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Chronic Lymphocytic Leukemia

The CD37-targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

Leukemia volume 28, pages 1501–1510 (2014)Cite this article

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Abstract

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody–drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.

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Acknowledgements

This work was supported by the the National Cancer Institute (7P01CA095426-09 and 1R01CA159296-01A1), Leukemia and Lymphoma Society (LLS 7080-06 / 7004-11), Michael and Judy Thomas, Harry Mangurian Foundation and the D Warren Brown Foundation. KAB received additional support from a Pelotonia fellowship.

Author contributions

KAB planned the research, performed experiments, analyzed data and wrote the manuscript; FWF generated the hCD37-Tg and identified founder lines; MRS and WHT maintained the mouse colonies and contributed to animal studies; CC helped perform some experiments; XM performed statistical analysis of data; JD provided vital reagents; CMC provided the Eμ-TCL1 mouse; JMF, LAA, JAJ and KJM provided invaluable clinical samples; GL contributed reagents, classified clinical cases, reviewed and approved the final manuscript draft; and JCB and NM planned and supervised the research, obtained funding and reagents for the research, analyzed data, reviewed manuscript drafts and approved the final version of the manuscript.

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Author notes

  1. J C Byrd and N Muthusamy: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA

    K A Beckwith

  2. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    K A Beckwith, F W Frissora, M R Stefanovski, W H Towns, C Cheney, J M Flynn, L A Andritsos, J A Jones, K J Maddocks, J C Byrd & N Muthusamy

  3. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Mo

  4. ImmunoGen, Inc., Waltham, MA, USA

    J Deckert

  5. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA

    C M Croce & N Muthusamy

  6. Department of Pathology, The Ohio State University, Columbus, OH, USA

    G Lozanski

  7. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    J C Byrd

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  1. K A Beckwith
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Correspondence to N Muthusamy.

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Competing interests

JD is an employee of ImmunoGen Inc. All the remaining authors declare no conflict of interest.

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Beckwith, K., Frissora, F., Stefanovski, M. et al. The CD37-targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. Leukemia 28, 1501–1510 (2014). https://doi.org/10.1038/leu.2014.32

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