Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAIL fusion protein.
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.
Chair of Genetics, University of Erlangen-Nuremberg, BTE-Building, Erwin-Rommel-Strasse 3, 91058 Erlangen, Germany. jstiegl@biologie.uni-erlangen.de
Julia
J
Stieglmaier
Edwin
E
Bremer
Christian
C
Kellner
Tanja M
TM
Liebig
Bram
B
ten Cate
Matthias
M
Peipp
Hendrik
H
Schulze-Koops
Matthias
M
Pfeiffer
Hans-Jörg
HJ
Bühring
Johann
J
Greil
Fuat
F
Oduncu
Bertold
B
Emmerich
Georg H
GH
Fey
Wijnand
W
Helfrich
D000818:Animals; D018941:Antigens, CD19; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016572:Cyclosporine / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014635:Valproic Acid / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014635:Valproic Acid; D016572:Cyclosporine