Bispecific monoclonal antibodies mediate binding of dengue virus to erythrocytes in a monkey model of passive viremia

Dengue viruses (DEN), causative agents of dengue fever (DF) and more severe dengue hemorrhagic fever (DHF)/dengue shock syndrome, infect over 100 mill ion people every year. Among those infected, up to one-half million people develop DHF, which requires an extensive hospital stay. Recent reports indi cate that there is a significant correlation between virus titer in the blo odstream of infected individuals and the severity of the disease, especiall y the development of DHF. This suggests that if there is a procedure to red uce viremia in infected subjects, then the severity of the disease may be c ontrolled during the critical early stages of the disease before it progres ses to DHF. We have generated bispecific mAb complexes (heteropolymer(s), H P), which contain a mAb specific for the DEN envelope glycoprotein cross-li nked with a second mAb specific for the primate E complement receptor 1. Th ese HP facilitate rapid binding of DEN to human and monkey E in vitro, with similar to 90% bound within 5 min. Furthermore, in a passive viremia monke y model established by continuous steady state infusion of DEN, injection o f HP during the steady state promoted rapid binding of DEN to the E, follow ed by subsequent clearance from the vascular system. Moreover, HP previousl y infused into the circulation is capable of efficiently capturing a subseq uent challenge dose of DEN and binding it to E. These data suggest that HP potentially can be useful for alleviating DEN infection-associated symptoms by reducing titers of free virus in the vascular system.