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

50 Pages Posted: 16 Jun 2020 Sneak Peek Status: Under Review

See all articles by Bronwyn M. Gunn

Bronwyn M. Gunn

Ragon Institute of MGH, MIT and Harvard

Richard Lu

Ragon Institute of MGH, MIT and Harvard

Matthew D. Slein

Ragon Institute of MGH, MIT and Harvard

Philipp A. Ilinykh

University of Texas Medical Branch-Galveston - Department of Pathology

Kai Huang

University of Texas Medical Branch-Galveston - Department of Pathology

Caroline Atyeo

Ragon Institute of MGH, MIT and Harvard

Sharon L. Schendel

La Jolla Institute for Immunology

Jiyoung Kim

Ragon Institute of MGH, MIT and Harvard

Caitlin Cain

Ragon Institute of MGH, MIT and Harvard

Vicky Roy

Ragon Institute of MGH, MIT and Harvard

Todd J. Suscovich

Ragon Institute of MGH, MIT and Harvard

Ayato Takada

Hokkaido University - Division of Global Epidemiology

Peter J. Halfmann

University of Wisconsin - Madison - Department of Pathobiological Sciences

Yoshihiro Kawaoka

University of Wisconsin - Madison - Department of Pathobiological Sciences

Matthias Pauthner

Scripps Research Institute - Department of Immunology and Microbiology; The Scripps Research Institute - Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; The Scripps Research Institute - IAVI Neutralizing Antibody Center

Mambu Momo

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Augustine Goba

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Lansana Kanneh

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Kristian G. Andersen

The Scripps Research Institute - Department of Immunology and Microbiology

John S. Schieffelin

Tulane University - Department of Pediatrics

Donald Grant

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Robert F. Garry

Tulane University - Department of Microbiology and Immunology

Erica Ollmann Saphire

La Jolla Institute for Immunology

Alexander Bukreyev

University of Texas Medical Branch-Galveston - Department of Pathology

Galit Alter

Ragon Institute of MGH, MIT and Harvard

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Abstract

Monoclonal antibodies are emerging as effective therapies for viral infections, including for Ebola virus (EBOV). Protective EBOV antibodies have neutralizing activity and induction of 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 may 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; thus, we applied an Fc-engineering platform to define the most protective profiles. We generated a library of Fc-variants with identical Fabs from an EBOV neutralizing antibody. Fc-variants with antibody-mediated complement deposition and moderate NK cell activity demonstrated complete protective activity in vivo. These data highlight the importance of specific effector functions in antibody-mediated protection and provide a platform for rapid identification of correlates of immunity to guide therapeutic design.

Keywords: Antibody engineering, Ebola virus, Fc effector function

Suggested Citation

Gunn, Bronwyn M. and Lu, Richard and Slein, Matthew D. and Ilinykh, Philipp A. and Huang, Kai and Atyeo, Caroline and Schendel, Sharon L. and Kim, Jiyoung and Cain, Caitlin and Roy, Vicky and Suscovich, Todd J. and Takada, Ayato and Halfmann, Peter J. and Kawaoka, Yoshihiro and Pauthner, Matthias and Momo, Mambu and Goba, Augustine and Kanneh, Lansana and Andersen, Kristian G. and Schieffelin, John S. and Grant, Donald and Garry, Robert F. and Saphire, Erica Ollmann and Bukreyev, Alexander and Alter, Galit, A Fc-Engineering Approach to Define Functional Humoral Correlates of Immunity Against Ebola Virus. Available at SSRN: https://ssrn.com/abstract=3608385 or http://dx.doi.org/10.2139/ssrn.3608385
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Bronwyn M. Gunn

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Richard Lu

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Matthew D. Slein

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Philipp A. Ilinykh

University of Texas Medical Branch-Galveston - Department of Pathology

Galveston, TX
United States

Kai Huang

University of Texas Medical Branch-Galveston - Department of Pathology

Galveston, TX
United States

Caroline Atyeo

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Sharon L. Schendel

La Jolla Institute for Immunology

La Jolla, CA
United States

Jiyoung Kim

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Caitlin Cain

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Vicky Roy

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Todd J. Suscovich

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Ayato Takada

Hokkaido University - Division of Global Epidemiology

5 Kita 8 Jonishi, Kita Ward
Hokkaido Prefecture
Sapporo, 060-0808
Japan

Peter J. Halfmann

University of Wisconsin - Madison - Department of Pathobiological Sciences

716 Langdon Street
Madison, WI 53706-1481
United States

Yoshihiro Kawaoka

University of Wisconsin - Madison - Department of Pathobiological Sciences

716 Langdon Street
Madison, WI 53706-1481
United States

Matthias Pauthner

Scripps Research Institute - Department of Immunology and Microbiology

United States

The Scripps Research Institute - Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery ( email )

La Jolla, CA
United States

The Scripps Research Institute - IAVI Neutralizing Antibody Center ( email )

La Jolla, CA
United States

Mambu Momo

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Kenema
Sierra Leone

Augustine Goba

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Kenema
Sierra Leone

Lansana Kanneh

Kenema Government Hospital - Viral Hemorrhagic Fever Program ( email )

Kenema
Sierra Leone

Kristian G. Andersen

The Scripps Research Institute - Department of Immunology and Microbiology

La Jolla, CA 92037
United States

John S. Schieffelin

Tulane University - Department of Pediatrics

6823 St Charles Ave
New Orleans, LA 70118
United States

Donald Grant

Kenema Government Hospital - Viral Hemorrhagic Fever Program

Kenema
Sierra Leone

Robert F. Garry

Tulane University - Department of Microbiology and Immunology

6823 St Charles Ave
New Orleans, LA 70118
United States

Erica Ollmann Saphire

La Jolla Institute for Immunology

La Jolla, CA
United States

Alexander Bukreyev

University of Texas Medical Branch-Galveston - Department of Pathology

Galveston, TX
United States

Galit Alter (Contact Author)

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

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