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.
authors: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors: Pankaj
authors: P
authors: Pal
authors: Kimberly A
authors: KA
authors: Dowd
authors: James D
authors: JD
authors: Brien
authors: Melissa A
authors: MA
authors: Edeling
authors: Sergey
authors: S
authors: Gorlatov
authors: Syd
authors: S
authors: Johnson
authors: Iris
authors: I
authors: Lee
authors: Wataru
authors: W
authors: Akahata
authors: Gary J
authors: GJ
authors: Nabel
authors: Mareike K S
authors: MK
authors: Richter
authors: Jolanda M
authors: JM
authors: Smit
authors: Daved H
authors: DH
authors: Fremont
authors: Theodore C
authors: TC
authors: Pierson
authors: Mark T
authors: MT
authors: Heise
authors: Michael S
authors: MS
authors: Diamond
mesh_terms: D016475:3T3 Cells; D000330:Aedes; D018354:Alphavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000276:immunology; D002522:Chlorocebus aethiops; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000276:immunology; D015678:Viral Structural Proteins / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C508032:Ifnar1 protein, mouse; D014759:Viral Envelope Proteins; D015678:Viral Structural Proteins; D053633:Receptor, Interferon alpha-beta
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