant / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism*; D013379:Substrate Specificity; D025101:Vitamin B 6 / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017151:Antibodies, Catalytic; D000970:Antineoplastic Agents; D006241:Haptens; D011355:Prodrugs; D002699:Chlorambucil; D025101:Vitamin B 6; D007052:Ibuprofen