Antigenic modulation of rituximab results in its rapid consumption in vivo and limits its ability to deplete target B cells


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Stephen Beers, Ruth French, Claude Chan, Sandra Dixon, Timothy Jarrett, Jinny Kim, Regina Mora, Martin Glennie, Mark Cragg

Southampton University School of Medicine, Southampton General Hospital, UK

Abstract

Rituximab was the first monoclonal antibody approved for the treatment of malignant disease and has since been used to treat more than a million patients. Despite its undoubted success and impact on patient survival, a substantial proportion of those treated develop resistant disease despite retaining CD20 expression. Therefore, greater understanding of anti-CD20 mAb therapy is required.

We have previously defined anti-CD20 mAb as either Type I or II, based upon their efficacy in various in vitro assays. We have shown that Type II mAb provide superior therapy in xenograft tumour models compared with Type I mAb such as rituximab. More recently we have demonstrated, using a Tg mouse model expressing human CD20, that Type II mAb are also more effective at depleting normal B cells. The mechanisms underlying these varying therapeutic effects are unclear.

Here we show that Type I anti-CD20 mAb, in marked contrast to their Type II counterparts, induce significant modulation of CD20 from the surface of B cells. This Type I modulation occurs both in vivo, using a Tg mouse model, and vitro with normal human B cells and primary clinical samples. Modulation from the cell surface has at least two linked but different effects; firstly a marked reduction in effector cell recruitment and secondly a profound increase in antibody consumption and reduction in half-life. These effects we believe lead to the differences observed in efficacy. We are currently investigating whether the extent and rate of modulation of CD20 by rituximab on primary samples can also explain the varying responses seen clinically in various B cell malignancies.

These results have further strengthened our belief that Type II anti-CD20 mAb have greater therapeutic potential than Type I mAb in the treatment of B cell diseases. Furthermore, this knowledge will allow us to design rational combination therapies for augmenting existing anti-CD20 mAb treatments through a reduction in antigenic modulation.