Blood Journal
Leading the way in experimental and clinical research in hematology

Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

  1. Stephen A Beers1,
  2. Ruth R French1,
  3. Claude HT Chan1,
  4. Sean H Lim1,
  5. Timothy C Jarrett1,
  6. Regina Mora Vidal1,
  7. Sahan S Wijayaweera1,
  8. Sandra V Dixon1,
  9. Hyung J Kim1,
  10. Kerry L Cox1,
  11. Jonathan P Kerr1,
  12. David A Johnston2,
  13. Peter W M Johnson3,
  14. Sjef Verbeek4,
  15. Martin J Glennie1, and
  16. Mark S Cragg1,*
  1. 1 Tenovus Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton, United Kingdom;
  2. 2 Biomedical Imaging Unit, Southampton University School of Medicine, General Hospital, Southampton, United Kingdom;
  3. 3 Cancer Research UK Cancer Centre, Southampton University School of Medicine, General Hospital, Southampton, United Kingdom;
  4. 4 Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
  1. * Corresponding author; email: msc{at}soton.ac.uk

Abstract

Rituximab, a monoclonal antibody which targets CD20 on B-cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 mAb are continually being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAb are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B-cells, despite both operating exclusively via activatory FcR-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B-cells leading to reduced macrophage recruitment and the degradation of CD20:mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors, and most cases of Chronic Lymphatic Leukemia (CLL) and Mantle Cell Lymphoma, showed rapid CD20 internalization which paralleled that seen in the Tg mouse B cells, while most Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

  • Submitted January 8, 2010.
  • Accepted February 22, 2010.