A MERS-CoV Receptor Decoy

DESCRIPTION provided by applicant Middle East respiratory syndrome coronavirus MERS CoV is a newly emerging human health threat with a case fatality rate MERS CoV uses dipeptidyl peptidase DPP a cell surface protein to enter and infect cells During our Phase I study using a transient plant expression system we produced fusions of human DPP and the human immunoglobulin Fc sequences of IgG IgA and IgA to produce andquot receptor decoysandquot to block cellular infection with MERS CoV We demonstrated that DPP Fc binds to the S domain of MERS CoV S protein and that DPP Fc is a more potent inhibitor of MERS CoV cellular infection than soluble DPP We showed that a DPP Fc fusion based on IgA might possibly be more effective than one based on IgG In addition we demonstrated that binding and virus neutralization could be improved by more than fold by modifying a single amino acid where human DPP and MERS CoV spike protein contact DPP Fc is also expected to have superior pharmacokinetics as Fc will confer a long circulating half life and the ability to be delivered to airway mucosal surfaces the site of MERS CoV infection In a phase II study we will produce new DPP Fc constructs to improve DPP andapos s affinity for MERS CoV spike protein and eliminate DPP andapos s peptidase activity by mutating the active site We will optimize new constructs to improve expression in plants and to produce DPP Fc with human like N linked glycans New DPP Fc fusions will be ranked for MERS CoV spike protein binding by ELISA and tested for the ability to neutralize MERS CoV infection in susceptible cells The best performing DPP Fc variants will be tested for protective efficacy in a mouse MERS model evaluating both intraperitoneal and intranasal routes of administration We will scale up production and purification of our lead molecule to purify grams of DPP Fc which will be used for a pilot week repeat dose safety toxicology study in rats We will evaluate safety and quantify DPP Fc in serum to obtain pharmacokinetic parameters We will also screen for anti DPP Fc antibodies in these studies PUBLIC HEALTH RELEVANCE Middle East respiratory syndrome coronavirus MERS CoV also termed hCoV EMC was first identified in humans in in the Middle East To date known people have contracted MERS in countries resulting in deaths Epidemiology studies suggest human to human transmission of this deadly virus leading to global concern about a MERS pandemic We propose a novel therapeutic a recombinant protein comprised of the extracellular domain of DPP the MERS CoV cellular receptor fused to Fc of a human immunoglobulin e g IgG which could be used as a andquot receptor decoyandquot to block the interaction of MERS CoV with DPP on human cells and thus stop infection