The research plan is designed to evaluate the potential of specific passive immunotherapy within the context of multimodal therapy to improve therapeutic modalities for metastatic prostate cancer. Novel hybrid immunotoxin monoclonal antibodies (HIT MABs), capable of recognizing prostate-restricted antigen via one antigen combining site and the toxic ricin A chain via the remaining antigen combining site, will be evaluated extensively in vitro for ability to achieve selective prostate carcinoma cell kill. The use of primary anti-RAC MABs as immunomodulators to enhance the cytotoxic impact of HIT-RAC conjugates will be investigated. More specifically, anti-RAC MABs to which ricin B chain has been chemically coupled will be tested for ability to drive the internalization of the HIT-RAC conjugate and also tested for ability to allow more efficient transport of RAC within the intracellular membrane compartment; enhanced transport could be accomplished by recombination of ricin toxic A chain and binding B chain at the cell surface or within endocytotic vesicles. Delivery of both A and B ricin subunits would be separate but site-directed. Mixtures of prostate-directed MABs reactive with different molecules and with different epitopes on the same prostate-restricted molecule, chemically coupled immunotoxins derived from prostate-directed MABs, and HIT-RAC conjugates will be used to construct a defined synthetic antiserum in order to enhance both selectivity and magnitude of prostate carcinoma cell kill. Immunotherapeutic reagents will be evaluated for synergy with selected chemotherapeutic drugs to achieve greater prostate cancer cell kill at a subclinical drug dose. Those conditions that have been found optimal for in vitro carcinoma cell kill will be used as guidelines to achieve cell kill in vivo. An athymic nude mouse model system in which metastasis of human prostatic carcinoma cells occurs in a predictable manner with regard to both time and site of metastasis will be used to evaluate the in vivo impact of chemoimmunotherapeutic regimes defined in vitro. In vivo parameters evaluated will consist of eradicating, decreasing, or delaying the onset of metastatic disease.
| Donaldson, J T; Tucker, J A; Keane, T E et al. (1990) Characterization of a new model of human prostatic cancer: the multicellular tumor spheroid. Int J Cancer 46:238-44 |
| Webb, K S; Poulton, S H; Liberman, S N et al. (1989) Rationale for immunotoxin therapy of metastatic prostate carcinoma formatted as a multi-stage delivery system. J Urol 142:425-32 |
