Radioimmunotherapy of opportunistic infections

DESCRIPTION (Provided by the applicant): The existence of certain AIDS-associated opportunistic infections for which there is no cure combined with the emergence of multidrug-resistant strains of bacteria and fungi creates an urgent need for new approaches to antimicrobial therapy. This application proposes to develop radioimmunotherapy as an anti-infective strategy. We have recently suggested the use of radioimmunotherapy as a novel modality for treatment of infections employing C. neoformans as a model opportunistic infection. C. neoformans has several advantages as a model system for radioimmunotherapy of AIDS-associated opportunistic infections that include the existence of excellent animal models and the availability of several well characterized immunological reagents. Furthermore, monoclonal antibody therapy is already in clinical testing for C. neoformans using the monoclonal antibody (mAb) 1887. We have radiolabeled mAb 18B7 with therapeutic radioisotopes 188-Rhenium (1 88-Re) and 21 3-Bismuth (21 3-Bi) and have shown that these radiolabeled antibodies can efficiently eradicate C. neoformans cells in vitro as well as significantly prolong survival of complement-deficient animals lethally infected with C. neoformans. We hypothesize that 18B7 antibody may serve as an efficient delivery vehicle to deliver fungicidal doses of therapeutic radioisotopes to the sites of C. neoformans infection in vivo without radiation injury to the surrounding tissue and major organs. We also hypothesize that while inducing apoptosis and cell cycle arrest in C. neoformans cells through treatment with radiolabeled antibodies, no significant damage will be done to the certain components of immune system such as macrophages. The Specific Aims of this proposal are: 1. To generate radiolabeled derivatives of antibodies to C. neoformans and their fragments. 2. To identify the structural and functional characteristics of immunoglobulins that determine their suitability as anti-infective radioimmunotherapeutic agents in vitro and in vivo. 3. To elucidate the mechanisms of interaction between radiolabeled antibodies and C. neoformans cells in vitro. The research proposed here will contribute to development of a novel therapeutic modality based on radioimmunotherapy for treatment of currently incurable or multidrug-resistant AIDS-associated opportunistic infections. It will also provide some understanding of the fundamentals of interactions between microorganisms and antibodies radiolabeled with particulate-emitting radioisotopes in vitro and in vivo.