Abstract
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.
Highlights
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent childhood malignancy
Aggregates and fragment crystallizable (Fc) homodimers were removed by size exclusion chromatography, resulting in a homogenous protein preparation with a single protein peak with a higher molecular mass compared to CD19IgG1, indicating the insertion of the TRAIL unit (Figure 1B)
SDS-PAGE under reducing conditions followed by Coomassie blue staining of purified CD19-TRAIL revealed three single bands according to the predicted molecular masses of the three different antibodychains (LC = 25 kDa; HC = 50 kDa; HC + TRAIL = 112 kDa) (Figure 1C)
Summary
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent childhood malignancy. An attractive therapeutic target in BCP-ALL is the pan B-lymphocyte antigen CD19, a type I membrane protein of the immunoglobin superfamily that is expressed by the majority of B-lineage lymphoid malignancies [7,8,9,10]. To this end, targeting CD19 with novel immunotherapeutic approaches, such as the (CD3 × CD19) bispecific T-cell engager molecule (BiTE) blinatumomab or chimeric antigen receptor (CAR) T-cells, have entered routine clinical care in specific situations [11,12,13]. The DE-modified antibody tafasitamab is currently being tested in BCP-ALL patients (ClinicalTrials.gov identifier NCT01685021)
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