[Frontiers in Bioscience 16, 277-306, January 1, 2011]

Molecular mechanisms of the antitumor effects of anti-CD20 antibodies

Magdalena Winiarska1, Eliza Glodkowska-Mrowka1, Jacek Bil1, Jakub Golab1,2

1Department of Immunology, Centre of Biostructure Research, Medical University of Warsaw, Banacha 1A F building, 02-097 Warsaw, Poland, 2Institute of Physical Chemistry, Polish Academy of Sciences, Department 3, 01-224 Warsaw, Poland

TABLE OF CONTENTS

1. Abstract
2. Introduction
2. Introduction
3. Why anti-CD20 mAbs are so effective?
4. Antibodies and molecules targeting CD20
5. CD20 - A target for rituximab
5.1. Gene structure and expression
5.2. Protein structure and localization
5.3. CD20 function
5.4. The epitopes recognized by anti-CD20 mAbs
6. Effector mechanisms of anti-CD20 mAbs
6.1. Complement-dependent cytotoxicity
6.1.1. CDC - in vitro studies
6.1.2. CDC - in vivo studies
6.2. FcγR-mediated cytotoxicity
6.2.1. FcγR-mediated cytotoxicity - in vitro studies
6.2.2. FcγR-mediated cytotoxicity - in vivo studies
6.3. Direct cell killing
6.3.1. Direct cell killing - in vitro studies
6.3.2. Direct cell killing - in vivo studies
6.4. Vaccinal effects
7. Factors affecting the activity of anti-CD20 mAbs
7.1. The expression of CD20
7.1.1. Transcriptional regulation
7.1.2. Posttranscriptional regulation
7.1.3. CD20 mutations
7.1.4. Other mechanisms
7.2. CD20 independent mechanisms of resistance to anti-CD20 mAbs
8. Approaches to improve antitumor efficacy of anti-CD20 mAbs
8.1. Complement-dependent cytotoxicity
8.2. Antibody-dependent cell-mediated cytotoxicity
8.3. Combination therapies
9. Conclusions
10. Acknowledgments
11. References

1. ABSTRACT

Anti-CD20 monoclonal antibodies (mAbs) have become the mainstay in the treatment of non-Hodgkin's lymphomas and have shown significant activity in patients with B-cell chronic lymphocytic leukemia. Antitumor action of these antibodies results from triggering of indirect effector mechanisms of the immune system that include activation of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or phagocytosis. Moreover, some studies indicate direct influence of anti-CD20 mAbs on tumor cells that leads to induction of various types of cell death. Despite the wealth of data on the mechanisms of cytotoxicity that accumulated over the last two decades their relative contribution to the therapeutic outcome is still difficult to predict in individual patients. Elucidation of molecular mechanisms of anti-CD20 mAbs action is necessary to deliver their maximal activity in rationally deigned combinations with other therapeutic approaches and to design next generation anti-CD20 mAb with improved ability to eliminate tumor cells.