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01-02-2008 | Original Article

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

Authors: Julia Stieglmaier, Edwin Bremer, Christian Kellner, Tanja M. Liebig, Bram ten Cate, Matthias Peipp, Hendrik Schulze-Koops, Matthias Pfeiffer, Hans-Jörg Bühring, Johann Greil, Fuat Oduncu, Bertold Emmerich, Georg H. Fey, Wijnand Helfrich

Published in: Cancer Immunology, Immunotherapy | Issue 2/2008

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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Title: Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAIL fusion protein
Authors: Julia Stieglmaier
Edwin Bremer
Christian Kellner
Tanja M. Liebig
Bram ten Cate
Matthias Peipp
Hendrik Schulze-Koops
Matthias Pfeiffer
Hans-Jörg Bühring
Johann Greil
Fuat Oduncu
Bertold Emmerich
Georg H. Fey
Wijnand Helfrich
Publication date: 01-02-2008
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 2/2008
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-007-0370-8

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