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

JOURNAL OF MOLECULAR BIOLOGY

卷:420

Article

Baruah, Kavitha¹  Bowden, Thomas A.²  Krishna, Benjamin A.¹  Dwek, Raymond A.¹  Crispin, Max¹  Scanlan, Christopher N.¹ 

[1] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England

关键词: antibody;    endoglycosidase;    Fc receptor;    ADCC;    glycosylation;   

DOI  :  10.1016/j.jmb.2012.04.002

来源: Elsevier

【 摘 要 】

Serum IgG is a potent inhibitor of monoclonal antibody (mAb) binding to the cell-surface Fc gamma receptors (Fc gamma 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 gamma 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 gamma 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 gamma 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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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