Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus: e1003312
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...
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| Veröffentlicht in: | PLoS pathogens 2013-04, Vol.9 (4) |
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| creator | Pal, Pankaj Dowd, Kimberly A Brien, James D Edeling, Melissa A Gorlatov, Sergey Johnson, Syd Lee, Iris Akahata, Wataru Nabel, Gary J Richter, Mareike KS Smit, Jolanda M Fremont, Daved H Pierson, Theodore C Heise, Mark T Diamond, Michael S |
| description | 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. |
| doi_str_mv | 10.1371/journal.ppat.1003312 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1003312</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Alphavirus ; Cell culture ; Chikungunya virus ; Experiments ; Genotypes ; Industrial development ; Infections ; Mosquitoes ; Mutation ; Prophylaxis ; Proteins ; Vector-borne diseases</subject><ispartof>PLoS pathogens, 2013-04, Vol.9 (4)</ispartof><rights>2013 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Pal P, Dowd KA, Brien JD, Edeling MA, Gorlatov S, et al. 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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. 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| source | Public Library of Science (PLoS) Journals Open Access; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access |
| subjects | Alphavirus Cell culture Chikungunya virus Experiments Genotypes Industrial development Infections Mosquitoes Mutation Prophylaxis Proteins Vector-borne diseases |
| title | Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus: e1003312 |
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