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Quantitative evaluation of fucose reducing effects in a humanized antibody on Fcγ receptor binding and antibody-dependent cell-mediated cytotoxicity activities

Authors :
Xiaoying Gao
Wendy Lau
An Song
Martin Vanderlaan
Amy Shen
Linda Lin
Chris B Fong
Valerie Quarmby
Shan Chung
Yong Ying
Zhihua J. Qiu
Chae Janeka Reed
Source :
mAbs. 4:326-340
Publication Year :
2012
Publisher :
Informa UK Limited, 2012.

Abstract

The presence or absence of core fucose in the Fc region N-linked glycans of antibodies affects their binding affinity toward FcγRIIIa as well as their antibody-dependent cell-mediated cytotoxicity (ADCC) activity. However, the quantitative nature of this structure-function relationship remains unclear. In this study, the in vitro biological activity of an afucosylated anti-CD20 antibody was fully characterized. Further, the effect of fucose reduction on Fc effector functions was quantitatively evaluated using the afucosylated antibody, its "regular" fucosylated counterpart and a series of mixtures containing varying proportions of "regular" and afucosylated materials. Compared with the "regular" fucosylated antibody, the afucosylated antibody demonstrated similar binding interactions with the target antigen (CD20), C1q and FcγRIa, moderate increases in binding to FcγRIIa and IIb, and substantially increased binding to FcγRIIIa. The afucosylated antibodies also showed comparable complement-dependent cytotoxicity activity but markedly increased ADCC activity. Based on EC 50 values derived from dose-response curves, our results indicate that the amount of afucosylated glycan in antibody samples correlate with both FcγRIIIa binding activity and ADCC activity in a linear fashion. Furthermore, the extent of ADCC enhancement due to fucose depletion was not affected by the FcγRIIIa genotype of the effector cells.

Details

ISSN :
19420870 and 19420862
Volume :
4
Database :
OpenAIRE
Journal :
mAbs
Accession number :
edsair.doi.dedup.....781e45425190045074f6f2c62a445a50
Full Text :
https://doi.org/10.4161/mabs.19941