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.

In Silico Study of Cryo-Em Structures of Antigen-Antibody Complex of Chikungunya for the Development of Diagnostic Agent

“…This is in agreement with the fact that CHIK-152 has a better neutralization effect than m10 [8]. Pal and colleagues also reported that CHIK-152 prevented CHIKV infection up to 90% in all phylogroups, i.e., African and Asian strains [12]. The binding profile of CHIK-152 on E1-E2 CHIKV, at the atomic level, should be useful to provide structural basis in designing a specific antibody that can be used for a sensitive diagnostic agent, or even therapeutics.…”

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

“…174). Passive transfer of antisera (104,106,175) or isolated monoclonal antibodies protects against CHIKV disease in mice (160,161,176) or NHPs (177). Furthermore, in postexposure therapeutic trials, monoclonal antibodies protect against CHIKV disease in mice, even when administered at late times of infection (160,161), suggesting that immunotherapy would be effective for treatment of CHIKV infection.…”

“…An IgG response can be detected approximately 7-10 days after onset of illness, often after viremia has been cleared (37,(154)(155)(156). Many mouse and human IgM and IgG antibodies broadly and potently neutralize CHIKV (157)(158)(159)(160)(161)(162). The most potently neutralizing antibodies target domains A and B of the E2 glycoprotein, with those targeting domain B often displaying broad neutralization against multiple strains of CHIKV and other related alphaviruses (157,(159)(160)(161).…”

“…Many mouse and human IgM and IgG antibodies broadly and potently neutralize CHIKV (157)(158)(159)(160)(161)(162). The most potently neutralizing antibodies target domains A and B of the E2 glycoprotein, with those targeting domain B often displaying broad neutralization against multiple strains of CHIKV and other related alphaviruses (157,(159)(160)(161). In B cell-deficient (μMT) mice, persistent, steady-state viremia occurs following CHIKV infection (147,150), further highlighting the importance of neutralizing antibodies in mitigating CHIKV disease.…”

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

“…Many monoclonal antibodies (mAbs) that neutralize CHIKV infection recognize epitopes on the solvent-accessible surface of the E2 protein (28)(29)(30)(31)(32). The only previous structural studies of CHIKVantibody complexes were of four neutralizing murine mAbs.…”