Infections caused by the fungus Cryptococcus neoformans are a major medical problem. Cryptococcus afflicts 6-8% of patients with advanced HIV infection. Other groups at risk are cancer patients, organ transplant recipients, and those on immunosuppressive therapy. In patients with AIDS, cryptococcosis is virtually incurable since existing chemotherapy does not eradicate the infection. Furthermore, 20-30% of patients die despite aggressive antifungal therapy. This application proposes to continue the pre-clinical development of the novel therapy for cryptococcosis: passive antibody therapy. In the past funding period the author has identified a highly protective murine antibody that is about to go into a Phase 1 clinical trial to evaluate safety. Furthermore, great progress was made in understanding the structural features of antibodies that contribute to protective efficacy and in determining their mechanism of action. The concept of antibody therapy for this opportunistic infection has been accepted by the medical community and the goal now is to design more effective reagents and learn how to use them. Unfortunately, vary little is known about antibody efficacy against the fungi and many basic science studies need to be done to insure the success of this novel therapy. The main goal of this application is to explore the structure- function relationship for human isotypes against C. neoformans. A secondary goal is to generate new reagents that have potential clinical usefulness.
Three specific aims are proposed:
Aim 1. To construct IgG1, IgG2, IgG3, IgG4, and IgA1 mouse-human chimeric antibodies of Mab 18B7 and determined their relative opsonic efficacy in vitro;
Aim 2. To establish the most effective and least toxic human constant region against C. neoformans in mice;
and Aim 3. To determine the consequences of antibody-mediated deposition of cryptococcal polysaccharide in reticuloendothelial cells.
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