@article{ebbf31d98f7e4504a01b7e41a04eadd0,
title = "Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever",
abstract = "Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.",
keywords = "CCHFV, Crimean-Congo hemorrhagic fever virus, antibody therapeutic, bunyavirus, emerging virus, human monoclonal antibody, monoclonal antibody, nairovirus, tickborne, viral glycoprotein",
author = "Fels, {J. Maximilian} and Maurer, {Daniel P.} and Herbert, {Andrew S.} and Wirchnianski, {Ariel S.} and Olivia Vergnolle and Cross, {Robert W.} and Abelson, {Dafna M.} and Moyer, {Crystal L.} and Mishra, {Akaash K.} and Aguilan, {Jennifer T.} and Kuehne, {Ana I.} and Pauli, {Noel T.} and Bakken, {Russell R.} and Nyakatura, {Elisabeth K.} and Jan Hellert and Gregory Quevedo and Leslie Lobel and Stephen Balinandi and Lutwama, {Julius J.} and Larry Zeitlin and Geisbert, {Thomas W.} and Rey, {Felix A.} and Simone Sidoli and McLellan, {Jason S.} and Lai, {Jonathan R.} and Bornholdt, {Zachary A.} and Dye, {John M.} and Walker, {Laura M.} and Kartik Chandran",
note = "Funding Information: This manuscript is dedicated to the memory of our dear colleague and co-author, Dr. Leslie Lobel, whose vision and energy helped to initiate and drive this project. We thank Isabel Gutierrez, Estefania Valencia, and Laura Polanco for laboratory management and technical assistance. All IgGs, but not bsAbs, were sequenced by Adimab{\textquoteright}s Molecular Core, and yeast-expressed mAbs and Fabs were produced by Adimab{\textquoteright}s High Throughput Expression group. Biolayer interferometry binding experiments with IgGs were performed by Adimab{\textquoteright}s Protein Analytics group. We thank Scott Garforth and the Macromolecular Therapeutics Development Facility for their support with size-exclusion chromatographic analyses of the DVD-Igs. We thank Christina Spiropoulou, {\'E}ric Bergeron, and Marko Zivcec at the Centers for Disease Control and Prevention for kindly providing the plasmids and protocols necessary to generate tecVLPs. We thank members of all of our groups and the Prometheus consortium for their feedback on preliminary versions of the manuscript. Research was supported by NIAID of the National Institutes of Health (NIH) under award number U19AI142777 (Centers of Excellence in Translational Research) to K.C., L.M.W., J.M.D., Z.A.B., J.S.M., J.R.L., A.S.H., and L.Z. Z.A.B., D.M.A., C.L.M., L.Z., R.W.C., and T.W.G. were supported by NIH grant R01AI132246 . A.S.W. was supported by NIH training grant T32AI070117 to the Albert Einstein College of Medicine. E.K.N. was supported by a DAAD ( Deutscher Akademischer Austauschdienst [German Academic Exchange Service]) fellowship. S.S. was supported by the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), AFAR (Sagol Network GerOmics award for aging research), Einstein-Montefiore for (SARS-CoV-2 [COVID-19] grant), and the Nathan Shock Institute for Aging Research (Basic Biology of Aging 2020 award) F.A.R. acknowledges funding from Institut Pasteur , CNRS , and Labex IBEID (grant ANR-10-IHUB-0002 ). J.H. was supported by the GIS IBiSA (Infrastructures en biologie sant{\'e} et agronomie) (grant ANR-13-ISV8-0002-01 ) and the R{\'e}gion Ile de France . The content is solely the responsibility of the authors and does not necessarily represent the official views of our institutions or funders. Funding Information: This manuscript is dedicated to the memory of our dear colleague and co-author, Dr. Leslie Lobel, whose vision and energy helped to initiate and drive this project. We thank Isabel Gutierrez, Estefania Valencia, and Laura Polanco for laboratory management and technical assistance. All IgGs, but not bsAbs, were sequenced by Adimab's Molecular Core, and yeast-expressed mAbs and Fabs were produced by Adimab's High Throughput Expression group. Biolayer interferometry binding experiments with IgGs were performed by Adimab's Protein Analytics group. We thank Scott Garforth and the Macromolecular Therapeutics Development Facility for their support with size-exclusion chromatographic analyses of the DVD-Igs. We thank Christina Spiropoulou, ?ric Bergeron, and Marko Zivcec at the Centers for Disease Control and Prevention for kindly providing the plasmids and protocols necessary to generate tecVLPs. We thank members of all of our groups and the Prometheus consortium for their feedback on preliminary versions of the manuscript. Research was supported by NIAID of the National Institutes of Health (NIH) under award number U19AI142777 (Centers of Excellence in Translational Research) to K.C. L.M.W. J.M.D. Z.A.B. J.S.M. J.R.L. A.S.H. and L.Z. Z.A.B. D.M.A. C.L.M. L.Z. R.W.C. and T.W.G. were supported by NIH grant R01AI132246. A.S.W. was supported by NIH training grant T32AI070117 to the Albert Einstein College of Medicine. E.K.N. was supported by a DAAD (Deutscher Akademischer Austauschdienst [German Academic Exchange Service]) fellowship. S.S. was supported by the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), AFAR (Sagol Network GerOmics award for aging research), Einstein-Montefiore for (SARS-CoV-2 [COVID-19] grant), and the Nathan Shock Institute for Aging Research (Basic Biology of Aging 2020 award) F.A.R. acknowledges funding from Institut Pasteur, CNRS, and Labex IBEID (grant ANR-10-IHUB-0002). J.H. was supported by the GIS IBiSA (Infrastructures en biologie sant? et agronomie) (grant ANR-13-ISV8-0002-01) and the R?gion Ile de France. The content is solely the responsibility of the authors and does not necessarily represent the official views of our institutions or funders. Conceptualization, J.M.F. D.P.M. A.S.H. K.C. L.M.W. Z.A.B. L.L. J.M.D. J.R.L. and L.Z.; methodology, D.P.M. J.M.F. and A.S.H.; formal analysis, D.P.M. J.M.F. and A.S.H.; investigation, J.M.F. D.P.M. A.S.H. C.L.M. J.T.A. N.T.P. A.K.M. A.I.K. R.R.B. A.S.W. O.V. G.Q. E.K.N. R.W.C. and T.W.G.; resources, L.L. S.B. J.J.L. A.S.H. J.M.D. Z.A.B. and D.M.A.; writing ? original draft, J.M.F. D.P.M. L.M.W. and K.C.; writing ? review & editing, all authors; visualization, J.M.F. D.P.M. J.H. and K.C.; supervision, K.C. L.M.W. J.M.D. Z.A.B. J.R.L. J.S.M. S.S. F.A.R. T.W.G. and L.Z.; funding acquisition, K.C. L.M.W. J.M.D. Z.A.B. J.R.L. J.S.M. S.S. F.A.R. T.W.G. and L.Z. K.C. is a scientific advisory board member of Integrum Scientific and Biovaxys Technology Corporation. K.C. J.S.M. and J.R.L. are scientific advisory board members of the Pandemic Security Initiative of Celdara Medical. N.T.P. and L.M.W. are employees and shareholders of Adimab. D.P.M. is a shareholder of Adimab. Z.A.B. D.M.A. C.L.M. and L.Z. are shareholders and employees of Mapp Biopharmaceutical. Mapp Biopharmaceutical has filed a patent application related to this work. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "24",
doi = "10.1016/j.cell.2021.05.001",
language = "English (US)",
volume = "184",
pages = "3486--3501.e21",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "13",
}
