Isotype-dependent efficacy of human mAbs against Candida

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DESCRIPTION (provided by applicant): Hematogenously disseminated candidiasis has become a common and serious nosocomial infection. Recent studies established an important role for anti-Candida mannan mAb in host defense against systemic candidiasis in experimental mice. These studies are exciting and raise a possibility for prophylactic use of protective anti-Candida antibodies in patients at risk for disseminated candidiasis. However, such studies have been limited to murine antibodies and have not examined the role of antibody isotype in treatment efficacy. Our long term goal is to understand how human anti-Candida antibody participates in host defense against candidiasis. In preliminary studies, I have used bacteriophage display and DNA recombinant technology to generate human antimannan IgG antibodies. We will use these recombinant human antibodies to examine the hypothesis that antibody-mediated host defense against disseminated candidiasis is influenced by the IgG subclass. We will pursue three aims. In the first specific aim, I will construct a family of IgG-subclass variants of human antimannan antibody with the same binding specificity. To this end, a full length human recombinant IgG1 antimannan antibody has already been constructed. Studies for the second aim will analyze modulation of complement opsonization of Candida cells by IgG subclasses. In the third specific aim, I will assess protective efficacy of IgG-subclass variants of human antimannan antibody in a mouse model of homogeneously disseminated candidiasis. Data from aims 2 and 3 will set a foundation for further dissection of the mechanisms underlying antibody-mediated host defenses. Results from this study will enhance our knowledge of the role of human humoral immunity against disseminated candidiasis. Such knowledge is critical to designs of immunoprophylactics and immunotherapeutics that involve antibody-mediated effector mechanisms.