Issue 31, 2018

Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation

Abstract

We describe here two novel antibody-drug conjugates loaded with the HDAC inhibitor ST7612AA1 (IC50 equal to 0.07 μM on NCI-H460 cells), a thiol-based molecule with a moderate toxicity in vivo. Two payloads were prepared using cleavable and non-cleavable linkers. After anchoring to cetuximab through amide bond with lysines, the resulting HDAC inhibitor-antibody conjugates showed ability to recognize EGFR and efficient internalization in tumor cells. Both ADCs induced sensible increment of histones 3 and 4 and alpha-tubulin acetylation. Animal models of human solid tumors showed high anti-tumor efficacy of the conjugates without the toxicity generally observed with traditional ADCs delivering highly potent cytotoxic drugs. These compounds, the first ADCs charged with not highly cytotoxic warheads, are potentially suitable for epigenetic modulation, extending the ADC strategy to the targeted delivery of HDAC inhibitors with many possible therapeutic applications beyond cancer.

Graphical abstract: Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation

Supplementary files

Article information

Article type
Edge Article
Submitted
12 Dec 2017
Accepted
26 Jun 2018
First published
03 Jul 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 6490-6496

Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation

E. Cini, V. Faltoni, E. Petricci, M. Taddei, L. Salvini, G. Giannini, L. Vesci, F. M. Milazzo, A. M. Anastasi, G. Battistuzzi and R. De Santis, Chem. Sci., 2018, 9, 6490 DOI: 10.1039/C7SC05266A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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