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. Schieffelin; Donald Grant; Robert F. Garry; Erica Ollmann Saphire; Alexander Bukreyev; Galit Alter

doi:10.1016/j.immuni.2021.03.009

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

Pathology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Pages (from-to)	815-828.e5
Journal	Immunity
Volume	54
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2021.03.009
State	Published - Apr 13 2021

Keywords

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

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2021.03.009

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Gunn, B. M., Lu, R., Slein, M. D., Ilinykh, P. A., Huang, K., Atyeo, C., Schendel, S. L., Kim, J., Cain, C., Roy, V., Suscovich, T. J., Takada, A., Halfmann, P. J., Kawaoka, Y., Pauthner, M. G., Momoh, M., Goba, A., Kanneh, L., Andersen, K. G., ... Alter, G. (2021). A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus. Immunity, 54(4), 815-828.e5. https://doi.org/10.1016/j.immuni.2021.03.009

Gunn, BM, Lu, R, Slein, MD, Ilinykh, PA, Huang, K, Atyeo, C, Schendel, SL, Kim, J, Cain, C, Roy, V, Suscovich, TJ, Takada, A, Halfmann, PJ, Kawaoka, Y, Pauthner, MG, Momoh, M, Goba, A, Kanneh, L, Andersen, KG, Schieffelin, JS, Grant, D, Garry, RF, Saphire, EO, Bukreyev, A & Alter, G 2021, 'A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus', Immunity, vol. 54, no. 4, pp. 815-828.e5. https://doi.org/10.1016/j.immuni.2021.03.009

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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",

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AU - Gunn, Bronwyn M.

AU - Lu, Richard

AU - Slein, Matthew D.

AU - Ilinykh, Philipp A.

AU - Huang, Kai

AU - Atyeo, Caroline

AU - Schendel, Sharon L.

AU - Kim, Jiyoung

AU - Cain, Caitlin

AU - Roy, Vicky

AU - Suscovich, Todd J.

AU - Takada, Ayato

AU - Halfmann, Peter J.

AU - Kawaoka, Yoshihiro

AU - Pauthner, Matthias G.

AU - Momoh, Mambu

AU - Goba, Augustine

AU - Kanneh, Lansana

AU - Andersen, Kristian G.

AU - Schieffelin, John S.

AU - Grant, Donald

AU - Garry, Robert F.

AU - Saphire, Erica Ollmann

AU - Bukreyev, Alexander

AU - Alter, Galit

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N2 - 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.

AB - 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.

KW - ADCC

KW - Ebola virus

KW - Fc effector function

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KW - monoclonal antibody therapeutics

KW - phagocytosis

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

Abstract

Keywords

ASJC Scopus subject areas

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