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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

225 Citations (Scopus)
423 Downloads (Pure)

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
Article numbere1003312
Number of pages16
JournalPLoS Pathogens
Volume9
Issue number4
DOIs
Publication statusPublished - 18-Apr-2013

Keywords

  • SEMLIKI-FOREST-VIRUS
  • WEST-NILE-VIRUS
  • SINDBIS VIRUS
  • E2 GLYCOPROTEIN
  • ESCAPE MUTANTS
  • ANTIGENIC SITE
  • MOUSE MODEL
  • INFECTION
  • FUSION
  • MICE

Fingerprint

Dive into the research topics of 'Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus'. Together they form a unique fingerprint.

Cite this