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Immunotherapy

Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858

Leukemia volume 31, pages 2172–2180 (2017)Cite this article

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Abstract

We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33+HLA-DR−Lin−, has a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it has an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity, which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU-GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and γH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients.

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Acknowledgements

This work was supported by grants from the Taub foundation to Alan List, DOD BM140087 to Sheng Wei and K01CA187020 to Erika A Eksioglu. This work has been supported by the Flow cytometry Core Facility and the Microscopy Core Facility of the H Lee Moffitt Cancer Center, a comprehensive cancer center designated by the NCI (Cancer Center support grant P30CA076292).

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Author notes

  1. E A Eksioglu and X Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    E A Eksioglu, X Chen, M Wei, A Burnette, P Cheng, J Lancet, R Komrokji, J Djeu, A List & S Wei

  2. Boehringer Ingelheim RCV, Vienna, Austria

    K-H Heider

  3. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany

    B Rueter

  4. Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    K L McGraw

  5. Department of Malignant Hematology, H. Lee Moffitt Cancer Center and the Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA

    A A Basiorka

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  1. E A Eksioglu
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Correspondence to S Wei.

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Karl-Heinz Heider and Bjoern Reuter are employees of Boehringer Ingelheim.

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Eksioglu, E., Chen, X., Heider, KH. et al. Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858. Leukemia 31, 2172–2180 (2017). https://doi.org/10.1038/leu.2017.21

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