Engineering of CD19 Antibodies: A CD19-TRAIL Fusion Construct Specifically Induces Apoptosis in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Cells In Vivo

Journal of Clinical Medicine

Fotini Vogiatzi¹  Dorothee Winterberg¹  Lennart Lenk¹  Denis Martin Schewe¹  Katja Klausz²  Thomas Valerius²  Thies Rösner²  Matthias Peipp²  Maren Oßwald²  Carina Lynn Gehlert²  Christian Kellner³  Anna Trauzold⁴  Fabian-Simon Frielitz⁵ 

[1] ALL-BFM Study Group, Department of Pediatrics I, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Arnold-Heller Str. 3, Haus C, 24105 Kiel, Germany;Department of Medicine II Christian-Albrechts, Division of Stem Cell Transplantation and Immunotherapy, Campus Kiel, University Kiel and University Hospital Schleswig-Holstein, 24105 Kiel, Germany;Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, LMU University Hospital Munich, 81377 Munich, Germany;Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, 24104 Kiel, Germany;Institute for Social Medicine and Epidemiology, University of Lübeck, 23538 Lübeck, Germany;

关键词: BCP-ALL;    leukemia;    TRAIL;    antibody;    Fc-engineering;    xenograft;   

DOI  :  10.3390/jcm10122634

来源: DOAJ

【 摘 要 】

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent malignancy in children and also occurs in adulthood. Despite high cure rates, BCP-ALL chemotherapy can be highly toxic. This type of toxicity can most likely be reduced by antibody-based immunotherapy targeting the CD19 antigen which is commonly expressed on BCP-ALL cells. In this study, we generated a novel Fc-engineered CD19-targeting IgG1 antibody fused to a single chain tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) domain (CD19-TRAIL). As TRAIL induces apoptosis in tumor cells but not in healthy cells, we hypothesized that CD19-TRAIL would show efficient killing of BCP-ALL cells. CD19-TRAIL showed selective binding capacity and pronounced apoptosis induction in CD19-positive (CD19⁺) BCP-ALL cell lines in vitro and in vivo. Additionally, CD19-TRAIL significantly prolonged survival of mice transplanted with BCP-ALL patient-derived xenograft (PDX) cells of different cytogenetic backgrounds. Moreover, simultaneous treatment with CD19-TRAIL and Venetoclax (VTX), an inhibitor of the anti-apoptotic protein BCL-2, promoted synergistic apoptosis induction in CD19⁺ BCP-ALL cells in vitro and prolonged survival of NSG-mice bearing the BCP-ALL cell line REH. Therefore, IgG1-based CD19-TRAIL fusion proteins represent a new potential immunotherapeutic agent against BCP-ALL.

【 授权许可】

Unknown