@article{a2afe357bb9d470896003a580089b565,
title = "Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope",
abstract = "Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design.",
keywords = "Fc effector, alphavirus, antibody, arthritis, encephalitis, immunity, inhiibtion, mice, pathogenesis, protection",
author = "Kim, {Arthur S.} and Kafai, {Natasha M.} and Winkler, {Emma S.} and Gilliland, {Theron C.} and Cottle, {Emily L.} and Earnest, {James T.} and Jethva, {Prashant N.} and Paulina Kaplonek and Shah, {Aadit P.} and Fong, {Rachel H.} and Edgar Davidson and Malonis, {Ryan J.} and Quiroz, {Jose A.} and Williamson, {Lauren E.} and Lo Vang and Matthias Mack and Crowe, {James E.} and Doranz, {Benjamin J.} and Lai, {Jonathan R.} and Galit Alter and Gross, {Michael L.} and Klimstra, {William B.} and Fremont, {Daved H.} and Diamond, {Michael S.}",
note = "Funding Information: This study was supported by NIH grants and contracts R01 AI143673, U19 AI142790, R01 AI095436, R01 AI125462, HHSN272201400058C, HHSN272201700060C, HHSN272201400018C, P41 GM103422, R24 GM136766, T32 AI007172, T32 GM007288, F30 AI152327, F30 AI150055, and F30 GM007288; the Defense Threat Reduction Agency (HDTRA1-15-1-0013 and HDTRA1-15-1-0047); and the University Hospital Regensburg. J.R.L. gratefully acknowledges an XSeed Grant Award from Deerfield. A.S.K. performed infection studies with assistance from A.P.S. A.S.K. generated proteins and performed binding studies. A.S.K. R.H.F. and E.D. performed mutagenesis experiments. P.N.J. performed HDX-MS experiments. P.K. performed effector function experiments. N.M.K. E.S.W. T.C.G. E.L.C. and J.T.E. performed in vivo experiments. A.S.K. N.M.K. E.S.W. P.N.J. B.J.D. G.A. M.L.G. W.B.K. D.H.F. and M.S.D. designed experiments. A.S.K. N.M.K. E.S.W. J.T.E. P.N.J. P.K. R.H.F. and E.D. performed data analysis. R.J.M. J.A.Q. L.E.W. L.V. M.M. J.E.C. and J.R.L. contributed key reagents. A.S.K. and M.S.D. wrote the initial draft, with the other authors providing comments. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond and Fremont laboratories received support from Emergent BioSolutions under a sponsored research agreement. The Diamond laboratory has unrelated research agreements from Moderna and Vir Biotechnology. D.H.F. is a founder of Courier Therapeutics. J.R.L. is a consultant for Celdara Medical. DC2.112 and DC2.315 are the subject of a US patent application with R.J.M. J.A.Q. and J.R.L. as co-inventors. R.H.F. E.D. and B.J.D. are employees of Integral Molecular, and B.J.D. is a shareholder of Integral Molecular. J.E.C. has served as a consultant for Lilly and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory has received unrelated sponsored research agreements from Astra Zeneca and IDBiologics. M.L.G. is an unpaid member of the scientific advisory boards of Protein Metrics and GenNext. G.A. is a founder of SeromYx Systems. Funding Information: This study was supported by NIH grants and contracts R01 AI143673 , U19 AI142790 , R01 AI095436 , R01 AI125462 , HHSN272201400058C , HHSN272201700060C , HHSN272201400018C , P41 GM103422 , R24 GM136766 , T32 AI007172 , T32 GM007288 , F30 AI152327 , F30 AI150055 , and F30 GM007288 ; the Defense Threat Reduction Agency ( HDTRA1-15-1-0013 and HDTRA1-15-1-0047 ); and the University Hospital Regensburg . J.R.L. gratefully acknowledges an XSeed Grant Award from Deerfield. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "19",
doi = "10.1016/j.cell.2021.07.006",
language = "English (US)",
volume = "184",
pages = "4414--4429.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "17",
}
