The anti-CD20 antibody rituximab augments the immunospecific therapeutic effectiveness of an anti-CD19 immunotoxin directed against human B-cell lymphoma
The anti-CD20 antibody rituximab augments the immunospecific therapeutic effectiveness of an anti-CD19 immunotoxin directed against human B-cell lymphoma
The chimaeric anti-CD20 antibody rituximab (Rituxan) sensitises lymphoma cells to small molecule cytotoxic drugs and to protein toxins. We have explored the augmentive effect of rituximab on the anti-CD19 immunotoxin BU12-SAPORIN in a model of human lymphoma. Intact rituximab and its F(ab)(2) derivative both augmented the immunospecific protein synthesis inhibitory effects of BU12-SAPORIN in a complement-independent manner. A combination of rituximab + BU12-SAPORIN completely abolished the proliferation of Ramos cells in vitro and also induced a significantly greater degree of apoptosis in these cells. Treatment with rituximab, BU12-SAPORIN or a combination of both induced poly(ADPribose) polymerase and caspase 3 cleavage, although this was always consistently greater in combination-treated cells. zVAD almost completely inhibited apoptosis in rituximab- or BU12-SAPORIN-treated cells but only partially in combination-treated cells. In severe combined immunodeficient (SCID)-Ramos mice the combination of rituximab + BU12-SAPORIN was significantly better therapeutically than either single agent. The immunological fidelity of the therapeutic effect because of combination treatment was demonstrated through the failure of rituximab to augment an irrelevant anti-CD7 immunotoxin. The therapeutic efficacy of rituximab and combination treatment was reduced in SCID-Ramos mice depleted of serum complement while natural killer cell depletion failed to show any convincing role for antibody-dependent cellular cytotoxicity. This study shows a clear therapeutic advantage from using rituximab to immunospecifically augment immunotoxin cytotoxicity warranting further investigation.
malignant lymphomas, immunotherapy, apoptosis, antibody therapy
157-170
Flavell, David J.
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Warnes, Sarah L.
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Bryson, Christine J.
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Field, Sarah A.
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Noss, Armorel L.
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Packham, Graham
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Flavell, Sopsamorn U.
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July 2006
Flavell, David J.
3a0f7124-7d44-42bc-b6f6-6fb12552fbd6
Warnes, Sarah L.
f724f4bf-86cf-4b7b-bf0a-69ba86e0185c
Bryson, Christine J.
e1279e8b-35e2-45cb-a194-861a0d23d444
Field, Sarah A.
a7b1dfb4-4e02-4b96-8232-c9304136ae08
Noss, Armorel L.
6e9849eb-93cd-42bd-8e3c-b6bce650cae5
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Flavell, Sopsamorn U.
fa2b4670-1836-42e2-b68a-5d646899d711
Flavell, David J., Warnes, Sarah L., Bryson, Christine J., Field, Sarah A., Noss, Armorel L., Packham, Graham and Flavell, Sopsamorn U.
(2006)
The anti-CD20 antibody rituximab augments the immunospecific therapeutic effectiveness of an anti-CD19 immunotoxin directed against human B-cell lymphoma.
British Journal of Haematology, 134 (2), .
(doi:10.1111/j.1365-2141.2006.06155.x).
(PMID:16771848)
Abstract
The chimaeric anti-CD20 antibody rituximab (Rituxan) sensitises lymphoma cells to small molecule cytotoxic drugs and to protein toxins. We have explored the augmentive effect of rituximab on the anti-CD19 immunotoxin BU12-SAPORIN in a model of human lymphoma. Intact rituximab and its F(ab)(2) derivative both augmented the immunospecific protein synthesis inhibitory effects of BU12-SAPORIN in a complement-independent manner. A combination of rituximab + BU12-SAPORIN completely abolished the proliferation of Ramos cells in vitro and also induced a significantly greater degree of apoptosis in these cells. Treatment with rituximab, BU12-SAPORIN or a combination of both induced poly(ADPribose) polymerase and caspase 3 cleavage, although this was always consistently greater in combination-treated cells. zVAD almost completely inhibited apoptosis in rituximab- or BU12-SAPORIN-treated cells but only partially in combination-treated cells. In severe combined immunodeficient (SCID)-Ramos mice the combination of rituximab + BU12-SAPORIN was significantly better therapeutically than either single agent. The immunological fidelity of the therapeutic effect because of combination treatment was demonstrated through the failure of rituximab to augment an irrelevant anti-CD7 immunotoxin. The therapeutic efficacy of rituximab and combination treatment was reduced in SCID-Ramos mice depleted of serum complement while natural killer cell depletion failed to show any convincing role for antibody-dependent cellular cytotoxicity. This study shows a clear therapeutic advantage from using rituximab to immunospecifically augment immunotoxin cytotoxicity warranting further investigation.
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Published date: July 2006
Keywords:
malignant lymphomas, immunotherapy, apoptosis, antibody therapy
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Local EPrints ID: 62739
URI: http://eprints.soton.ac.uk/id/eprint/62739
ISSN: 0007-1048
PURE UUID: ebdce7e7-e250-43eb-baa2-0583e12ed7a1
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Date deposited: 17 Nov 2008
Last modified: 16 Mar 2024 03:14
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Contributors
Author:
David J. Flavell
Author:
Sarah L. Warnes
Author:
Christine J. Bryson
Author:
Sarah A. Field
Author:
Armorel L. Noss
Author:
Sopsamorn U. Flavell
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