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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1003312
JournalPLoS Pathogens
Volume9
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Pal, P., Dowd, K. A., Brien, J. D., Edeling, M. A., Gorlatov, S., Johnson, S., Lee, I., Akahata, W., Nabel, G. J., Richter, M. K. S., Smit, J. M., Fremont, D. H., Pierson, T. C., Heise, M. T., & Diamond, M. S. (2013). Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus. PLoS Pathogens, 9(4), [e1003312]. https://doi.org/10.1371/journal.ppat.1003312