Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic lymphocytic leukaemia cells by autologous macrophages

A. K. Church, K. R. Vandermeid, N. A. Baig, A. M. Baran, Thomas Elmer Witzig, Grzegorz S Nowakowski, C. S. Zent

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Unconjugated monoclonal antibodies (mAbs) are an important component of effective combination therapies for chronic lymphocytic leukaemia (CLL). Antibody-dependent phagocytosis (ADP) is a major mediator of mAb cytotoxicity, but there is limited knowledge of the determinants of ADP efficacy. We used macrophages derived in vitro from autologous circulating monocytes to test the effects of mAb structure and concentration, target:effector cell ratio, duration of co-incubation and CLL cell CD20 expression on ADP. Next-generation anti-CD20 mAbs (ofatumumab, ublituximab, obinutuzumab, ocaratuzumab) were significantly more effective at inducing ADP compared to rituximab, but none were as effective as the anti-CD52 mAb alemtuzumab. Ofatumumab (10μg/ml) used as a representative next-generation anti-CD20 mAb achieved an ADP plateau at 3h co-incubation with a target:effector ratio of 10:1 (mean=2.1 CLL cells/macrophage, range=1.5-3.5). At 0.156μg/ml (the lowest concentration tested) ofatumumab ADP was significantly higher than alemtuzumab. However, ofatumumab-induced ADP did not increase significantly at higher mAb concentrations. We show that anti-CD20 mAb ADP efficacy is determined by the mAb characteristics, target:effector ratio and incubation time. We suggest that preclinical evaluation of anti-CD20mAbs to understand the determinants of ADP could be useful in designing future combination therapies for CLL.

Original languageEnglish (US)
Pages (from-to)90-101
Number of pages12
JournalClinical and Experimental Immunology
Volume183
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
Phagocytosis
Macrophages
Monoclonal Antibodies
Antibodies
AME 133
Monocytes
ofatumumab
Therapeutics

Keywords

  • Alemtuzumab
  • Anti-CD20 monoclonal antibodies
  • Antibody-dependent phagocytosis
  • Chronic lymphocytic leukaemia
  • CLL
  • Macrophage
  • Obinotuzumab
  • Ocaratuzumab
  • Ofatumumab
  • Rituximab
  • Ublituximab

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic lymphocytic leukaemia cells by autologous macrophages. / Church, A. K.; Vandermeid, K. R.; Baig, N. A.; Baran, A. M.; Witzig, Thomas Elmer; Nowakowski, Grzegorz S; Zent, C. S.

In: Clinical and Experimental Immunology, Vol. 183, No. 1, 01.01.2016, p. 90-101.

Research output: Contribution to journalArticle

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