Antibody-dependent cellular cytotoxicity of the optimized anti-CD20 monoclonal antibody ublituximab on chronic lymphocytic leukemia cells with the 17p deletion

Garff‐Tavernier, Magali Le; Herbi, Linda; Romeuf, Christophe de; Nguyen‐Khac, Florence; Davi, F; Grelier, Aurore; Boudjoghra, Myriam; Maloum, Karim; Choquet, Sylvain; Urbain, Rémi; Vieillard, Vincent; Merle-Béral, Hélène

doi:10.1038/leu.2013.240

Cited by 53 publications

(37 citation statements)

References 16 publications

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“…Additional support for the findings of the ADCC assays was provided from the degranulation capacities of NK cells, which are highlighted by CD107a cell-surface expression by flow cytometry in the presence of these two anti-CD20 mAbs, as described. 6 Indeed, regardless of the concentration, ublituximab triggered better effector functions to clear WM cells in patients with a circulating B-cell clone compared with rituximab ( Figure 2C), which is consistent with findings in CLL patients.…”

supporting

confidence: 79%

“…Direct cytotoxicity was assessed on purified NK cells before or after IL-2 stimulation (1,000 U/ml, Proleukin, Chiron) for 48 h with a standard 51 Cr-release assay against the K562 cell line, at a different effector/target (E:T) cell ratio. 5,6 A slight but non-significant decrease in the cytotoxicity mediated by non-or IL2-activated NK cells was observed in the group of WM patients with a circulating B-cell clone compared with two other groups (Figure 2A). Of note, granzyme-B and perforin were expressed at equivalent levels in all samples (Online Supplementary Appendix).…”

mentioning

confidence: 97%

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The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenstrom macroglobulinemia

et al. 2014

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confidence: 79%

mentioning

confidence: 97%

The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenstrom macroglobulinemia

et al. 2014

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“…and immune effector cell effects (Table 1) [10][11][12][13][14]. Most anti-CD20 mAbs investigated are of type I (rituximab, ofatumumab, ublituximab, veltuzumab, ocaratuzumab; Table 2) [15][16][17][18][19], and binding to CD20 on lymphoma cells induces rapid translocation of anti-CD20 mAb-CD20 antigen complexes into lipid rafts (Fig. 1A) [13].…”

Section: Introductionmentioning

confidence: 99%

Obinutuzumab in hematologic malignancies: Lessons learned to date

Illidge

Klein

Sehn

et al. 2015

Cancer Treatment Reviews

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The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.

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“…Ublituximab (TG-1101)-A chimeric anti-CD20 mAb with low fucose content in the Fc region, and increased ADCC as compared to rituximab [139]. In a phase I trial it produced an ORR of 45% with manageable toxicity in relapsed or refractory patients with CLL (n 5 11) [140].…”

Section: Selinexor (Previously Kpt-330)mentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

134

108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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Antibody-dependent cellular cytotoxicity of the optimized anti-CD20 monoclonal antibody ublituximab on chronic lymphocytic leukemia cells with the 17p deletion

Cited by 53 publications

References 16 publications

The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenstrom macroglobulinemia

The optimized anti-CD20 monoclonal antibody ublituximab bypasses natural killer phenotypic features in Waldenstrom macroglobulinemia

Obinutuzumab in hematologic malignancies: Lessons learned to date

Chronic lymphocytic leukemia (CLL)—Then and now

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