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The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD2013

The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD2013
The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD2013
We have previously defined a panel of fully human CD20 mAb. Most of these were unexpectedly efficient in their ability to recruit C1q to the surface of CD20-positive cells and mediate tumor lysis via activation of the classical pathway of complement. This complement-dependent cytotoxicity (CDC) potency appeared to relate to the unusually slow off-rate of these human Abs. However, we now present epitope-mapping data, which indicates that all human mAb bind a novel region of CD20 that may influence CDC potency. Epitope mapping, using both mutagenesis studies and overlapping 15-mer peptides of the extracellular loops of CD20, defined the amino acids required for binding by an extensive panel of mouse and human mAb. Binding by rituximab and mouse CD20 mAb, had an absolute requirement for alanine and proline at positions 170 and 172, respectively, within the large extracellular loop of CD20. Surprisingly, however, all of the human CD20 mAb recognize a completely novel epitope located N-terminally of this motif, also including the small extracellular loop of CD20. Thus, although off-rate may influence biological activity of mAb, another critical factor for determining CDC potency by CD20 mAb appears to be the region of the target molecule they recognize. We conclude that recognition of the novel epitope cooperates with slow off-rate in determining the activity of CD20 Ab in activation of complement and induction of tumor cell lysis.
cell, cdc, monoclonal-antibodies, mhc class-ii, apoptosis induction, induction, human b-cells, rituximab, mouse, chronic lymphocytic-leukemia, cd20, activation, cell-cycle progression, time, region, binding, cells, immunotherapy, surface, lymphoma, monoclonal antibody, insoluble membrane compartment, tumor-cells
0022-1767
362-371
Teeling, Jessica L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Mackus, Wendy J. M.
be341e2e-da69-4280-8710-2895571d0780
Wiegman, Luus J. J. M.
74fb1ecf-06c8-4801-a94d-f8ad2eca0430
van den Brakel, Jeroen H. N.
c4b8d87b-6e54-4c06-b89e-8a0c3dfb17da
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
van Meerten, Tom
ded85650-3838-4f3b-ae1b-f96b998479a5
Ebeling, Saskia
0c2448dc-cdbd-4f61-81e7-bf075b8d7137
Vink, Tom
710bf4e3-44d4-419a-b0fc-b30d37c22142
Slootstra, Jerry W.
c01eeac0-fcf3-43d2-ba0a-670007d953b4
Parren, Paul W. H. I.
af8f0002-9785-4a3b-8696-17f26ce97d7f
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
van de Winkel, Jan G. J.
0a997f4a-2488-4355-93bd-b649935dd9c0
Teeling, Jessica L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Mackus, Wendy J. M.
be341e2e-da69-4280-8710-2895571d0780
Wiegman, Luus J. J. M.
74fb1ecf-06c8-4801-a94d-f8ad2eca0430
van den Brakel, Jeroen H. N.
c4b8d87b-6e54-4c06-b89e-8a0c3dfb17da
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
van Meerten, Tom
ded85650-3838-4f3b-ae1b-f96b998479a5
Ebeling, Saskia
0c2448dc-cdbd-4f61-81e7-bf075b8d7137
Vink, Tom
710bf4e3-44d4-419a-b0fc-b30d37c22142
Slootstra, Jerry W.
c01eeac0-fcf3-43d2-ba0a-670007d953b4
Parren, Paul W. H. I.
af8f0002-9785-4a3b-8696-17f26ce97d7f
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
van de Winkel, Jan G. J.
0a997f4a-2488-4355-93bd-b649935dd9c0

Teeling, Jessica L., Mackus, Wendy J. M., Wiegman, Luus J. J. M., van den Brakel, Jeroen H. N., Beers, Stephen A., French, Ruth R., van Meerten, Tom, Ebeling, Saskia, Vink, Tom, Slootstra, Jerry W., Parren, Paul W. H. I., Glennie, Martin J. and van de Winkel, Jan G. J. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD2013. The Journal of Immunology, 177 (1), 362-371.

Record type: Article

Abstract

We have previously defined a panel of fully human CD20 mAb. Most of these were unexpectedly efficient in their ability to recruit C1q to the surface of CD20-positive cells and mediate tumor lysis via activation of the classical pathway of complement. This complement-dependent cytotoxicity (CDC) potency appeared to relate to the unusually slow off-rate of these human Abs. However, we now present epitope-mapping data, which indicates that all human mAb bind a novel region of CD20 that may influence CDC potency. Epitope mapping, using both mutagenesis studies and overlapping 15-mer peptides of the extracellular loops of CD20, defined the amino acids required for binding by an extensive panel of mouse and human mAb. Binding by rituximab and mouse CD20 mAb, had an absolute requirement for alanine and proline at positions 170 and 172, respectively, within the large extracellular loop of CD20. Surprisingly, however, all of the human CD20 mAb recognize a completely novel epitope located N-terminally of this motif, also including the small extracellular loop of CD20. Thus, although off-rate may influence biological activity of mAb, another critical factor for determining CDC potency by CD20 mAb appears to be the region of the target molecule they recognize. We conclude that recognition of the novel epitope cooperates with slow off-rate in determining the activity of CD20 Ab in activation of complement and induction of tumor cell lysis.

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More information

Published date: 2006
Keywords: cell, cdc, monoclonal-antibodies, mhc class-ii, apoptosis induction, induction, human b-cells, rituximab, mouse, chronic lymphocytic-leukemia, cd20, activation, cell-cycle progression, time, region, binding, cells, immunotherapy, surface, lymphoma, monoclonal antibody, insoluble membrane compartment, tumor-cells

Identifiers

Local EPrints ID: 62953
URI: http://eprints.soton.ac.uk/id/eprint/62953
ISSN: 0022-1767
PURE UUID: ad3b67bd-dadb-4ab5-9372-5d495cdcb5d1
ORCID for Jessica L. Teeling: ORCID iD orcid.org/0000-0003-4004-7391

Catalogue record

Date deposited: 05 Sep 2008
Last modified: 19 Jun 2019 00:35

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Contributors

Author: Wendy J. M. Mackus
Author: Luus J. J. M. Wiegman
Author: Jeroen H. N. van den Brakel
Author: Ruth R. French
Author: Tom van Meerten
Author: Saskia Ebeling
Author: Tom Vink
Author: Jerry W. Slootstra
Author: Paul W. H. I. Parren
Author: Jan G. J. van de Winkel

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