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A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus.
- Source :
-
Immunity [Immunity] 2021 Apr 13; Vol. 54 (4), pp. 815-828.e5. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests G.A. is a founder of Seromyx Systems Inc., and T.J.S. is currently an employee of Seromyx Systems Inc.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antibodies, Neutralizing immunology
Antibodies, Viral immunology
Antibody Formation immunology
Antibody-Dependent Cell Cytotoxicity immunology
Female
HEK293 Cells
Hemorrhagic Fever, Ebola virology
Humans
Immunoglobulin G immunology
Mice, Inbred BALB C
Receptors, Fc immunology
Mice
Ebolavirus immunology
Hemorrhagic Fever, Ebola immunology
Immunoglobulin Fab Fragments immunology
Immunoglobulin Fc Fragments immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 54
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 33852832
- Full Text :
- https://doi.org/10.1016/j.immuni.2021.03.009