Journal
MABS
Volume 5, Issue 2, Pages 229-236Publisher
LANDES BIOSCIENCE
DOI: 10.4161/mabs.23452
Keywords
antibody engineering; ADCC; A/I ratio; Fc engineering; Fc gamma R
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Funding
- Chugai Pharmaceutical Co. Ltd.
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Fc engineering is a promising approach to enhance the antitumor efficacy of monoclonal antibodies (mAbs) through antibody-dependent cell-mediated cytotoxicity (ADCC). Glyco-and protein-Fc engineering have been employed to enhance Fc gamma R binding and ADCC activity of mAbs; the drawbacks of previous approaches lie in their binding affinity to both Fc gamma RIIIa allotypes, the ratio of activating Fc gamma R binding to inhibitory Fc gamma R binding (A/I ratio) or the melting temperature (T-M) of the C(H)2 domain. To date, no engineered Fc variant has been reported that satisfies all these points. Herein, we present a novel Fc engineering approach that introduces different substitutions in each Fc domain asymmetrically, conferring optimal binding affinity to Fc gamma R and specificity to the activating Fc gamma R without impairing the stability. We successfully designed an asymmetric Fc variant with the highest binding affinity for both Fc gamma RIIIa allotypes and the highest A/I ratio compared with previously reported symmetrically engineered Fc variants, and superior or at least comparable in vitro ADCC activity compared with afucosylated Fc variants. In addition, the asymmetric Fc engineering approach offered higher stability by minimizing the use of substitutions that reduce the T-M of the C(H)2 domain compared with the symmetric approach. These results demonstrate that the asymmetric Fc engineering platform provides best-in-class effector function for therapeutic antibodies against tumor antigens.
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