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Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAIL fusion protein

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Abstract

Although the treatment outcome of lymphoid malignancies has improved in recent years by the introduction of transplantation and antibody-based therapeutics, relapse remains a major problem. Therefore, new therapeutic options are urgently needed. One promising approach is the selective activation of apoptosis in tumor cells by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This study investigated the pro-apoptotic potential of a novel TRAIL fusion protein designated scFvCD19:sTRAIL, consisting of a CD19-specific single-chain Fv antibody fragment (scFv) fused to the soluble extracellular domain of TRAIL (sTRAIL). Potent apoptosis was induced by scFvCD19:sTRAIL in several CD19-positive tumor cell lines, whereas normal blood cells remained unaffected. In mixed culture experiments, selective binding of scFvCD19:sTRAIL to CD19-positive cells resulted in strong induction of apoptosis in CD19-negative bystander tumor cells. Simultaneous treatment of CD19-positive cell lines with scFvCD19:sTRAIL and valproic acid (VPA) or Cyclosporin A induced strongly synergistic apoptosis. Treatment of patient-derived acute B-lymphoblastic leukemia (B-ALL) and chronic B-lymphocytic leukemia (B-CLL) cells resulted in strong tumoricidal activity that was further enhanced by combination with VPA. In addition, scFvCD19:sTRAIL prevented engraftment of human Nalm-6 cells in xenotransplanted NOD/Scid mice. The pre-clinical data presented here warrant further investigation of scFvCD19:sTRAIL as a potential new therapeutic agent for CD19-positive B-lineage malignancies.

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Abbreviations

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

scFv:

Single-chain Fv antibody fragment

sTRAIL:

Soluble extracellular domain of TRAIL

CsA:

Cyclosporin A

B-ALL:

Acute B-lymphoblastic leukemia

B-CLL:

Chronic B-lymphocytic leukemia

MNC:

Peripheral blood mononuclear cells

EGFR:

Epidermal growth factor receptor

HDACi:

Histone deacetylase inhibitor

VPA:

Valproic acid

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Acknowledgments

We thank Domenica Saul, Kristin Mentz, Linda van Genne and Douwe Samplonius for excellent technical assistance and Thorsten Haferlach for determining the p53 deletion status of B-CLL samples. The personnel of the University of Erlangen animal research facility is kindly acknowledged for breeding and taking care of the mice and Teresa M. Allen for commenting on the manuscript.

Author information

Authors and Affiliations

  1. Chair of Genetics, University of Erlangen-Nuremberg, BTE-Building, Erwin-Rommel-Straße 3, 91058, Erlangen, Germany

    Julia Stieglmaier, Christian Kellner & Georg H. Fey

  2. Groningen University Institute for Drug Exploration, Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center, Groningen, The Netherlands

    Edwin Bremer, Bram ten Cate & Wijnand Helfrich

  3. Department of Molecular Tumorbiology and Tumorimmunology, University Medical Center, Cologne, Germany

    Tanja M. Liebig

  4. Section of Stem Cell Transplantation and Immunotherapy, University Medical Center University of Schleswig-Holstein, Kiel, Germany

    Matthias Peipp

  5. Clinical Research Group III, Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany

    Hendrik Schulze-Koops

  6. Department of Pediatric Oncology, University Children’s Hospital, Tuebingen, Germany

    Matthias Pfeiffer

  7. Department of Internal Medicine II, University Hospital, Tuebingen, Germany

    Hans-Jörg Bühring

  8. Department of Pediatrics III, University Children’s Hospital, Heidelberg, Germany

    Johann Greil

  9. Medizinische Klinik-Innenstadt, Klinikum der Universität München, München, Germany

    Fuat Oduncu & Bertold Emmerich

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  1. Julia Stieglmaier
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  2. Edwin Bremer
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  3. Christian Kellner
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  14. Wijnand Helfrich
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Corresponding authors

Correspondence to Julia Stieglmaier or Georg H. Fey.

Additional information

This work was supported by Schickedanz KinderKrebs Stiftung (JS) and grants from the Association “Kaminkehrer helfen krebskranken Kindern” (CK, GHF), the Association of supporters of the University of Erlangen Childrens’s Hospital (GHF) and the Dutch Cancer Society (RUG 2002-2668 and 2005-3358) (EB, BC, WH).

Julia Stieglmaier and Edwin Bremer contributed equally.

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Stieglmaier, J., Bremer, E., Kellner, C. et al. Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAIL fusion protein. Cancer Immunol Immunother 57, 233–246 (2008). https://doi.org/10.1007/s00262-007-0370-8

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