Role for ZAP-70 signaling in the differential effector functions of rituximab and obinutuzumab (GA101) in chronic lymphocytic leukemia B cells

Sladjana Skopelja-Gardner, Jonathan D. Jones, B. Jonell Hamilton, Alexey Danilov, William F.C. Rigby

Research output: Contribution to journalArticle

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Abstract

Rituximab (RTX) has been the hallmark anti-CD20 mAb for the treatment of B cell neoplasms, including B cell chronic lymphocytic leukemia (B-CLL). Recently, a novel humanized anti-CD20 mAb obinutuzumab (GA101) has been implemented as first-line CLL therapy. Treatment of CLL patients with RTX is associated with CD20 loss via an FcgR-mediated process, trogocytosis. RTXinduced trogocytosis has been characterized as both the means of resistance to therapy, via loss of cell surface target proteins (antigenic modulation), as well as a process that alters B cell phenotype and function. This study investigates the nature and clinical relevance of GA101-mediated trogocytosis. In this study, we demonstrate that GA101 is a more potent mediator of trogocytosis than RTX in vitro in both normal B cells and B-CLL cells. Qualitative differences in the effector function of these anti-CD20 Abs appear specific to B-CLL cells. GA101-mediated CD19 and CD20 trogocytosis from B-CLL cells is associated with its ability to induce homotypic adhesion (HA). The degree of HA varies between CLL patients and positively correlates with the expression of ZAP-70, a BCR-associated kinase. Deregulation of ZAP-70 using tyrosine kinase inhibitors, gefitinib or ibrutinib, diminishes HA formation and trogocytosis by GA101. Taken together, these findings elucidate the differences in trogocytosis and HA formation mediated by anti-CD20 mAbs RTX and GA101, as well as provide a novel link between ZAP-70 expression and these effector functions.

Original languageEnglish (US)
Pages (from-to)1275-1282
Number of pages8
JournalJournal of Immunology
Volume199
Issue number4
DOIs
StatePublished - Aug 15 2017

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B-Cell Chronic Lymphocytic Leukemia
B-Lymphocytes
Antigenic Modulation
Therapeutics
Protein-Tyrosine Kinases
Membrane Proteins
Phosphotransferases
Phenotype
obinutuzumab
Rituximab
Neoplasms

ASJC Scopus subject areas

  • Immunology

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Role for ZAP-70 signaling in the differential effector functions of rituximab and obinutuzumab (GA101) in chronic lymphocytic leukemia B cells. / Skopelja-Gardner, Sladjana; Jones, Jonathan D.; Hamilton, B. Jonell; Danilov, Alexey; Rigby, William F.C.

In: Journal of Immunology, Vol. 199, No. 4, 15.08.2017, p. 1275-1282.

Research output: Contribution to journalArticle

Skopelja-Gardner, Sladjana ; Jones, Jonathan D. ; Hamilton, B. Jonell ; Danilov, Alexey ; Rigby, William F.C. / Role for ZAP-70 signaling in the differential effector functions of rituximab and obinutuzumab (GA101) in chronic lymphocytic leukemia B cells. In: Journal of Immunology. 2017 ; Vol. 199, No. 4. pp. 1275-1282.
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