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Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy

Lim, Sean, Vaughan, Andrew, Ashton-Key, Margaret, Williams, E.L., Dixon, S., Chan, H.T. Claude, Beers, Stephen, French, R.R., Cox, K., Davies, AJ, Potter, Kathleen N., Mockridge, C.I., Oscier, David G., Johnson, P.W.M., Cragg, Mark and Glennie, Martin (2011) Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy Blood, 118, (9), pp. 2530-2540. (doi:10.1182/blood-2011-01-330357). (PMID:21768293).

Record type: Article

Abstract

The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory Fc?RIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with Fc?RIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of Fc?RIIb into Fc?RIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell Fc?RIIb promoted rituximab internalization in a cis fashion and was independent of Fc?RIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high Fc?RIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell Fc?RIIb provides a potential biomarker of response to type I anti-CD20 mAb

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Published date: 1 September 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 339294
URI: http://eprints.soton.ac.uk/id/eprint/339294
ISSN: 0006-4971
PURE UUID: 0f753199-244e-40cf-9488-ec9919e7e430
ORCID for Andrew Vaughan: ORCID iD orcid.org/0000-0001-6076-3649
ORCID for P.W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 28 May 2012 13:53
Last modified: 18 Jul 2017 05:53

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Contributors

Author: Sean Lim
Author: Andrew Vaughan ORCID iD
Author: Margaret Ashton-Key
Author: E.L. Williams
Author: S. Dixon
Author: H.T. Claude Chan
Author: Stephen Beers
Author: R.R. French
Author: K. Cox
Author: AJ Davies
Author: C.I. Mockridge
Author: David G. Oscier
Author: P.W.M. Johnson ORCID iD
Author: Mark Cragg ORCID iD
Author: Martin Glennie

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