4ACP

Deactivation of human IgG1 Fc by endoglycosidase treatment

Summary for 4ACP

• Entry DOI: 10.2210/pdb4acp/pdb
• Related: 1AJ7 1AQK 1BEY 1D5B 1D5I 1D6V 1DN2 1E4K 1FC1 1FC2 1FCC 1H3T 1H3U 1H3V 1H3W 1H3Y 1I7Z 1L6X 1OQX 1T83 1T89 2IWG 2J6E 2RCS 2WAH
• Descriptor: IG GAMMA-1 CHAIN C REGION, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: immune system, igg, antibody, kifunensine
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P01857
• Total number of polymer chains: 2
• Total formula weight: 54252.26

Authors

Raman, K.,Bowden, T.A.,Krishna, B.A.,Dwek, R.A.,Crispin, M.,Scanlan, C.N. (deposition date: 2011-12-16, release date: 2012-04-25, Last modification date: 2024-11-20)

Primary citation

Baruah, K.,Bowden, T.A.,Krishna, B.A.,A Dwek, R.,Crispin, M.,Scanlan, C.N.
Selective Deactivation of Serum Igg: A General Strategy for the Enhancement of Monoclonal Antibody Receptor Interactions.
J.Mol.Biol., 420:1-, 2012

PubMed Abstract: Serum IgG is a potent inhibitor of monoclonal antibody (mAb) binding to the cell-surface Fcγ receptors (FcγRs), 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 FcγRs 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 FcγR 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 FcγR 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.

PubMed: 22484364
DOI: 10.1016/J.JMB.2012.04.002

Experimental method

X-RAY DIFFRACTION (2.49 Å)