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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

Leukemia volume 28, pages 230–233 (2014)Cite this article

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The increasing number of biological prognostic factors described in chronic lymphocytic leukemia (CLL) supports the clinical heterogeneity of this disease. Among them, the deletion of the short arm of chromosome 17 (del17p), where the tumor suppressor gene TP53 is located, consistently appears as the most significant adverse prognostic factor in CLL.1 Its incidence represents 5–7% of patients at diagnosis and increases sharply, up to 40–50%, among patients refractory to fludarabine-based therapy. Del17p provides an important mechanism of chemorefractoriness that has been confirmed in prospective trials,2, 3 and its detection by fluorescent in situ hybridization (FISH) is now routinely included at diagnosis to guide the decisions about therapy.3 Current treatment approaches for these patients with poor clinical outcomes rely on agents acting independently of TP53, such as alemtuzumab and high doses of corticosteroids, lenalidomide and flavopiridol, and when possible, consolidation with allogeneic stem cell transplantation. Despite these aggressive alternative strategies, which are responsible for frequent serious side effects, this high-risk CLL population constitutes an unmet medical need. A growing number of novel compounds are currently available in CLL clinical trials, including new optimized anti-CD20 monoclonal antibodies (mAb), which have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity and/or antibody-dependent cellular cytotoxicity (ADCC). We previously described a novel chimeric anti-CD20 mAb, ublituximab, characterized by a low fucose content in its Fc region that improved the FcγRIIIA binding.4 Compared with rituximab, ublituximab induced a higher ADCC activity against Raji and CLL cells, and enhanced the percentage of natural killer (NK) cell-mediated degranulation in the presence of autologous CLL cells, particularly at lower concentrations.4, 5 Based on these results, an in vitro evaluation of the ublituximab-induced functional capacities of autologous NK cells from del17p CLL patients appeared to be particularly interesting. The aim of this study was to determine whether ublituximab could be considered an adapted treatment for this group of high-risk CLL patients.

The CLL patients (n=42) were diagnosed according to classical morphological and immunophenotypic criteria.6 They were untreated or received no treatment during 6 months before the study. In 14/42 patients (33%), del17p was detected by FISH analysis. The p53 pathway was further investigated in order to determine the functional status of p537 and the mutational status of the TP53 gene8 (Table 1). This study was conducted after approval by the Institutional Ethics Committee at Pitié-Salpêtrière Hospital (Paris, France). All patients gave their written informed consent. The ADCC and degranulation experiments were performed with fresh peripheral blood in the presence of ublituximab (LFB, Les Ulis, France) or rituximab (Roche Ltd, Basel, Switzerland) at various concentrations, as previously described.5

Table 1 p53 status of CLL patients with 17p deletion
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Acknowledgements

We thank V Leblond, Z Azgui and D Roos-Weil from the Hematology Department at Pitié-Salpêtrière Hospital (AP-HP, Paris, France) for the recruitment of the CLL patients. We thank the patients for providing the research samples used in this study. We thank C Blanc and B Hoareau from the Flow Cytometry Core CyPS (Pierre & Marie Curie University, Pitié-Salpêtrière Hospital, Paris, France) for the cell sorting; E Chapiro for cytogenetic data; and H Blons for molecular data. J Decocq, M Brissard, S Gueguen and P Bonnemye are acknowledged for their technical assistance. This study was supported in part by funds from the Laboratoire Français de Fractionnement et des Biotechnologies (LFB, Les Ulis, France), the association la Ligue contre le cancer (RS08/75-4) and INSERM. V Vieillard is a researcher from the Centre National de la Recherche Scientifique (CNRS) and the recipient of a Contrat Hospitalier de Recherche Translationnelle (CHRT).

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  1. V Vieillard and H Merle-Béral: These authors are senior co-authors.

Authors and Affiliations

  1. INSERM, UMR-S 945, Paris, France

    M Le Garff-Tavernier, L Herbi, S Choquet & V Vieillard

  2. AP-HP, Hôpital Pitié-Salpêtrière, Service d’Hématologie Biologique, Paris, France

    M Le Garff-Tavernier, F Nguyen-Khac, F Davi, A Grelier, M Boudjoghra, K Maloum & H Merle-Béral

  3. UPMC University Paris 06, Paris, France

    M Le Garff-Tavernier, L Herbi, F Nguyen-Khac, F Davi, S Choquet, V Vieillard & H Merle-Béral

  4. Laboratoire Français de Fractionnement et des Biotechnologies (LFB), Les Ulis, France

    L Herbi, C de Romeuf & R Urbain

  5. INSERM, UMR-S 872, Programmed cell death and physiopathology of tumor cells, team 19, Centre de Recherche des Cordeliers, Paris, France

    F Nguyen-Khac, F Davi & H Merle-Béral

  6. AP-HP, Hôpital Pitié-Salpêtrière, Service d’Hématologie Clinique, Paris, France

    S Choquet

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  1. M Le Garff-Tavernier
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Correspondence to M Le Garff-Tavernier.

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Competing interests

CdR and RU are employed by LFB. Ublituximab was designed, manufactured and provided by LFB Biotechnologies (Les Ulis, France). LFB Biotechnologies licensed the exclusive rights to develop and commercialize ublituximab to TG Therapeutics, Inc. (New York, NY USA) since January 2012. The remaining authors declare no conflict of interest.

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Le Garff-Tavernier, M., Herbi, L., de Romeuf, C. et al. Antibody-dependent cellular cytotoxicity of the optimized anti-CD20 monoclonal antibody ublituximab on chronic lymphocytic leukemia cells with the 17p deletion. Leukemia 28, 230–233 (2014). https://doi.org/10.1038/leu.2013.240

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