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A monoclonal antibody from human immunoglobulin transgenic mice protects mice against Cryptococcus neoformans challenge



A monoclonal antibody from human immunoglobulin transgenic mice protects mice against Cryptococcus neoformans challenge



Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy 43: 435



Background: Current anti-fungal therapy is unable to cure cryptococcosis in the setting of AIDS. We and others have shown that antibodies can alter cryptococcal infection to the benefit of the host and we have pursued the possibility that vaccination may be a useful approach to the prevention of cryptococcosis. Methods: In this study, we generated monoclonal antibodies in XenoMouse(R) G2 mice (Abgenix, Inc.), a strain of transgenic mice producing human IgG2 immunized with a glucuronoxylomannan (GXM) strain 24067-diphteria toxoid (DT) conjugate. G2 mice were vaccinated subcutaneously on days 0, 14 and 39 and their splenocytes isolated and fused to NS/0 cells to produce hybridomas. Three human IgM-kappa monoclonal antibodies (mAbs), G14, G15 and G19, were generated and their specificities determined by ELISA. Results: G14 and G19 bind to C. neoformans serotype D strain 24067, and serotype A strains H99 and SB4 equally well. G15 binds strains 24067 and SB4, but not H99. Preliminary sequence analysis revealed that all 3 mAbs use VH3 gene segments and distinct V kappa genes. The mAbs were passively administered to BALB/c mice to determine their protective efficacy against C. neoformans strain 24067 as follows: 1000, 100, 50, 5 and 0.5 mug of each mAb or a control IgM was given intraperitoneally (ip) 1 hr prior to an ip C. neoformans challenge. A dose of 100 mug of mAb G15 significantly prolonged survival. G19 led to an accelerated rate of death despite having the highest affinity for GXM. Conclusions: This panel of human mAbs to GXM illustrates that GXM consists of epitopes eliciting antibodies that can be beneficial or detrimental to the host, and thus provides a possible explanation for the apparent inability of human serum antibodies to GXM to protect certain individuals from cryptococcal infection. Further structure-function analysis of the mAbs is underway to reveal the characteristics of the antibodies that are protective and the epitopes that elicit them.

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