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

Fingerprint

Chikungunya virus
Monoclonal Antibodies
Neutralizing Antibodies
Alphavirus
Therapeutics
Culicidae
Arthritis
Epitopes
Genotype
Infection
Proteins

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., ... 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

Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus. / Pal, Pankaj; Dowd, Kimberly A.; Brien, James D.; Edeling, Melissa A.; Gorlatov, Sergey; Johnson, Syd; Lee, Iris; Akahata, Wataru; Nabel, Gary J.; Richter, Mareike K S; Smit, Jolanda M.; Fremont, Daved H.; Pierson, Theodore C.; Heise, Mark T.; Diamond, Michael S.

In: PLoS Pathogens, Vol. 9, No. 4, e1003312, 04.2013.

Research output: Contribution to journalArticle

Pal, P, Dowd, KA, Brien, JD, Edeling, MA, Gorlatov, S, Johnson, S, Lee, I, Akahata, W, Nabel, GJ, Richter, MKS, Smit, JM, Fremont, DH, Pierson, TC, Heise, MT & Diamond, MS 2013, 'Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus', PLoS Pathogens, vol. 9, no. 4, e1003312. https://doi.org/10.1371/journal.ppat.1003312
Pal, Pankaj ; Dowd, Kimberly A. ; Brien, James D. ; Edeling, Melissa A. ; Gorlatov, Sergey ; Johnson, Syd ; Lee, Iris ; Akahata, Wataru ; Nabel, Gary J. ; Richter, Mareike K S ; Smit, Jolanda M. ; Fremont, Daved H. ; Pierson, Theodore C. ; Heise, Mark T. ; Diamond, Michael S. / Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus. In: PLoS Pathogens. 2013 ; Vol. 9, No. 4.
@article{b36e4c3ebc74412f8e91878b6bbddb3e,
title = "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.",
author = "Pankaj Pal and Dowd, {Kimberly A.} and Brien, {James D.} and Edeling, {Melissa A.} and Sergey Gorlatov and Syd Johnson and Iris Lee and Wataru Akahata and Nabel, {Gary J.} and Richter, {Mareike K S} and Smit, {Jolanda M.} and Fremont, {Daved H.} and Pierson, {Theodore C.} and Heise, {Mark T.} and Diamond, {Michael S.}",
year = "2013",
month = "4",
doi = "10.1371/journal.ppat.1003312",
language = "English (US)",
volume = "9",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus

AU - Pal, Pankaj

AU - Dowd, Kimberly A.

AU - Brien, James D.

AU - Edeling, Melissa A.

AU - Gorlatov, Sergey

AU - Johnson, Syd

AU - Lee, Iris

AU - Akahata, Wataru

AU - Nabel, Gary J.

AU - Richter, Mareike K S

AU - Smit, Jolanda M.

AU - Fremont, Daved H.

AU - Pierson, Theodore C.

AU - Heise, Mark T.

AU - Diamond, Michael S.

PY - 2013/4

Y1 - 2013/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84876818205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876818205&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1003312

DO - 10.1371/journal.ppat.1003312

M3 - Article

VL - 9

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 4

M1 - e1003312

ER -