Journal
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
Volume 149, Issue 13, Pages 12203-12225Publisher
SPRINGER
DOI: 10.1007/s00432-023-05031-3
Keywords
Triple-negative breast cancer (TNBC); Chondroitin sulfate proteoglycan 4 (CSPG4); Click chemistry for single-chain antibody fragment (scFv); Recombinant antibody-drug conjugate (ADC); SNAP-tag based fusion protein; Benzylguanine (BG)-modified auristatin F (AURIF)
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This study engineered a CSPG4-targeting ADC using SNAP-tag technology, which demonstrated selective delivery of drugs to TNBC cells through in vitro experiments, and showed its cell-killing ability on target cells.
PurposeTriple-negative breast cancer (TNBC) is phenotypic of breast tumors lacking expression of the estrogen receptor (ER), the progesterone receptor (PgR), and the human epidermal growth factor receptor 2 (HER2). The paucity of well-defined molecular targets in TNBC, coupled with the increasing burden of breast cancer-related mortality, emphasizes the need to develop targeted diagnostics and therapeutics. While antibody-drug conjugates (ADCs) have emerged as revolutionary tools in the selective delivery of drugs to malignant cells, their widespread clinical use has been hampered by traditional strategies which often give rise to heterogeneous mixtures of ADC products.MethodsUtilizing SNAP-tag technology as a cutting-edge site-specific conjugation method, a chondroitin sulfate proteoglycan 4 (CSPG4)-targeting ADC was engineered, encompassing a single-chain antibody fragment (scFv) conjugated to auristatin F (AURIF) via a click chemistry strategy.ResultsAfter showcasing the self-labeling potential of the SNAP-tag component, surface binding and internalization of the fluorescently labeled product were demonstrated on CSPG4-positive TNBC cell lines through confocal microscopy and flow cytometry. The cell-killing ability of the novel AURIF-based recombinant ADC was illustrated by the induction of a 50% reduction in cell viability at nanomolar to micromolar concentrations on target cell lines.ConclusionThis research underscores the applicability of SNAP-tag in the unambiguous generation of homogeneous and pharmaceutically relevant immunoconjugates that could potentially be instrumental in the management of a daunting disease like TNBC.
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