PLoS Pathogens (Jan 2013)

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

DOI
https://doi.org/10.1371/journal.ppat.1003312
Journal volume & issue
Vol. 9, no. 4
p. e1003312

Abstract

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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.