Academic Journals Database
Disseminating quality controlled scientific knowledge

Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells

ADD TO MY LIST
 
Author(s): George W. Small | Howard L. McLeod | Kristy L. Richards

Journal: PeerJ
ISSN 2167-8359

Volume: 1;
Start page: e31;
Date: 2013;
VIEW PDF   PDF DOWNLOAD PDF   Download PDF Original page

Keywords: Rituximab | Ofatumumab | CD20 expression | mRNA splice variants | Complement-dependent cytotoxicity | Drug resistance | Lymphoblastoid cell line

ABSTRACT
The anti-CD20 monoclonal antibody, rituximab, provides a significant therapeutic benefit for patients with B-cell disorders. However, response to therapy varies and relapses are common, so an understanding of both inherited and acquired rituximab resistance is needed. In order to identify mechanisms of inherited resistance, sensitive versus resistant individuals were selected from a survey of 92 immortalized lymphoblastoid B-cell lines from normal individuals. Levels of CD20 protein and surface expression were lower in the resistant group. In contrast, CD20 mRNA levels were not correlated with susceptibility, suggesting regulation at a post-transcriptional level. To examine acquired resistance, resistant sublines were selected from both lymphoblastoid as well as lymphoma cell lines. Confirming previous findings, there was significant down-regulation of CD20 protein expression in all the resistant sublines. CD20 mRNA splice variants are reported to be associated with development of resistance. Three splice variants were observed in our cell lines, each lacking the binding epitope for rituximab, but none were associated with rituximab resistance. The second generation anti-CD20 mAb, ofatumumab, was more active compared with rituximab in vitro in the survey of all B-cell lines, mirroring results that have been reported previously with malignant B-cells. These studies show that normal B-lymphoblastoid cell lines can be used to model both innate and acquired mechanisms of resistance. They validate the important role of CD20 expression and enable future genetic studies to identify additional mediators of anti-CD20 mAb resistance.

Tango Jona
Tangokurs Rapperswil-Jona

     Save time & money - Smart Internet Solutions