Humanized monoclonal antibodies to treat mucormycosis

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Mucormycosis, caused by Mucorales fungi, is a life-threatening infection that occurs in patients immunocom- promised by diabetic ketoacidosis, neutropenia, corticosteroid use, and/or increased serum iron. Because of the rising prevalence of mucormycosis risk factors, the incidence of the infection has risen. The increased number of mucormycosis cases is highlighted by the recent epidemic seen among COVID-19 patients (>47,000 cases have been reported in India alone since May of 2021). Despite disfiguring surgery and aggres- sive antifungal therapy, the overall mortality of mucormycosis remains at 50%, and approaches 100% in pa- tients with disseminated disease, persistent neutropenia, or brain infection. Clearly new strategies to prevent and treat mucormycosis are needed. The spore coating proteins (CotH) are cell surface antigens that are universally present among, and highly ex- pressed on, spores and hyphae of Mucorales fungi. CotH proteins are critical determinants of pathogenesis by enabling fungi to invade host tissues during initiation of infection and further hematogenous dissemination. The importance of CotH proteins to infection is highlighted by the high protective/curative capabilities of anti-CotH monoclonal antibodies (MAbs) against murine mucormycosis. Through a Phase I SBIR funding, Vitalex Biosciences was able to humanize a protective murine MAb (VX01) that shows 10-fold higher binding ability to CotH3 antigen and is as protective as its parent mouse MAb against murine mucormycosis. Importantly, combination therapy of the humanized MAb and current standard of care of antifungal agents show high degree of synergy in protecting immunosuppressed mice from mucormycosis. In a GLP-compliant tissue cross reactivity studies, we show that VX01 has favorable cross reactivity to human tis- sues. Finally, we are now in possession of three Chinese hamster ovary (CHO) Research Cell Banks that are capable of producing 2-3 g/L of VX01. Thus, it is our intention to continue with the manufacturing of the human- ized MAb to enable IND-filing and initiation of clinical trials. Our specific aims are to : 1) perform Research Cell Bank (RCB) clonal candidate selection and develop/optimize upstream and downstream processes of VX01 production and purification; 2) perform analytical method development, formulation development and produce GLP material for toxicity studies; and 3) perform IND-application enabling studies including tissue cross reac- tivity and GLP-toxicity (main, recovery and toxicokinetics) studies in rats. The preclinical synergy between the VX01 and antifungals strongly indicate that developing VX01 as adjunc- tive therapy will strongly improve the abysmal outcome of mucormycosis. If successful, this study will shift the treatment paradigm by introducing the first adjunctive immunotherapy against fungal infections by targeting unique and pivotal aspects of mucormycosis pathogenesis. Achieving the manufacturing Aims of this proposal will position Vitalex to collaborate with big Pharma to conduct cGMP production, and clinical testing.