Selective Deactivation of Serum IgG: A General Strategy for the Enhancement of Monoclonal Antibody Receptor Interactions

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• 作者：Kavitha Baruah¹ ; ^&dagger ; ; Thomas A. Bowden² ; ^&dagger ; ; Benjamin A. Krishna¹ ; Raymond A. Dwek¹ ; Max Crispin¹ ; ^{max.crispin@bioch.ox.ac.uk} ; Christopher N. Scanlan¹ ; ^{chris.scanlan@bioch.ox.ac.uk}
• 关键词：ADCC ; antibody-dependent cellular cytotoxicity ; Fc纬R ; Fc纬 receptor ; mAb ; monoclonal antibody ; PDB ; Protein Data Bank ; sAb ; serum antibody
• 刊名：Journal of Molecular Biology
• 出版年：2012
• 期刊代码：102_00222836
• 类别：imm
• 出版时间：29 June, 2012
• 卷：420
• 期：1-2
• 页码：1-7
• 文件大小：739 K

摘要

Serum IgG is a potent inhibitor of monoclonal antibody (mAb) binding to the cell-surface Fc纬 receptors (Fc纬Rs), which mediate cytotoxic and phagocytic effector functions. Here, we show that this competition can be eliminated, selectively, by the introduction to serum of (i) an enzyme that displaces Fc from Fc纬Rs and (ii) a modification present in the therapeutic mAb that renders it resistant to that enzyme. Specifically, we show that (i) EndoS (endoglycosidase S) cleaves only complex-type glycans of the type found on IgG but (ii) is inactive against an engineered IgG Fc with oligomannose-type glycans. EndoS thus reduces Fc纬R binding of serum IgG, but not that of engineered mAb. Introduction of both the engineered mAb and endoglycosidase in serum leads to a dramatic increase in Fc纬R binding compared to the introduction of mAb in serum alone. Antibody receptor refocusing is a general technique for boosting the effector signal of therapeutic antibodies.