Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies
Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies
Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo.
1901-1909
Tipton, Thomas R.W.
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Roghanian, Ali
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Oldham, Robert J.
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Carter, Matthew J.
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Cox, Kerry L.
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Mockridge, C. Ian
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French, Ruth R.
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Dahal, Lekh N.
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Duriez, Patrick J.
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Hargreaves, Philip G.
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Cragg, Mark S.
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Beers, Stephen A.
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19 March 2015
Tipton, Thomas R.W.
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Roghanian, Ali
e2b032c2-60a0-4522-a3d8-56a768792f36
Oldham, Robert J.
f43d1416-0b93-4dfd-a504-2850cb43e87e
Carter, Matthew J.
3baac102-d80c-42ba-ab4d-ad339a48169e
Cox, Kerry L.
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Dahal, Lekh N.
1e993a7a-b007-4187-82ea-e28dd3920b66
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Hargreaves, Philip G.
96dec2f0-9af2-439a-80d2-fc49e789aaf9
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Tipton, Thomas R.W., Roghanian, Ali, Oldham, Robert J., Carter, Matthew J., Cox, Kerry L., Mockridge, C. Ian, French, Ruth R., Dahal, Lekh N., Duriez, Patrick J., Hargreaves, Philip G., Cragg, Mark S. and Beers, Stephen A.
(2015)
Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies.
Blood, 125 (12), .
(doi:10.1182/blood-2014-07-588376).
(PMID:25631769)
Abstract
Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo.
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Accepted/In Press date: 17 January 2015
e-pub ahead of print date: 28 January 2015
Published date: 19 March 2015
Organisations:
Cancer Sciences
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Local EPrints ID: 376433
URI: http://eprints.soton.ac.uk/id/eprint/376433
ISSN: 0006-4971
PURE UUID: 6d441930-3a59-4331-abf2-6cca2a1b2c09
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Date deposited: 28 Apr 2015 12:37
Last modified: 15 Mar 2024 03:34
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Author:
Thomas R.W. Tipton
Author:
Robert J. Oldham
Author:
Kerry L. Cox
Author:
C. Ian Mockridge
Author:
Ruth R. French
Author:
Lekh N. Dahal
Author:
Patrick J. Duriez
Author:
Philip G. Hargreaves
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