Novel asymmetrically engineered antibody Fc variant with superior Fc?R binding affinity and specificity compared with afucosylated Fc variant.

ABSTRACT: 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?R binding and ADCC activity of mAbs; the drawbacks of previous approaches lie in their binding affinity to both Fc?RIIIa allotypes, the ratio of activating Fc?R binding to inhibitory Fc?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?R and specificity to the activating Fc?R without impairing the stability. We successfully designed an asymmetric Fc variant with the highest binding affinity for both Fc?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.

SUBMITTER: Mimoto F 

PROVIDER: S-EPMC3893233 | biostudies-literature | 2013 Mar-Apr

REPOSITORIES: biostudies-literature