The University of Southampton
University of Southampton Institutional Repository

Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
Rituximab, a monoclonal antibody which targets CD20 on B-cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 mAb are continually being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAb are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B-cells, despite both operating exclusively via activatory FcR-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B-cells leading to reduced macrophage recruitment and the degradation of CD20:mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors, and most cases of Chronic Lymphatic Leukemia (CLL) and Mantle Cell Lymphoma, showed rapid CD20 internalization which paralleled that seen in the Tg mouse B cells, while most Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

0006-4971
5191-5201
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Chan, Claude H.T.
9b7d97e7-f135-478b-883e-3ff52d49af85
Lim, Sean H.
4e9421a0-67d8-4226-b59f-1230afe78177
Jarrett, Timothy C.
251da0a9-04b1-45ca-a3e5-5cccdb1c3d1a
Mora Vidal, Regina
0938f547-c2fb-4603-921c-3d3b5d122499
Wijayaweera, Sahan S.
764b8fb0-9350-45e9-9405-451769869ade
Dixon, Sandra V.
3d5b061e-0e17-4437-9d10-659330869410
Kim, Hyung J.
0d5e914d-8064-438e-9191-cf6982efcb8d
Cox, Kerry L.
b55123a9-7cd2-4dea-9dc9-54d1bd34b4cc
Kerr, Jonathan P.
a9c20862-c7f3-431d-a9fb-454bcbc0054a
Johnston, David A.
33902f48-0d71-467c-b481-637b4d8a055b
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Verbeek, Sjef
423a19e9-e911-425b-b1ca-4e1dddf9c8b4
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Chan, Claude H.T.
9b7d97e7-f135-478b-883e-3ff52d49af85
Lim, Sean H.
4e9421a0-67d8-4226-b59f-1230afe78177
Jarrett, Timothy C.
251da0a9-04b1-45ca-a3e5-5cccdb1c3d1a
Mora Vidal, Regina
0938f547-c2fb-4603-921c-3d3b5d122499
Wijayaweera, Sahan S.
764b8fb0-9350-45e9-9405-451769869ade
Dixon, Sandra V.
3d5b061e-0e17-4437-9d10-659330869410
Kim, Hyung J.
0d5e914d-8064-438e-9191-cf6982efcb8d
Cox, Kerry L.
b55123a9-7cd2-4dea-9dc9-54d1bd34b4cc
Kerr, Jonathan P.
a9c20862-c7f3-431d-a9fb-454bcbc0054a
Johnston, David A.
33902f48-0d71-467c-b481-637b4d8a055b
Johnson, Peter W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Verbeek, Sjef
423a19e9-e911-425b-b1ca-4e1dddf9c8b4
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c

Beers, Stephen A., French, Ruth R., Chan, Claude H.T., Lim, Sean H., Jarrett, Timothy C., Mora Vidal, Regina, Wijayaweera, Sahan S., Dixon, Sandra V., Kim, Hyung J., Cox, Kerry L., Kerr, Jonathan P., Johnston, David A., Johnson, Peter W.M., Verbeek, Sjef, Glennie, Martin J. and Cragg, Mark S. (2010) Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood, 115 (25), 5191-5201. (doi:10.1182/blood-2010-01-263533). (PMID:20223920)

Record type: Article

Abstract

Rituximab, a monoclonal antibody which targets CD20 on B-cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 mAb are continually being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAb are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B-cells, despite both operating exclusively via activatory FcR-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B-cells leading to reduced macrophage recruitment and the degradation of CD20:mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors, and most cases of Chronic Lymphatic Leukemia (CLL) and Mantle Cell Lymphoma, showed rapid CD20 internalization which paralleled that seen in the Tg mouse B cells, while most Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

Text
Beers_et_al_Modulation_Blood_2010.pdf - Other
Download (667kB)

More information

Submitted date: 8 January 2010
Published date: 22 February 2010
Additional Information: Blood First Edition Paper, prepublished online March 16, 2010
Organisations: Faculty of Medicine, Cancer Sciences

Identifiers

Local EPrints ID: 79346
URI: http://eprints.soton.ac.uk/id/eprint/79346
ISSN: 0006-4971
PURE UUID: 03dac50a-93f7-43a4-af85-c06ed96dfbea
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 26 Mar 2010
Last modified: 26 Nov 2019 01:57

Export record

Altmetrics

Contributors

Author: Ruth R. French
Author: Claude H.T. Chan
Author: Sean H. Lim
Author: Timothy C. Jarrett
Author: Regina Mora Vidal
Author: Sahan S. Wijayaweera
Author: Sandra V. Dixon
Author: Hyung J. Kim
Author: Kerry L. Cox
Author: Jonathan P. Kerr
Author: David A. Johnston
Author: Sjef Verbeek
Author: Mark S. Cragg ORCID iD

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×