A Fc Engineering Approach to Define Functional Humoral Correlates of Immunity Against Ebola Virus

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2021 Apr 14

PMID 33852832

Citations 30

Authors

Bronwyn M Gunn

Richard Lu

Matthew D Slein

Philipp A Ilinykh

Kai Huang

Caroline Atyeo

Sharon L Schendel

Jiyoung Kim

Caitlin Cain

Vicky Roy

Todd J Suscovich

Ayato Takada

Peter J Halfmann

Yoshihiro Kawaoka

Matthias G Pauthner

Mambu Momoh

Augustine Goba

Lansana Kanneh

Kristian G Andersen

John S Schieffelin

Donald Grant

Robert F Garry

Erica Ollmann Saphire

Alexander Bukreyev

Galit Alter

Affiliations

Soon will be listed here.

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.

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