| First Author | Bournazos S | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 2 | Pages | 725-9 |
| PubMed ID | 24401277 | Mgi Jnum | J:207991 |
| Mgi Id | MGI:5560405 | Doi | 10.1172/JCI72676 |
| Citation | Bournazos S, et al. (2014) Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity. J Clin Invest 124(2):725-9 |
| abstractText | The effector activity of antibodies is dependent on engagement with Fcgamma receptors (FcgammaRs) 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 FcgammaRs is hampered by substantial structural and functional FcgammaR diversity among species. In this report, we used mice expressing only human FcgammaRs to evaluate the contribution of FcgammaR-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 FcgammaR engagement, with minimal protection against anthrax toxin observed in FcgammaR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcgammaRs and assessed their activity in FcgammaR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcgammaRs 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. |
