Anti-Flavivirus Immunotherapeutics

DESCRIPTION (provided by the applicant): There are 100 million cases of dengue infection each year with 250,000 cases of the life-threatening Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHS/DSS). Treatment options are limited to symptoms management. Passive immunoprophylaxis and immunotherapy are standard treatments for a number of viral diseases. However, the undefined nature of hyperimmune serum is unsuitable for dengue virus disease treatment. To provide a defined reagent treatment for severe disease, we propose to examine the efficacy of using cobra venom factor linked antibodies to the viral structural envelope (E) and the viral first non-structural (NS1) proteins as immunotherapeutic agents. In Phase I a combinatorial human Fab library will be constructed, and Fab fragments which recognize either E or NS1 proteins will be identified. These fragments will be evaluated for cross-reactivity, non-overlapping epitope recognition and affinity. All Fab fragments will be conjugated to cobra venom factor and evaluated for complement mediated cytolysis and anti-E conjugates for reduction in virus infectivity. To further evaluate the immunoprophylaxis potential of the conjugates, in vivo mouse challenge studies will also be performed. In Phase II, F(ab)2-humanized CVF conjugates will be expressed in mammalian cells and their efficacy evaluated in mice and non-human primates. PROPOSED COMMERCIAL APPLICATION: The dengue virus complex specific anti-E and NS1 Fab fragments identified in Phase I research have the potential to relieve severe dengue disease symptoms. More than 250,000 annual cases of severe dengue disease are reported each year.