A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus

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. SchieffelinDonald Grant, Robert F. Garry, Erica Ollmann Saphire, Alexander Bukreyev, Galit Alter

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Pages (from-to)815-828.e5
    JournalImmunity
    Volume54
    Issue number4
    DOIs
    StatePublished - Apr 13 2021

    Keywords

    • ADCC
    • antibody engineering
    • complement
    • Ebola virus
    • Fc effector function
    • humoral immunity
    • infectious diseases
    • monoclonal antibody therapeutics
    • phagocytosis

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology
    • Infectious Diseases

    Fingerprint

    Dive into the research topics of 'A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus'. Together they form a unique fingerprint.

    Cite this