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Therapy

A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells

Leukemia volume 21, pages 1405–1412 (2007)Cite this article

Abstract

CD19 is a B-lineage-specific transmembrane signaling protein participating in the control of proliferation and differentiation. It is present at high surface density on chronic B-lymphocytic leukemia (B-CLL) cells and cells of other B-cell malignancies, and is a prime target for therapy with antibody-derived agents. Many attempts have been made to target malignant cells via CD19, but to date none of these agents have received drug approval. Here we report the design of a monovalent immunotoxin consisting of a CD19-specific single-chain Fv antibody fragment fused to a derivative of Pseudomonas Exotoxin A. This fusion protein induced efficient antigen-restricted apoptosis of several human leukemia- and lymphoma-derived cell lines including Nalm-6, which it eliminated at an effective concentration (EC50) of 2.5 nM. The agent displayed synergistic toxicity when used in combination with valproic acid and cyclosporin A in cell-culture assays. It induced apoptosis of primary malignant cells in 12/12 samples from B-CLL patients, including patients responding poorly to fludarabine, and of cells from one pediatric acute lymphoblastic leukemia patient. In NOD/SCID mice transplanted with Nalm-6 cells, the toxin prevented engraftment and significantly prolonged survival of treated mice. Owing to its efficient antigen-restricted antileukemic activity, the agent deserves further development towards clinical testing.

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Acknowledgements

We thank Dr W Wels for the Pseudomonas ETA cDNA, and Dr Torsten Haferlach for determining the p53 status of the B-CLL patients. We also thank Th Lange for administrative assistance. This study was supported by research grant 2003.015.1 from the Wilhelm Sander Stiftung, Neustadt, Germany; Association of Supporters of the University Children's Hospital, Erlangen, Germany; Association ‘Kaminkehrer helfen krebskranken Kindern’, Untersiemau, Germany (to GHF); Beitlich Foundation, Tuebingen, Germany (to PL and GHF); Research Training Grant GK592 from the Deutsche Forschungsgemeinschaft; intramural funding from the University of Erlangen's ELAN program; stipends from the Sofie Wallner-Stiftung, Erlangen, Germany (to MS); Schickedanz KinderKrebs Stiftung, Fuerth, Germany (to JS).

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Authors and Affiliations

  1. Chair of Genetics, University of Erlangen-Nuremberg, Erwin-Rommel-Strasse 3, Erlangen, Germany

    M Schwemmlein, J Stieglmaier, C Kellner, D Saul & G H Fey

  2. Division of Stem Cell Transplantation and Immunotherapy, 2nd Medical Department, University of Kiel, Schittenhelmstrasse 12, Kiel, Germany

    M Peipp

  3. Medizinische Klinik Innenstadt, Klinik der Ludwig-Maximilians-Universitaet, Ziemssenstrasse 1, Munich, Germany

    F Oduncu & B Emmerich

  4. Division of Hematology, Medical Department 3, University of Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen, Germany

    B Stockmeyer

  5. Department of Pediatric Oncology, University Children's Hospital, University of Tuebingen, Hoppe-Seyler-Strasse 1, Tuebingen, Germany

    P Lang

  6. Department of Pediatric Oncology, University Children's Hospital, University of Erlangen-Nuremberg, Loschgestrasse 15, Erlangen, Germany

    J D Beck

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  1. M Schwemmlein
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Correspondence to G H Fey.

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Schwemmlein, M., Stieglmaier, J., Kellner, C. et al. A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells. Leukemia 21, 1405–1412 (2007). https://doi.org/10.1038/sj.leu.2404687

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