期刊
JOURNAL OF CLINICAL MEDICINE
卷 10, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/jcm10122634
关键词
BCP-ALL; leukemia; TRAIL; antibody; Fc-engineering; xenograft; CD19
资金
- Deutsche Jose Carreras Leukamie Stiftung [DJCLS 17R/2017, DJCLS 13R/2020]
- Deutsche Krebshilfe e.V [70113524]
- Wilhelm Sander Stiftung [2019.119.1, 2016.110.1]
- Deutsche Krebshilfe e. V.
BCP-ALL is a common malignancy in children with high cure rates but toxic chemotherapy. A novel CD19-TRAIL antibody showed efficient killing of BCP-ALL cells and prolonged survival of mice, suggesting its potential as an immunotherapeutic agent against BCP-ALL.
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.
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