title: Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy.
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.
authors.affiliation: Tenovus Research Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton, UK.
authors.forename: Sean H
authors.initials: SH
authors.lastname: Lim
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Vaughan
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashton-Key
authors.forename: Emily L
authors.initials: EL
authors.lastname: Williams
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Dixon
authors.forename: H T Claude
authors.initials: HT
authors.lastname: Chan
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Beers
authors.forename: Ruth R
authors.initials: RR
authors.lastname: French
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Cox
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davies
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.forename: C Ian
authors.initials: CI
authors.lastname: Mockridge
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Johnson
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015415:Biomarkers; D045744:Cell Line, Tumor / Q000276:immunology / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D010587:Phagocytosis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000069283:Rituximab; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D000936:Antigen-Antibody Complex; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D015415:Biomarkers; C499173:FCGR2B protein, human; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D000069283:Rituximab