期刊
CANCER LETTERS
卷 381, 期 2, 页码 323-330出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.08.003
关键词
SNAP-tag technology; Auristatin; EGFR; HER2; ADC
类别
资金
- RWTH Aachen University scholarship of Young Researchers at RWTH Aachen University (RFwN)
- Federal Ministry of Education and Research (Bundesministerium fur Bildung and Forschung, BMBF) [03V0348]
Antibody-drug conjugates (ADCs) combine the potency of cytotoxic drugs with the specificity of monoclonal antibodies (mAbs). Most ADCs are currently generated by the nonspecific conjugation of drug linker reagents to certain amino acid residues in mAbs, resulting in a heterogeneous product. To overcome this limitation and prepare ADCs with a defined stoichiometry, we use SNAP-tag technology as an alternative conjugation strategy. This allows the site-specific conjugation of O(6)-benzylguanine (BG)-modified small molecules to SNAP-tag fusion proteins. To demonstrate the suitability of this system for the preparation of novel recombinant ADCs, here we conjugated SNAP-tagged single chain antibody fragments (scFvs) to a BG-modified version of auristatin F (AURIF). We used two scFv-SNAP fusion proteins targeting members of the epidermal growth factor receptor (EGFR) family that are frequently overexpressed in breast cancer. The conjugation of BG-AURIF to EGFR-specific 425(scFv)-SNAP and HER2-specific alpha HER2(scFv)-SNAP resulted in two potent recombinant ADCs that specifically killed breast cancer cell lines by inducing apoptosis when applied at nanomolar concentrations. These data confirm that SNAP tag technology is a promising tool for the generation of novel recombinant ADCs. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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