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Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies

Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies
Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies
The anti-CD20 monoclonal antibody (mAb) rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-Fc?R interactions appear to underlie much of the therapeutic success with rituximab, certain type II anti-CD20 mAbs efficiently induce programmed cell death (PCD), whereas rituximab-like type I anti-CD20 mAbs do not. Here we show that the humanized, glycoengineered anti-CD20 mAb GA101 and derivatives harboring non-glycoengineered Fc regions are type II mAb that trigger non-apoptotic PCD in a range of B-lymphoma cell lines and primary B-cell malignancies. We demonstrate that GA101-induced cell death is dependent on actin reorganization, can be abrogated by inhibitors of actin polymerization and is independent of BCL-2 over-expression and caspase activation. GA101-induced PCD is executed by lysosomes which disperse their contents into the cytoplasm and surrounding environment. Taken together, these findings reveal that GA101 is able to potently elicit actin-dependent, lysosomal cell death, which may potentially lead to improved clearance of B-cell malignancies in vivo.
0006-4971
4519-4529
Alduaij, Waleed
7f5e4406-1a05-419f-ab2a-64855d7e693c
Ivanov, Andrei
803a3bb6-5673-4498-b300-80f81aaeb1b4
Honeychurch, Jamie
4ecce821-9d37-4c35-bcb3-871ff832a3d2
Cheadle, Eleanor
ba958199-e60e-43d2-9e22-744d6c16fc69
Potluri, Sandeep
4f6fecc2-152e-4180-8ee6-c6d17ec5a421
Lim, Sean H.
1afe5aa1-61a4-4a7b-927f-5e671f885196
Shimada, Kazuyuki
4817dc2a-d67c-4fc5-9266-4a91e171982a
Chan, Claude H.T.
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Tutt, Alison L.
46ce577b-aea1-412d-84ea-fc4dab794469
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Illidge, Tim M.
2a7357b3-0340-42bc-9716-2dd278590747
Alduaij, Waleed
7f5e4406-1a05-419f-ab2a-64855d7e693c
Ivanov, Andrei
803a3bb6-5673-4498-b300-80f81aaeb1b4
Honeychurch, Jamie
4ecce821-9d37-4c35-bcb3-871ff832a3d2
Cheadle, Eleanor
ba958199-e60e-43d2-9e22-744d6c16fc69
Potluri, Sandeep
4f6fecc2-152e-4180-8ee6-c6d17ec5a421
Lim, Sean H.
1afe5aa1-61a4-4a7b-927f-5e671f885196
Shimada, Kazuyuki
4817dc2a-d67c-4fc5-9266-4a91e171982a
Chan, Claude H.T.
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Tutt, Alison L.
46ce577b-aea1-412d-84ea-fc4dab794469
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Illidge, Tim M.
2a7357b3-0340-42bc-9716-2dd278590747

Alduaij, Waleed, Ivanov, Andrei, Honeychurch, Jamie, Cheadle, Eleanor, Potluri, Sandeep, Lim, Sean H., Shimada, Kazuyuki, Chan, Claude H.T., Tutt, Alison L., Beers, Stephen A., Glennie, Martin J., Cragg, Mark S. and Illidge, Tim M. (2011) Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood, 117 (17), 4519-4529. (doi:10.1182/blood-2010-07-296913). (PMID: 21378274)

Record type: Article

Abstract

The anti-CD20 monoclonal antibody (mAb) rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-Fc?R interactions appear to underlie much of the therapeutic success with rituximab, certain type II anti-CD20 mAbs efficiently induce programmed cell death (PCD), whereas rituximab-like type I anti-CD20 mAbs do not. Here we show that the humanized, glycoengineered anti-CD20 mAb GA101 and derivatives harboring non-glycoengineered Fc regions are type II mAb that trigger non-apoptotic PCD in a range of B-lymphoma cell lines and primary B-cell malignancies. We demonstrate that GA101-induced cell death is dependent on actin reorganization, can be abrogated by inhibitors of actin polymerization and is independent of BCL-2 over-expression and caspase activation. GA101-induced PCD is executed by lysosomes which disperse their contents into the cytoplasm and surrounding environment. Taken together, these findings reveal that GA101 is able to potently elicit actin-dependent, lysosomal cell death, which may potentially lead to improved clearance of B-cell malignancies in vivo.

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Published date: 2011
Organisations: Faculty of Medicine, Cancer Sciences

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Local EPrints ID: 179873
URI: https://eprints.soton.ac.uk/id/eprint/179873
ISSN: 0006-4971
PURE UUID: 27512c92-eb95-4de0-9742-ce532420b2b2
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 07 Apr 2011 11:23
Last modified: 12 Nov 2019 01:56

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Contributors

Author: Waleed Alduaij
Author: Andrei Ivanov
Author: Jamie Honeychurch
Author: Eleanor Cheadle
Author: Sandeep Potluri
Author: Sean H. Lim
Author: Kazuyuki Shimada
Author: Claude H.T. Chan
Author: Alison L. Tutt
Author: Mark S. Cragg ORCID iD
Author: Tim M. Illidge

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