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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)233-246
Number of pages14
JournalCancer Immunology Immunotherapy
Volume57
Issue number2
DOIs
Publication statusPublished - Feb-2008

Keywords

  • TRAIL
  • CD19
  • leukemia
  • antibody-derived therapeutics
  • apoptosis
  • CHRONIC LYMPHOCYTIC-LEUKEMIA
  • CYTOTOXIC LIGAND TRAIL
  • NON-HODGKINS-LYMPHOMA
  • CHAIN FV ANTIBODY
  • MONOCLONAL-ANTIBODY
  • IN-VIVO
  • MEDIATED APOPTOSIS
  • ANTITUMOR-ACTIVITY
  • FLOW-CYTOMETRY
  • VALPROIC ACID

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