Humanized monoclonal antibodies to treat mucormycosis

Mucormycosismost commonly caused by Rhizopus oryzaeis a life threatening infection that occurs in patients immunocompromised by diabetic ketoacidosisDKAneutropeniacorticosteroid useincreased serum iron and or severe traumaBecause of the rising prevalence of these risk factorsthe incidence of mucormycosis has risenDespite disfiguring surgery and aggressive antifungal therapythe mortality of mucormycosis ranges fromtoThe obvious unmet need for neweffective treatments and preventive strategies has been the driving force of our research program for over seventeen yearsWe propose to develop a passive vaccine targeting mucormycosisi ean antibody that can be administered to patients with mucormycosisData in the academic laboratory of our founderDrIbrahimindicate that antibody based therapy is a promising strategy to treat mucormycosisThis technology is based on the important discovery that the fungal cell surface proteins encoded by CotH facilitate disease progression by allowing Roryzae to invade mammalian cells via binding to Glucose Regulated ProteinGRPa heat shock conserved protein expressed on endothelial cells lining blood vessels during mucormycosisImportantlyCotH proteins were found to be conserved among Mucoralesorganisms that cause mucormycosisand absent from any other cell type including mammalianOur data also show that CotH proteins are key determinants of mucormycosis pathogenesis since Roryzae coth null mutants have markedly reduced virulence in mouse models of mucormycosisFurtherpolyclonal antibodies targeting CotH are highly protective against murine mucormycosis caused by RoryzaeMucorLichtheimiaCunninghamellaRhizomucorand ApophysomycesImportantly and highly relevant to this applicationanti CotH murine monoclonal antibodiesmAbraised against a peptide predicted to be present in the binding domain to GRPprevent the ability of Roryzae to invade and injure endothelial cells in vitro and protect mice from mucormycosis caused by several Mucorales to levels that exceed those seen with antifungal therapyWhile these mAbs are a promising new therapy for mucormycosisthe feasibility of further clinical development will hinge upon successful humanization of the AbsMouse mAbs cannot be used to treat humansbecause humans mount an immune reaction to mouse mAbs that can cause rapid removal of the mAbssystemic inflammationsevere allergic reactionsand even a risk for deathThe humanization process prevents these undesirable effectsThuswe propose two AIMSDevelop our lead murine mAb into a humanized version with retained enhanced binding ability to CotH proteinsandDetermine the protective activity of the humanized Ab in vitro in vivo and evaluate its toxicity to human tissuesWe propose conservative feasibility milestones that are part of a standardmethodical development pathway for our unique mAbs as a novel treatment for mucormycosisThe proposed work will identify a lead humanized Ab that will go into further development to ultimately test in clinical trials as an adjunctive therapy Mucormycosis is a life threatening fungal infection that afflicts patients with weakened immune systemCurrent treatment fail in andgtof patients despite current intervention with antibiotics and surgical removal of destroyed tissuesWe will develop a novel antibody therapy that is proven in mice to enhance the efficiency of the current therapy