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Selective deactivation of serum IgG: a general strategy for the enhancement of monoclonal antibody receptor interactions

Selective deactivation of serum IgG: a general strategy for the enhancement of monoclonal antibody receptor interactions
Selective deactivation of serum IgG: a general strategy for the enhancement of monoclonal antibody receptor interactions

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.

ADCC, antibody, endoglycosidase, Fc receptor, glycosylation
0022-2836
1-7
Baruah, Kavitha
a02f59f3-5e0f-4735-9fdd-639bdbb8f563
Bowden, Thomas A.
4b17a588-ac01-4112-807a-8b99a6c20d0f
Krishna, Benjamin A.
9e933528-ebde-4618-b25c-12703a1a00b7
Dwek, Raymond A.
d8d9d5f8-f2c0-414e-b6b0-df77a33f0da4
Crispin, Matthew
cd980957-0943-4b89-b2b2-710f01f33bc9
Scanlan, Christopher N.
04dd1b57-b6fc-414c-8595-08310dbb3d32
Baruah, Kavitha
a02f59f3-5e0f-4735-9fdd-639bdbb8f563
Bowden, Thomas A.
4b17a588-ac01-4112-807a-8b99a6c20d0f
Krishna, Benjamin A.
9e933528-ebde-4618-b25c-12703a1a00b7
Dwek, Raymond A.
d8d9d5f8-f2c0-414e-b6b0-df77a33f0da4
Crispin, Matthew
cd980957-0943-4b89-b2b2-710f01f33bc9
Scanlan, Christopher N.
04dd1b57-b6fc-414c-8595-08310dbb3d32

Baruah, Kavitha, Bowden, Thomas A., Krishna, Benjamin A., Dwek, Raymond A., Crispin, Matthew and Scanlan, Christopher N. (2012) Selective deactivation of serum IgG: a general strategy for the enhancement of monoclonal antibody receptor interactions. Journal of Molecular Biology, 420 (1-2), 1-7. (doi:10.1016/j.jmb.2012.04.002).

Record type: Article

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.

Full text not available from this repository.

More information

Published date: 29 June 2012
Keywords: ADCC, antibody, endoglycosidase, Fc receptor, glycosylation

Identifiers

Local EPrints ID: 414596
URI: https://eprints.soton.ac.uk/id/eprint/414596
ISSN: 0022-2836
PURE UUID: 9ae5af04-f5b2-4e4e-b08c-a6e9a8db04a2
ORCID for Matthew Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 04 Oct 2017 16:30
Last modified: 14 Mar 2019 01:25

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