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

Pankaj Pal, Kimberly A. Dowd, James D. Brien, Melissa A. Edeling, Sergey Gorlatov,

Syd Johnson, Iris Lee, Wataru Akahata, Gary J. Nabel, Mareike K. S. Richter,

Jolanda M. Smit, Daved H. Fremont, Theodore C. Pierson, Mark T. Heise,

Michael S. Diamond. PLoS Pathog. (2013) 9: e1003312.

Speaker: Pei-Wei Chen (陳珮瑋)                           Time: 14:10~15:00, Oct. 2, 2013

Commentator: Dr. Shun-Hua Chen (陳舜華 老師)     Place: Room 601

Abstract:

Chikungunya virus (CHIKV) is an enveloped alphavirus prevalent in tropical regions. Infection by CHIKV is often characterized by acute and persistent arthralgia in humans. Currently, there is no available vaccine or specific treatment against CHIKV (1). The authors developed 230 CHIKV-specific monoclonal antibodies (MAbs) and screened for their ability to neutralize all three CHIKV genotypes in vitro and in vivo. The MAbs CHK-102 and CHK-152 completely prevented lethal infection in Ifnar^-/- C57BL/6 mice and also protected wild-type C57BL/6 from CHIKV-induced swelling and arthritis as prophylaxis. The authors determined the mechanism of MAb neutralization by viral fusion from without (FFWO) assay which can confirm CHIKV only via low-pH-triggered membrane fusion (2). The results show that CHK-152 neutralizes infection by preventing the structural changes on the virion which is necessary for viral fusion with host cell membranes. In the therapeutic studies, the combination of MAbs CHK-102+CHK-152 or CHK-166+CHK-152 limited the generation of viral resistance and remarkably protected Ifnar^-/- mice against mortality when administration 24 to 36 hours prior death. The amino acid residues of neutralizing MAbs were determined by escape selection, sequencing, and reverse genetic confirmation. CHK-102 and CHK-263 recognize the B domain on E2, CHK-152 recognizes a residue on the wings of the A domain on E2, and CHK-166 recognizes an amino acid in domain II of E1 proximal to the conserved fusion loop. Furthermore, the authors generated humanized CHK-152 as a possible therapeutic Abs for humans. The humanized CHK-152 and mouse CHK-152 showed similar efficacy. In summary, combinations of highly neutralizing MAbs may be an option against CHIKV infection in humans.

References:

1.      Fric J, Bertin-Maghit S, Wang C-I, Nardin A, Warter L. (2013) Use of human monoclonal antibodies to treat chikungunya virus infection. J. Infect. Dis. 207, 319-322.

2.      Edwards J, Brown DT. (1986) Sindbis virus-mediated cell fusion from without is a two-step event. J Gen Virol. 67, 377-380.