Monoclonal Antibody Therapeutics for Candida auris

Johns Hopkins University, Baltimore MD

Investigators

Abstract

SUMMARY In the past decade Candida auris has emerged a new pathogenic fungus that causes disease associated with high morbidity and mortality. C. auris has an intrinsic resistance to azoles and polyenes, leaving echinocandins as the only reliably effective class of antifungal agents. Unfortunately, drug resistance to echinocandins is rising rapidly and there is an urgent need for new antifungal drugs and new approaches to therapy. This project proposes the pre-clinical development of mAb-based therapy against C. auris. In recent decades mAbs have emerged as major therapeutic agents in medicine but they are relatively underused in the field of infectious diseases. Antibody therapies have a storied history for the treatment of infectious diseases and there is considerable evidence that they are active against Candida spp., including C. auris. Immunotherapy in the form of mAbs makes sense because most C. auris- related disease occurs in debilitated individuals with impaired immunity and antibody therapies provide immediate immunity. Furthermore, antibody therapies represent a fundamentally different form of antifungal therapy than that associated with small molecule drugs and thus provide the opportunities for synergy and additivity with existing therapies. Unfortunately, no mAbs to C. auris have been made and relatively little work has been done to understand humoral and cellular immunity to this increasingly important fungal pathogen. Hence, we propose to generate a suite of new mAbs to identify suitable candidates for clinical development and will study their mechanisms of action and efficacy in combination with the three classes of antifungal drugs. Three Aims are proposed: 1) To generate a large repertoire of mAbs to C. auris surface determinants; 2) To identify protective mAbs to C. auris and establish their mechanism of action; and 3) To identify the most effective mAb combinations with antifungal drugs. This project will deliver mAbs for future clinical development, provide a new understanding of the mechanisms of antibody-mediated protection against C. auris and create an immunological knowledge base that is essential for the development of immune mediated therapies and vaccines.