A Novel Cost-Effective Multispecific Therapeutic for Dengue

PROJECT SUMMARY Dengue remains a major global health concern for which effective prophylactic and therapeutic options are urgently needed. The heightened dengue burden is driven by several factors including increased urbanization, world population growth, increased international trade and travel, and changes in human behavior that increase mosquito breeding sites. After malaria, dengue is the second most frequent mosquito-borne disease that affects humans. To date, traditional strategies have failed to generate an effective vaccine, and in some instances, vaccination resulted in enhanced disease. Dengvaxia is the only available dengue vaccine in the US and is only recommended to prevent dengue in children aged 9-16 years with laboratory-confirmed previous dengue infection. A safety signal in dengue seronegative vaccine recipients and in children 2-5 years old highlighted increasing evidence of a detrimental effect of vaccination in certain populations 1. Furthermore, no dengue therapeutic product is approved for intervention to control a dengue outbreak. Mapp Biopharmaceutical, Inc. (San Diego, CA), is developing a multi-specific antibody-derived therapeutic product that synergistically combines the efficacy of two broadly neutralizing antibodies into one half-life extended molecule. With higher potency (i.e. lower dose), a single dose due to the extended serum half-life, and manufacturing in microbial host cells, Mapp's objective is to develop a cost-effective dengue immunotherapeutic that will be globally accessible. Mapp's product candidate is a tri-specific antibody fragment molecule designed to enhance therapeutic efficacy against dengue virus infection by targeting two distinct epitopes of the envelope protein. This design aims to broaden coverage and mitigate the risk of escape mutants. Additionally, one arm of the molecule is designed to bind human serum albumin, extending the therapeutic's half-life. Excluding the Fe region of the antibody prevents antibody-dependent enhancement of infection, a serious complication linked to the Fe region, and allows production in microbial host cells, significantly reducing costs. Mapp has already developed a platform to optimize the design, production, and characterization of the trispecific molecules. Considering the prevalence and the availability of published potent anti-dengue virus antibodies, Mapp is strategically investing in developing novel formats that address the specific needs of the dengue disease burden: potency, safety, and access. Phase I of this Fast-Track SBIR proposal aims to identify, manufacture, and characterize anti-dengue therapeutics with a synergistic mode of action. Phase II will involve evaluating the most promising therapeutic candidates in murine and non-human primate (NHP) models of dengue challenge and initiating IND enabling studies of the lead candidate.