Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies

Waleed Alduaij, Andrei Ivanov, Jamie Honeychurch, Eleanor J. Cheadle, Sandeep Potluri, Sean H. Lim, Kazuyuki Shimada, Claude H T Chan, Alison Tutt, Stephen A. Beers, Martin J. Glennie, Mark S. Cragg, Tim M. Illidge

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The anti-CD20 mAb rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-FcγR interactions appear to underlie much of the therapeutic success with rituximab, certain type II anti-CD20 mAbs efficiently induce programmed cell death (PCD), whereas rituximab-like type I anti-CD20 mAbs do not. Here, we show that the humanized, glycoengineered anti-CD20 mAb GA101 and derivatives harboring non-glycoengineered Fc regions are type II mAb that trigger nonapoptotic PCD in a range of B-lymphoma cell lines and primary B-cell malignancies. We demonstrate that GA101-induced cell death is dependent on actin reorganization, can be abrogated by inhibitors of actin polymerization, and is independent of BCL-2 overexpression and caspase activation. GA101-induced PCD is executed by lysosomes which disperse their contents into the cytoplasm and surrounding environment. Taken together, these findings reveal that GA101 is able to potently elicit actin-dependent, lysosomal cell death, which may potentially lead to improved clearance of B-cell malignancies in vivo. © 2011 by The American Society of Hematology.
    Original languageEnglish
    Pages (from-to)4519-4529
    Number of pages10
    JournalBlood
    Volume117
    Issue number17
    DOIs
    Publication statusPublished - 28 Apr 2011

    Fingerprint

    Dive into the research topics of 'Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies'. Together they form a unique fingerprint.

    Cite this