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Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents

Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents
Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents
Despite the success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about their mechanism(s) of action. Here, we show that certain of these reagents (rituximab and 1F5), which redistribute CD20 into membrane rafts, are bound efficiently by C1q, deposit C3b, and result in complement-dependent cytotoxicity (CDC). This activity is important in vivo, because complement depletion using cobra venom factor (CVF) markedly reduced the efficacy of rituximab and 1F5 in 2 lymphoma xenograft models. However, complement depletion had no effect on the potent therapeutic activity of B1, a mAb that does not redistribute CD20 into membrane rafts, bind C1q, or cause efficient CDC. Equivalent immunotherapy also occurred in the presence or absence of natural killer (NK) cells. Perhaps most surprising was the observation that F(ab')2 fragments of B1 but not 1F5 were able to provide substantial immunotherapy, indicating that non-Fc-dependent mechanisms are involved with B1. In accordance with this, B1 was shown to induce much higher levels of apoptosis than rituximab and 1F5. Thus, although complement is important for the action of rituximab and 1F5, this is not so for B1, which more likely functions through its ability to signal apoptosis.
0006-4971
2738-2743
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded

Cragg, Mark S. and Glennie, Martin J. (2004) Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood, 103 (7), 2738-2743. (doi:10.1182/blood-2003-06-2031).

Record type: Article

Abstract

Despite the success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about their mechanism(s) of action. Here, we show that certain of these reagents (rituximab and 1F5), which redistribute CD20 into membrane rafts, are bound efficiently by C1q, deposit C3b, and result in complement-dependent cytotoxicity (CDC). This activity is important in vivo, because complement depletion using cobra venom factor (CVF) markedly reduced the efficacy of rituximab and 1F5 in 2 lymphoma xenograft models. However, complement depletion had no effect on the potent therapeutic activity of B1, a mAb that does not redistribute CD20 into membrane rafts, bind C1q, or cause efficient CDC. Equivalent immunotherapy also occurred in the presence or absence of natural killer (NK) cells. Perhaps most surprising was the observation that F(ab')2 fragments of B1 but not 1F5 were able to provide substantial immunotherapy, indicating that non-Fc-dependent mechanisms are involved with B1. In accordance with this, B1 was shown to induce much higher levels of apoptosis than rituximab and 1F5. Thus, although complement is important for the action of rituximab and 1F5, this is not so for B1, which more likely functions through its ability to signal apoptosis.

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Published date: 2004

Identifiers

Local EPrints ID: 26262
URI: http://eprints.soton.ac.uk/id/eprint/26262
ISSN: 0006-4971
PURE UUID: 5f6b83bc-937d-4749-92ed-4a8d153e5f06
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 21 Apr 2006
Last modified: 17 Dec 2019 01:56

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