PRE-CLINICAL DEVELOPMENT OF HUMAN MONOCLONAL ANTIBODIES TARGETING NOVEL, CELL WALL PROTEINS IN DRUG RESISTANT FUNGAL PATHOGENS

Abstract

Intro: As the world begins to “run out” of anti-fungal drug options, the development of next generation alternatives remains dogged by the need to kill a eukaryotic pathogen within a eukaryotic host. For life-threatening systemic infections clinicians must balance drug toxicity and undesirable side effects against possible treatment failure or the development of new resistant strains. The success of monoclonal antibody-based therapies in cancer and other chronic immune disorders and a growing pipeline of investigational mAbs in the clinic for bacterial and viral infections, points the way to possible new strategies for antifungal drug development. Methods: Using proteomics-based approaches, we have identified several cell wall proteins (CWPs) on the surface of fungal pathogens that are upregulated in response to echinocandin treatment in vitro and in vivo (mouse systemic candidiasis) and present in higher abundance in echinocandin resistant isolates. Combining techniques to identify the surface exposed regions of CWPs, and employing conventional phage display technology, we have developed a platform to generate recombinant human mAbs binding to these well-defined peptide epitopes. Findings: These mAbs preferentially recognised C. albicans hyphal forms compared to yeast cells and an increased binding 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 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. Conclusion: These cellwall targeting mAbs can become a new antifungal drug class in providing alternatives to a much-limited therapeutic portfolio currently available for life-threatening fungal infections.