Humanized Monoclonal Antibodies that Specifically Bind Japanese Encephalitis Virus (JEV) and Their Use

Japanese encephalitis virus (JEV) is the prototype virus of the Japanese encephalitis (JE) group belonging to the Flavivirus genus of the Flaviviridae family. Other members of the group include Kunjin virus, St. Louis encephalitis virus, and West Nile encephalitis virus (WNV). JEV is widely distributed in South Asia, Southeast Asia, and the Asian Pacific Rim. In recent years, JE epidemics have spread to previously unaffected areas, such as northern Australia, Pakistan, India and Indonesia. The JE outbreak in India during July to November of 2005 was the longest and most severe in recent years, affecting more than 5,000 persons and causing more than 1,000 deaths. It is estimated that JEV causes 35,000 to 50,000 cases of encephalitis, including 10,000 deaths and as many neurologic sequelae, each year. The wide geographical distribution and the existence of multiple strains, coupled with the high rate of mortality and residual neurological complications in survivors, make JEV infection an important public health problem. Until a JEV vaccine becomes generally available, passive immunization with potently neutralizing anti-JEV antibodies remains an attractive strategy for short-term prevention of and therapeutic intervention in encephalitic JEV infections.

From a panel of 11 Fabs recovered by different panning strategies, three highly potent neutralizing antibodies, termed Fabs A3, B2, and E3, which recognized spatially separated regions on the JEV virion were identified. These antibodies reacted with epitopes in different domains: the major determinant for Fab A3 was Lys179 (domain I), that for Fab B2 was Ile126 (domain II), and that for Fab E3 was Gly302 (domain III) in the envelope protein, suggesting that these antibodies neutralize the virus by different mechanisms. These three Fabs and derived humanized monoclonal antibodies (MAbs) exhibited high neutralizing activities against a broad spectrum of JEV genotype strains. In preclinical testing, the monoclonal antibodies of the technology significantly prolonged the average survival time compared to the control group, suggesting a therapeutic potential for use of MAb B2 in humans.

This application claims the antibodies described above, methods of preventing and/or treating JEV with the antibodies, and diagnostics using the antibodies of the technology.