An afucosylated anti-CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity and B-cell depletion and lower complement-dependent cytotoxicity than rituximab

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• 作者：John R. Gasdaska^a ; ^{jgasdaska@biolex.com} ; Steven Sherwood^b ; Jeffrey T. Regan^a ; Lynn F. Dickey^a
• 关键词：CD20 ; Monoclonal antibody ; ADCC ; CDC ; Afucosylated
• 刊名：Molecular Immunology
• 出版年：2012
• 期刊代码：112_01615890
• 类别：bio
• 出版时间：March, 2012
• 卷：50
• 期：3
• 页码：134-141
• 文件大小：630 K

摘要

The objective of this study was to characterize the in vitro and in vivo activity of a novel afucosylated rituximab (BLX-300) expressed in a Lemna aquatic plant-based system free of zoonotic pathogens. The glycosylation of BLX-300 was shown to be homogeneous, composed of a single major N-glycan species without detectable fucose or xylose. Target cell binding and induction of apoptosis were similar for BLX-300 and rituximab. Antibody-dependent cellular cytotoxicity (ADCC) was increased by BLX-300 versus rituximab in phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V) and valine/valine (V/V) genotype donors, as indicated by respective log reductions of 0.82, 1.07 and 0.92 in EC₅₀. BLX-300 also showed greater B-cell depletion than rituximab in whole blood from donors of F/F, F/V and V/V genotype in vitro and cynomolgus monkeys in vivo. Temporal changes in circulating levels of BLX-300 and rituximab were similar in cynomolgus monkeys. Complement-dependent cytotoxicity (CDC) was attenuated by BLX-300 relative to rituximab, as judged by a log increase of 0.51 in EC₅₀. The higher ADCC and B-cell depletion suggest a potential improvement in effectiveness and potency, while lower CDC may mitigate infusion toxicity.