Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy

Sean H Lim, Andrew T Vaughan, Margaret Ashton-Key, Emily L Williams, Sandra V Dixon, H T Claude Chan, Stephen A Beers, Ruth R French, Kerry L Cox, Andrew J Davies, Kathleen N Potter, C Ian Mockridge, David G Oscier, Peter W M Johnson, Mark S Cragg, Martin J Glennie

Research output: Contribution to journalArticle (Academic Journal)peer-review

156 Citations (Scopus)

Abstract

The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.

Original languageEnglish
Pages (from-to)2530-40
Number of pages11
JournalBlood
Volume118
Issue number9
DOIs
Publication statusPublished - 1 Sep 2011

Keywords

  • Antibodies, Monoclonal, Murine-Derived
  • Antibodies, Neoplasm
  • Antigen-Antibody Complex
  • Antigens, CD20
  • Antigens, Neoplasm
  • Antineoplastic Combined Chemotherapy Protocols
  • B-Lymphocytes
  • Biomarkers
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Endocytosis
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphoma, B-Cell
  • Lymphoma, Mantle-Cell
  • Lysosomes
  • Macrophages
  • Phagocytosis
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptors, IgG
  • Recombinant Fusion Proteins
  • Rituximab
  • Transfection
  • Treatment Outcome

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