Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity

Stylianos Bournazos, Siu Kei Chow, Nareen Abboud, Arturo Casadevall, Jeffrey V. Ravetch

Research output: Contribution to journalArticle

Abstract

The effector activity of antibodies is dependent on engagement with Fcγ receptors (FcγRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcγRs is hampered by substantial structural and functional FcγR diversity among species. In this report, we used mice expressing only human FcγRs to evaluate the contribution of FcγR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcγR engagement, with minimal protection against anthrax toxin observed in FcγR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcγRs and assessed their activity in FcγR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)725-729
Number of pages5
JournalJournal of Clinical Investigation
Volume124
Issue number2
DOIs
StatePublished - Feb 3 2014
Externally publishedYes

Fingerprint

Antitoxins
Fc Receptors
Neutralizing Antibodies
Immunoglobulin G
Antibodies
anthrax toxin
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity. / Bournazos, Stylianos; Chow, Siu Kei; Abboud, Nareen; Casadevall, Arturo; Ravetch, Jeffrey V.

In: Journal of Clinical Investigation, Vol. 124, No. 2, 03.02.2014, p. 725-729.

Research output: Contribution to journalArticle

Bournazos, Stylianos ; Chow, Siu Kei ; Abboud, Nareen ; Casadevall, Arturo ; Ravetch, Jeffrey V. / Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 2. pp. 725-729.
@article{f5db6f6a14814bd1904987f9cdca9929,
title = "Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity",
abstract = "The effector activity of antibodies is dependent on engagement with Fcγ receptors (FcγRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcγRs is hampered by substantial structural and functional FcγR diversity among species. In this report, we used mice expressing only human FcγRs to evaluate the contribution of FcγR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcγR engagement, with minimal protection against anthrax toxin observed in FcγR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcγRs and assessed their activity in FcγR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy.",
author = "Stylianos Bournazos and Chow, {Siu Kei} and Nareen Abboud and Arturo Casadevall and Ravetch, {Jeffrey V.}",
year = "2014",
month = "2",
day = "3",
doi = "10.1172/JCI72676",
language = "English (US)",
volume = "124",
pages = "725--729",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

TY - JOUR

T1 - Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity

AU - Bournazos, Stylianos

AU - Chow, Siu Kei

AU - Abboud, Nareen

AU - Casadevall, Arturo

AU - Ravetch, Jeffrey V.

PY - 2014/2/3

Y1 - 2014/2/3

N2 - The effector activity of antibodies is dependent on engagement with Fcγ receptors (FcγRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcγRs is hampered by substantial structural and functional FcγR diversity among species. In this report, we used mice expressing only human FcγRs to evaluate the contribution of FcγR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcγR engagement, with minimal protection against anthrax toxin observed in FcγR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcγRs and assessed their activity in FcγR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy.

AB - The effector activity of antibodies is dependent on engagement with Fcγ receptors (FcγRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcγRs is hampered by substantial structural and functional FcγR diversity among species. In this report, we used mice expressing only human FcγRs to evaluate the contribution of FcγR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcγR engagement, with minimal protection against anthrax toxin observed in FcγR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcγRs and assessed their activity in FcγR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy.

UR - http://www.scopus.com/inward/record.url?scp=84893841403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893841403&partnerID=8YFLogxK

U2 - 10.1172/JCI72676

DO - 10.1172/JCI72676

M3 - Article

VL - 124

SP - 725

EP - 729

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -