Protective Efficacy of Anti-Hyr1p Monoclonal Antibody against Systemic Candidiasis Due to Multi-Drug-Resistant Candida auris.

Candida auris is a multi-drug-resistant fungal pathogen that can survive outside the host and can easily spread and colonize the healthcare environment, medical devices, and human skin. C. auris causes serious life-threatening infections (up to 60% mortality) in immunosuppressed patients staying in such contaminated healthcare facilities. Some isolates of C. auris are resistant to virtually all clinically available antifungal drugs. Therefore, alternative therapeutic approaches are urgently needed. Using in silico protein modeling and analysis, we identified a highly immunogenic and surface-exposed epitope that is conserved between C. albicans hyphal-regulated protein (Cal-Hyr1p) and Hyr1p/Iff-like proteins in C. auris (Cau-HILp). We generated monoclonal antibodies (MAb) against this Cal-Hyr1p epitope, which recognized several clinical isolates of C. auris representing all four clades. An anti-Hyr1p MAb prevented biofilm formation and enhanced opsonophagocytic killing of C. auris by macrophages. When tested for in vivo efficacy, anti-Hyr1p MAb protected 55% of mice against lethal systemic C. auris infection and showed significantly less fungal burden. Our study is highly clinically relevant and provides an effective alternative therapeutic option to treat infections due to MDR C. auris.

COVID-19-associated fungal infections.

Coronavirus disease 2019 (COVID-19)-associated invasive fungal infections are an important complication in a substantial number of critically ill, hospitalized patients with COVID-19. Three groups of fungal pathogens cause co-infections in COVID-19: Aspergillus, Mucorales and Candida species, including Candida auris. Here we review the incidence of COVID-19-associated invasive fungal infections caused by these fungi in low-, middle- and high-income countries. By evaluating the epidemiology, clinical risk factors, predisposing features of the host environment and immunological mechanisms that underlie the pathogenesis of these co-infections, we set the scene for future research and development of clinical guidance.

A Humanized Antibody Targeting the CotH Invasins is Protective Against Murine Mucormycosis

Background Despite antifungal therapy and surgical debridement, overall mortality of invasive mucormycosis is >40%. Currently the world is witnessing an explosion in mucormycosis in India among COVID-19 patients with an official count of 28,252 cases as of 06/07/2021. Thus, novel therapeutic modalities are needed. We previously reported on a mouse monoclonal antibody (C2) targeting CotH invasins being protective against mucormycosis. Here, we humanized C2 MAb and assessed its efficacy in vitro and in vivo. Methods The C2 (IgG1) paratopes of the heavy chain and light chain were grafted on the most suitable human IgG1 with back mutations in the paratopes needed to restore binding of humanized clones to CotH3 (by biolayer interferometry using Gator). Clones were compared to C2 in their ability to prevent Rhizopus delemar-induced injury to A549 alveolar epithelial and primary human endothelial cells and for enhancing human neutrophil killing of the fungus in vitro. C2 and the humanized clones were also compared for their ability to protect neutropenic mice from mucormycosis induced by R. delemar or Mucor cicrinelloides with and without antifungal therapy. Results Three humanized clones showed 10-fold enhanced binding affinity to CotH3 protein (~5 nM for humanized vs. ~50 nM for C2). One humanized clone (VX01) doubled the ability of neutrophils to kill R. delemar and resulted in ~50% reduction in host cell damage. A single low dose of VX01 (30 µg) given 24 h post infection resulted in comparable survival of 60-70% in mice infected intratracheally with either R. delemar or M. cicrinelloides vs. placebo mice (0% survival, P < 0.02). Importantly, VX01 acted synergistically in protecting mice when combined with liposomal amphotericin B or posaconazole in a severe model of mucormycosis with treatment starting 48 h post infection (~70% survival for combination vs. 0-20% survival for monotherapy and reduced lung fungal burden by 1.5 log, P< 0.001). GLP-tissue cross reactivity studies of VX01 showed favorable safety profiles. Conclusion VX01 shows enhanced binding to CotH3 protein and maintained the protective features of C2 MAb against murine mucormycosis. Clinical testing of combination therapy of VX01 + antifungals is warranted. VX01 is currently in manufacturing. Disclosures Yiyou Gu, PhD, Vitalex Biosciences (Shareholder) Ashraf S. Ibrahim, PhD, Vitalex Biosciences (Shareholder)