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Molecular targets for therapy

An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia

Leukemia volume 32, pages 510–519 (2018)Cite this article

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Abstract

The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 β2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-α-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML.

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Acknowledgements

This study is dedicated to the memory of Professor Thomas Büchner. We thank Irina Arnhold, Heike Hintelmann, Verena Mantke, Petra Fischer and Cordula Westermann for their technical assistance. This work was supported by the fund ‘Innovative Medical Research’ of the University of Münster Medical School (Grants SC211008 (to C Schliemann and SR), SC111411 (to C Schliemann) and SC221410 (to LA and C Schliemann)). WEB and GL are supported by the Deutsche Forschungsgemeinschaft (DFG EXC 1003, Cluster of excellence ‘Cells in Motion’).

Author contributions

LA, SR, CR and C Schliemann designed the project, performed the majority of the experiments, analyzed results and wrote the manuscript; ASB and CR performed the proteomic analysis; C Schwöppe, TK, LHS, TS, CB and J-HM contributed to immunohistochemistry experiments; ACM provided the BNML cell line; SR, DK and LA performed the perfusion experiments; WEB, WH and EW provided clinical data and human AML BM specimens; FN and JH performed confocal microscopy analyses; CM-T, GL, RMM, DN and WEB provided discussion and reviewed the manuscript.

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Author notes

  1. C Roesli & C Schliemann

    Present address: 12Current address: Novartis Pharma AG, Basel, Switzerland.,

  2. C Roesli: These two authors contributed equally to this work and share senior authorship.

Authors and Affiliations

  1. Department of Medicine A, University Hospital Münster, Münster, Germany

    L Angenendt, C Schwöppe, T Kessler, L H Schmidt, T Sauer, C Brand, J-H Mikesch, G Lenz, R M Mesters, W E Berdel & C Schliemann

  2. Department of Medicine D, University Hospital Münster, Münster, Germany

    S Reuter & D Kentrup

  3. HI-STEM gGmbH and German Cancer Research Center, Heidelberg, Germany

    A S Benk & C Roesli

  4. Fluorescence Microscopy Facility Münster, Institute of Medical Physics and Biophysics, Center for Nanotechnology, University of Münster, Münster, Germany

    F Neumann & J Hüve

  5. Department of Hematology, University Hospital Utrecht, Utrecht, The Netherlands

    A C Martens

  6. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    T Sauer

  7. Translational Oncology, University Hospital Münster, Münster, Germany

    G Lenz

  8. Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany

    G Lenz

  9. Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    C Müller-Tidow

  10. Gerhard Domagk-Institute for Pathology, University Hospital Münster, Münster, Germany

    W Hartmann & E Wardelmann

  11. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland

    D Neri

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  1. L Angenendt
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Correspondence to C Schliemann.

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Angenendt, L., Reuter, S., Kentrup, D. et al. An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia. Leukemia 32, 510–519 (2018). https://doi.org/10.1038/leu.2017.208

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