Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity.

ABSTRACT: The effector activity of antibodies is dependent on engagement with Fc? receptors (Fc?Rs) 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 Fc?Rs is hampered by substantial structural and functional Fc?R diversity among species. In this report, we used mice expressing only human Fc?Rs to evaluate the contribution of Fc?R-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 Fc?R engagement, with minimal protection against anthrax toxin observed in Fc?R-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human Fc?Rs and assessed their activity in Fc?R-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating Fc?Rs 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.

SUBMITTER: Bournazos S 

PROVIDER: S-EPMC3904629 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature