Monoclonal antibodies targeting surface exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model

Abstract

AbstractMAb based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development with currently no licensed antifungal mAbs available for patients at risk. The cell wall glycoproteins of Candida albicans are of particular interest as potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis. Here we describe the generation of recombinant human antibodies specifically targeting two key cell wall proteins (CWPs) in C. albicans - Utr2 and Pga31. These antibodies were isolated from a phage display antibody library using peptide antigens representing the surface exposed regions of CWPs expressed at elevated levels during in vivo infection. Reformatted human-mouse chimeric mAbs preferentially recognised C. albicans hyphal forms compared to yeast cells and an increased binding was observed when the cells were grown in the presence of the antifungal agent caspofungin. In J774.1 macrophage interaction assays, mAb pre-treatment resulted in a faster engulfment of C. albicans cells suggesting a role of the CWP antibodies as opsonising agents during phagocyte recruitment. Finally, in a series of clinically predictive, mouse models of systemic candidiasis, our lead mAb achieved an improved survival (83%) and several log reduction of fungal burden in the kidneys, similar to levels achieved for the fungicidal drug caspofungin, and superior to any anti-Candida mAb therapeutic efficacy reported to date.