PROTECTIVE ANTIBODIES FOR CRYPTOCOCCAL INFECTIONS

DESCRIPTION: (Adapted from Applicant's Abstract) Cryptococcus neoformans infections are usually incurable in patients with AIDS and there is a major need for new therapies. Although a phase 1 trial using the murine monoclonal antibody 18B7 to C. neoformans is expected to commence shortly, there is a need for antibody reagents with human constant region function because these may have superior efficacy in humans and are less immunogenic. Dr. Casadevall is funded to generate IgG1, IgG2, IgG3, and IgG4 mouse-human chimerics of Mab 18B7 and to study them for efficacy and toxicity in mice. This RO3 AIDS-FIRCA application seeks funds to support a collaboration between the laboratories of Dr. Casadevall at Albert Einstein and Dr. Vecchiarelli of the University of Perugia (Italy). Specifically, the application proposes two aims: 1. to identify the most effective human IgG subclass in promoting phagocytosis and killing of C. neoformans by human monocytes and neutrophils from patients with and without HIV infection; and 2. to identify the most effective human IgG subclass in promoting proinflammatory cytokine expression, T cell activation and co-stimulatory molecule expression in human leukocytes exposed to C. neoformans. Dr. Casadevall's laboratory will be responsible for production and purification of chimeric antibodies whereas Dr. Vecchiarelli's laboratory will test their efficacy with human cells.