Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar^−/−) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans. Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes outbreaks of polyarthritis in humans, and is currently a threat to spread to the United States due to the presence of its mosquito vector, Aedes albopictus. At present, there is no licensed human vaccine or therapeutic available to protect against CHIKV infection. The primary goal of this study was to develop an antibody-based therapeutic agent against CHIKV. To do this, we developed a panel of 230 new mouse anti-CHIKV MAbs and tested them for their ability to neutralize infection of different CHIKV strains in cell culture. We identified 36 MAbs with broad neutralizing activity, and then tested several of these for their ability to protect immunocompromised Ifnar^−/− mice against lethal CHIKV infection. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs limited the development of resistance and protected Ifnar^−/− mice against disease even when given just 24 to 36 hours before CHIKV-induced death. Analogous protection against CHIKV-induced arthritis was seen in a disease model in wild type mice. Our data suggest that pairs of highly neutralizing MAbs may be a therapeutic option against CHIKV infection.