Rationale for immunotoxin therapy of metastatic prostate carcinoma formatted as a multi-stage delivery system
A family of triple hybridomas secreting hybrid monoclonal antibodies has been developed in our laboratory. The hybrid monocloncal antibodies exhibit bimolecular specificity towards both antigenic determinants on the prostate carcinoma cell surface as well as toxin or toxic moieties (ricin A chain and pokeweed antiviral protein). These hybrid antibodies, when bound univalently to their cognate toxin, constitute the primary reagents responsible for selective in vitro prostate carcinoma cell kill; oncolytic impact is achieved by binding of the hybrid antibody-toxin complex (primary hybrid immunotoxin) to a prostate carcinoma cell surface-expressed antigen by the remaining univalent binding site of the hybrid antibody, allowing access of the toxin to the cytosol by internalization of the hybrid antibody-toxin complex. Internalization by endocytosis of a hybrid antibody-toxic subunit has been strikingly enhanced by the use of secondary monoclonal antibody reagents alone or in conjunction with other biomodifier reagents. For example, use of a second monoclonal antibody specific for ricin A chain to which ricin B chain (binding subunit) is chemically coupled results in selective and synergistic cell kill of targeted cancer cells. In vitro studies involving temporally staggered exposure of the cells to the individual components (primary hybrid antibody, toxin, and secondary antitoxin monoclonal antibody biomodifier) have been performed in a manner allowing maintenance of cytotoxic efficacy. It is concluded that sequential admministration of these immunotherapeutic components, individually nontoxic, is a feasible strategy to develop an effective immunotherapeutic treatment of human prostate carcinoma.
Webb, KS; Poulton, SHM; Liberman, SM; Walther, PJ
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