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.

A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo / A. Dal Corso, R. Gebleux, P. Murer, A. Soltermann, D. Neri. - In: JOURNAL OF CONTROLLED RELEASE. - ISSN 0168-3659. - 264(2017 Oct 28), pp. 211-218. [10.1016/j.jconrel.2017.08.040]

A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo

A. Dal Corso
Primo
;
2017

Abstract

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.
Anthracyclines; Antibodies; Antibody-drug conjugates; Protein engineering; Vascular targeting; Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Female; Humans; Immunoconjugates; Immunoglobulin G; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Tenascin; Tumor Burden
Settore CHIM/06 - Chimica Organica
28-ott-2017
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/659065
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