Signalling cascades induced by Type I and II anti-CD20 monoclonal antibodies

Abstract

Rituximab (ritux) is a chimeric IgG1 anti-CD20 monoclonal antibody (mAb) which has been used to treat over a half a million non Hodgkin’s lymphoma patients. Despite its success, not all patients respond to ritux treatment. The reason for this is currently unclear. One of the key aims of this work was to dissect the signalling cascades induced by different anti-CD20 mAb in order to better understand the mechanisms of CD20-directed therapy.

Using a range of techniques we have demonstrated that many of not all anti-CD20 mAb rapidly redistribute CD20 in the plasma membrane into Triton-X 100 insoluble raft domains. Monoclonal Ab which redistribute CD20 in this way, such as ritux, were also highly effective mediators of CDC, yet were poor inducers of PCD. These mAb were classified as Type 1. In contrast, mAb which were unable to redistribute CD20 into lipid rafts were also ineffective at mediating CDC, yet induced effective PCD. These mAb were classified as Type II mAb. Interestingly, Type I, but not Type II, mAb induced a calcium signalling cascade upon CD20 ligation in both B-lymphoma cell lines and primary B cells. This signalling event was dependent on the B-cell receptor (BCR) complex, in that BCR-negative cells failed to generate a CD20-mediated Ca²⁺ flux. Importantly, we demonstrate that even though Type I and Type II mAb bind the same target, they induce distinct signalling cascades. Insight into these signalling cascades should provides better understanding of the critical parameters required to maximise the potential of CD20-directed therapies.

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