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 - https://www.scopus.com/pages/publications/84876818205
UR - https://www.scopus.com/inward/citedby.url?scp=84876818205&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1003312
DO - 10.1371/journal.ppat.1003312
M3 - Article
C2 - 23637602
AN - SCOPUS:84876818205
SN - 1553-7366
VL - 9
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 4
M1 - e1003312
ER -