Universal Candidacell-surface-specific monoclonal antibodies protect mice against multidrug-resistant Candida aurisbloodstream infections

Abstract

Abstract Candidaspecies are the leading cause of life-threatening fungal infections in humans, especially among immunocompromised and hospitalized individuals. Of utmost concern is the emerging “superbug” Candida auriswhich has the potential to disseminate into bloodstream infections with up to 60% mortality in susceptible populations. Importantly, C. aurisis the first inherently multidrug-resistant fungal pathogen, which contributes to a delay in effective treatment and increased mortality rates. Consequently, C. aurisis the first fungal pathogen to cause a serious global public health threat. Our lab has identified and isolated a panel of universal monoclonal antibodies (mAbs) specific to Candidacell wall epitopes that share high homology among various human pathogenic Candidaspecies. Using an established murine model of disseminated infection, we showed that passive transfer of mAb C3.1 (anti-β-1,2-mannotriose) significantly extended survival and reduced fungal burdens and inflammation during early infection. We also showed that mAbs C3.1 and 9F2 (anti-phosphoglycerate kinase 1) significantly enhanced phagocytosis of C. aurisyeast by macrophages and inhibited the proliferation of multiple C. aurisclinical isolates in vitro. Since there are currently no approved antifungal vaccines or antibodies and current treatments are inadequate, critically needed antifungal antibodies can provide long-awaited effective therapies against this deadly pathogen. Our future directions include developing humanized mAbs to evaluate their protective efficacy in genetic mouse models of human immunodeficiency. We will then utilize Fc engineering to derive human IgG1 variants for enhanced complement-based effector efficacy. Supported by grants from NIH /NIAID (R21AI168929) and the Department of Defense (PR171482)