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Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas

Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas
Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas
Despite the rapid and widespread integration of chimeric CD20 monoclonal antibody (mAb), rituximab, into the management of non-Hodgkin lymphoma, its efficacy remains variable and often modest when used as a single agent. To develop more potent reagents, human immunoglobulin transgenic mice were used to generate a panel of immunoglobulin G1kappa (IgG1kappa) CD20 mAbs. All reagents bound strongly to CD20(+) cells and recruited mononuclear cells for the lysis of malignant B cells. However, 2 mAbs, 2F2 and 7D8, were exceptionally active in complement-dependent cytotoxicity (CDC), being able to lyse a range of rituximab-resistant targets, such as CD20-low chronic lymphocytic leukemia (CLL), in the presence of human plasma or unfractionated blood. Further analysis showed that 2F2 and 7D8, like rituximab, redistributed CD20 into Triton X-100-insoluble regions of the plasma membrane, but that they had markedly slower off-rates. To determine whether off-rate influenced CDC, a non-complement activating F(ab')(2) antihuman kappa reagent was used. This reagent markedly slowed the off-rate of rituximab and increased its CDC activity to that of 2F2 and 7D8. Thus, with increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity.
0006-4971
1793-1800
Teeling, J.L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
French, R.R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Cragg, M.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Van den Brakel, J.
4b30a895-0625-4787-b6eb-e1bc6d5bd020
Pluyter, M.
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Huang, H.
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Chan, C.
d3951155-a056-42ac-becf-13ed7d4b3073
Parren, P.W.
9483306e-37dd-4933-b811-876e43858176
Hack, C.E.
30fe6b07-f781-4eba-8476-5b4f509c36f8
Dechant, M.
9074beb5-f857-42b5-ae0b-6b5ace58244a
Valerius, T.
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Van de Winkel, J.G.
b13150c7-4db5-4a1e-80d4-926eff539b96
Glennie, M.J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Teeling, J.L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
French, R.R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Cragg, M.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Van den Brakel, J.
4b30a895-0625-4787-b6eb-e1bc6d5bd020
Pluyter, M.
f64a1d34-d663-4ae2-ad7f-858eb061acb3
Huang, H.
3f68d19e-069b-4157-9ae6-dbd4ebd2d59a
Chan, C.
d3951155-a056-42ac-becf-13ed7d4b3073
Parren, P.W.
9483306e-37dd-4933-b811-876e43858176
Hack, C.E.
30fe6b07-f781-4eba-8476-5b4f509c36f8
Dechant, M.
9074beb5-f857-42b5-ae0b-6b5ace58244a
Valerius, T.
39a2d564-ac9e-47b6-9030-e6d74dbcdbf5
Van de Winkel, J.G.
b13150c7-4db5-4a1e-80d4-926eff539b96
Glennie, M.J.
9f6f0eff-4560-48c2-80cd-0ec116110ded

Teeling, J.L., French, R.R., Cragg, M.S., Van den Brakel, J., Pluyter, M., Huang, H., Chan, C., Parren, P.W., Hack, C.E., Dechant, M., Valerius, T., Van de Winkel, J.G. and Glennie, M.J. (2004) Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood, 104 (6), 1793-1800. (doi:10.1182/blood-2004-01-0039).

Record type: Article

Abstract

Despite the rapid and widespread integration of chimeric CD20 monoclonal antibody (mAb), rituximab, into the management of non-Hodgkin lymphoma, its efficacy remains variable and often modest when used as a single agent. To develop more potent reagents, human immunoglobulin transgenic mice were used to generate a panel of immunoglobulin G1kappa (IgG1kappa) CD20 mAbs. All reagents bound strongly to CD20(+) cells and recruited mononuclear cells for the lysis of malignant B cells. However, 2 mAbs, 2F2 and 7D8, were exceptionally active in complement-dependent cytotoxicity (CDC), being able to lyse a range of rituximab-resistant targets, such as CD20-low chronic lymphocytic leukemia (CLL), in the presence of human plasma or unfractionated blood. Further analysis showed that 2F2 and 7D8, like rituximab, redistributed CD20 into Triton X-100-insoluble regions of the plasma membrane, but that they had markedly slower off-rates. To determine whether off-rate influenced CDC, a non-complement activating F(ab')(2) antihuman kappa reagent was used. This reagent markedly slowed the off-rate of rituximab and increased its CDC activity to that of 2F2 and 7D8. Thus, with increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity.

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More information

Published date: 2004

Identifiers

Local EPrints ID: 26635
URI: http://eprints.soton.ac.uk/id/eprint/26635
ISSN: 0006-4971
PURE UUID: 98542720-ceab-40e8-a8fc-b0d5600a24d7
ORCID for J.L. Teeling: ORCID iD orcid.org/0000-0003-4004-7391
ORCID for M.S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 21 Apr 2006
Last modified: 16 Mar 2024 03:41

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Contributors

Author: J.L. Teeling ORCID iD
Author: R.R. French
Author: M.S. Cragg ORCID iD
Author: J. Van den Brakel
Author: M. Pluyter
Author: H. Huang
Author: C. Chan
Author: P.W. Parren
Author: C.E. Hack
Author: M. Dechant
Author: T. Valerius
Author: J.G. Van de Winkel
Author: M.J. Glennie

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