Evolutionary lead optimization for immunotherapy of Marburg & Ebola viruses

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DESCRIPTION (provided by applicant): This proposal is aimed at developing a novel immunotherapeutic that will prevent and treat life-threatening infections with Marburg and Ebola viruses of the filovirus family that might be manipulated as bioweapons posing grave public threats. The proposal builds on the fact that the mannose-binding lectin (MBL) is a broad-spectrum molecule of innate immunity. This serum protein recognizes a wide range of pathogens, such as bacteria, parasites and viruses including filoviruses. Preliminary data indicate that recombinant human MBL (rHuMBL) recognizes the envelope glycoproteins of Ebola and Marburg viruses. This observation, together with the role of MBL in first line host defense, makes it a strong candidate as an immunotherapeutic agent for use before and/or after exposure to filoviruses. A key goal of this project is to evaluate clinical grade rHuMBL that has been used in Phase 1 clinical studies in the first instance, and second generation derivatives of MBL that incorporate a part of L-ficolin, another lectin-like protein. Preliminary studies demonstrated that these novel lectin chimeras bind mannan, the same carbohydrate that adorns filoviruses. This grant proposal will leverage the infrastructure of the Laboratory of Developmental Immunology at Massachusetts General Hospital, the extensive scientific experience of the investigators in the field of innate immunity, the product development expertise of Natlmmune, a Danish biotechnology company that developed therapeutic rHuMBL, and the highly specialized resources of the United States Army Medical Research Institute for Infectious Diseases where mouse and guinea pig models of filovirus infection have been established. We will evaluate the efficacy of rHuMBL and lectin chimeras to activate the lectin complement pathway and to modulate phagocytic function in vitro using HIV particles pseudotyped with filovirus glycoproteins. Furthermore, we will investigate the protective efficacy of these lectins in strains of genetically modified mice deficient in MBL, complement component 3, ficolin-A (murine form of L-ficolin) or combinations thereof to elucidate the relative roles of each innate immune molecule in rodents fatally challenged with native filoviruses. The ultimate goal of this proposal is to develop a formulation of rHuMBL or a derivative thereof that could be used prophylactically and/or therapeutically by soldiers or civilians exposed to filoviruses.