@article{69568a0ebec94aea8fb3441dcf431339,
title = "A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus",
abstract = "Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.",
keywords = "ADCC, Ebola virus, Fc effector function, antibody engineering, complement, humoral immunity, infectious diseases, monoclonal antibody therapeutics, phagocytosis",
author = "Gunn, {Bronwyn M.} and Richard Lu and Slein, {Matthew D.} and Ilinykh, {Philipp A.} and Kai Huang and Caroline Atyeo and Schendel, {Sharon L.} and Jiyoung Kim and Caitlin Cain and Vicky Roy and Suscovich, {Todd J.} and Ayato Takada and Halfmann, {Peter J.} and Yoshihiro Kawaoka and Pauthner, {Matthias G.} and Mambu Momoh and Augustine Goba and Lansana Kanneh and Andersen, {Kristian G.} and Schieffelin, {John S.} and Donald Grant and Garry, {Robert F.} and Saphire, {Erica Ollmann} and Alexander Bukreyev and Galit Alter",
note = "Funding Information: We would like to thank all members of the Alter laboratory, the Viral Hemorrhagic Fever Immunotherapeutics Consortium, and the Consortium for Viral Systems Biology for critical discussion and advice; Madeline Davis for administrative help; and Christina Karsten and Julie Boucau for help with the FPLC analysis. This work was supported by U19 AI109762, AI142790, and U19 AI135995, as well as partly by the Japan Agency for Medical Research and Development (JP17fk0108101). The graphical abstract was created with BioRender. B.M.G. R.L. E.O.S. A.B. and G.A. conceptualized the study. B.M.G. R.L. M.D.S. P.A.I. K.H. C.A. S.L.S. C.C. J.K. and V.R. performed experiments. K.G.A. R.F.G. E.O.S. A.B. and G.A. obtained funding. J.S.S. M.G.P. M.M. A.G. L.K. and D.G. collected clinical samples. T.J.S. contributed to analysis. P.J.H. A.T. and Y.K. provided sequences. B.M.G. and G.A. wrote the draft of the manuscript, and all authors edited the manuscript. G.A. is a founder of Seromyx Systems Inc. and T.J.S. is currently an employee of Seromyx Systems Inc. We worked to ensure gender balance in the recruitment of human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: We would like to thank all members of the Alter laboratory, the Viral Hemorrhagic Fever Immunotherapeutics Consortium, and the Consortium for Viral Systems Biology for critical discussion and advice; Madeline Davis for administrative help; and Christina Karsten and Julie Boucau for help with the FPLC analysis. This work was supported by U19 AI109762, AI142790, and U19 AI135995, as well as partly by the Japan Agency for Medical Research and Development ( JP17fk0108101 ). The graphical abstract was created with BioRender. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "13",
doi = "10.1016/j.immuni.2021.03.009",
language = "English (US)",
volume = "54",
pages = "815--828.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "4",
}