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Acute Leukemias

Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system

Leukemia volume 28, pages 59–69 (2014)Cite this article

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Abstract

Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.

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Acknowledgements

We thank Livia Schulze, Kristin Heidel, Barbara Uteß and Christine Gräfe for their excellent technical assistance; Professor Dr Dirk Lindemann for providing us with the lentiviral vector system; and Professor Dr Christian Thiede for providing the CD33+ cell lines MOLM-13, MV4-11 and OCI-AML3. This study was supported by a grant of the Medical faculty of the Technical University Dresden to Marc Cartellieri, a seed grant by the Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, and the José Carreras Stiftung to Michael Bachmann.

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  1. C Arndt and A Feldmann: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, Medical Faculty ‘Carl Gustav Carus’, Technical University Dresden, Dresden, Germany

    C Arndt, A Feldmann, M Cartellieri, E-M Ewen, S Koristka, I Michalk, S Stamova, N Berndt, A Gocht, M Schmitz & M Bachmann

  2. Department of Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany

    A Feldmann & M Bachmann

  3. Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, Technical University Dresden, Dresden, Germany

    M von Bonin, M Bornhäuser & G Ehninger

  4. Center for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, Technical University Dresden, Dresden, Germany

    M Schmitz & M Bachmann

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  1. C Arndt
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Corresponding author

Correspondence to M Bachmann.

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Competing interests

MB, SS and GE have filed provisional patent application related to the antibodies directed to CD33 and La.

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Arndt, C., Feldmann, A., von Bonin, M. et al. Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system. Leukemia 28, 59–69 (2014). https://doi.org/10.1038/leu.2013.243

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