Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity

Stylianos Bournazos, Siu Kei Chow, Nareen Abboud, Arturo Casadeval, 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

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ASJC Scopus subject areas

  • Medicine(all)

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