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Multiple Myeloma, Gammopathies

Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab

Leukemia volume 29, pages 2039–2049 (2015)Cite this article

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Abstract

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

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Author information

Authors and Affiliations

  1. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

    I S Nijhof, R W J Groen, H M Lokhorst, B van Kessel, R de Jong-Korlaar, W A Noort, A C M Martens, T Mutis & N W C J van de Donk

  2. Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    I S Nijhof & T Mutis

  3. Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    I S Nijhof & H M Lokhorst

  4. Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands

    R W J Groen & A C M Martens

  5. Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    A C Bloem & J van Velzen

  6. Xpand Biotechnology BV, Bilthoven, The Netherlands

    H Yuan

  7. Department of Internal Medicine, Meander Medisch Centrum, Amersfoort, The Netherlands

    S K Klein

  8. Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA, USA

    P Doshi & K Sasser

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  1. I S Nijhof
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Corresponding author

Correspondence to N W C J van de Donk.

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Competing interests

KS and PD are employees of Janssen Pharmaceuticals. HML,TM, ACM and NWCJvdD received research support from Janssen Pharmaceuticals. All other authors declared no conflicts of interest.

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Author Contributions

IN, RWJG, JvV, RdJ-K, WAN and BvK executed the experiments, analyzed and interpreted the results. KS and PD provided daratumumab. HY developed and provided the scaffolds for the mouse experiments. HML, SK and NWCJvdD provided patient materials. TM, ACMM, HML and NWCJvdD designed the study and interpreted the results. IN and NWCJvdD wrote the first draft of the manuscript. All authors helped critically review the manuscript and checked the final version of it.

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Nijhof, I., Groen, R., Lokhorst, H. et al. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia 29, 2039–2049 (2015). https://doi.org/10.1038/leu.2015.123

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