期刊
JOURNAL OF CONTROLLED RELEASE
卷 264, 期 -, 页码 211-218出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.08.040
关键词
Antibodies; Protein engineering; Vascular targeting; Antibody-drug conjugates; Anthracyclines
资金
- ETH Zurich
- Swiss National Science Foundation [310030B_163479/1, SINERGIA CRSII2_160699/1]
- ERC Advanced Grant [670603]
- Kommission fur Technologie und Innovation [17072.1]
- Bovena Foundation
- Maiores Foundation
- European Research Council (ERC) [670603] Funding Source: European Research Council (ERC)
Antibody-drug conjugates are generally believed to crucially rely on internalization into cancer cells for therapeutic activity. Here, we show that a non-internalizing antibody-drug conjugate, based on the F16 antibody specific to the alternatively spliced A1 domain of tenascin-C, mediates a potent therapeutic activity when equipped with the anthracycline PNU159682. The peptide linker, connecting the F16 antibody in IgG format at a specific cysteine residue to the drug, was stable in serum but could be efficiently cleaved in the subendothelial extracellular matrix by proteases released by the dying tumor cells. The results indicate that there may be a broader potential applicability of non-internalizing antibody-drug conjugates for cancer therapy than what had previously been assumed.
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