EV20‑sss‑vc/MMAF, an HER‑3 targeting antibody‑drug conjugate displays antitumor activity in liver cancer

D'Agostino,Daniela; Gentile,Roberta; Ponziani,Sara; Di Vittorio,Giulia; Dituri,Francesco; Giannelli,Gianluigi; Rossi,Cosmo; Marzullo,Liberato; Giansanti,Francesco; De Laurenzi,Vincenzo; Iacobelli,Stefano; Ippoliti,Rodolfo; Capone,Emily; Sala,Gianluca

doi:10.3892/or.2020.7893

EV20‑sss‑vc/MMAF, an HER‑3 targeting antibody‑drug conjugate displays antitumor activity in liver cancer

Authors:
- Daniela D'Agostino
- Roberta Gentile
- Sara Ponziani
- Giulia Di Vittorio
- Francesco Dituri
- Gianluigi Giannelli
- Cosmo Rossi
- Liberato Marzullo
- Francesco Giansanti
- Vincenzo De Laurenzi
- Stefano Iacobelli
- Rodolfo Ippoliti
- Emily Capone
- Gianluca Sala
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Affiliations: Department of Medical, Oral and Biotechnological Sciences, University of Chieti‑Pescara ‘G. D'Annunzio’, I‑66100 Chieti, Italy, Department of Life, Health and Environmental Sciences, University of L'Aquila, I‑67100 Coppito, Italy, National Institute of Gastroenterology ‘S. de Bellis’ Research Hospital, Castellana Grotte, I‑70013 Bari, Italy, Center for Advanced Studies and Technology (CAST), I‑66100 Chieti, Italy, Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, I‑84081 Baronissi (SA), Italy, MediaPharma SRL, I‑66100 Chieti, Italy
Published online on: December 9, 2020 https://doi.org/10.3892/or.2020.7893
Pages: 776-785

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Abstract

Liver cancer (LC) is an aggressive disease with a markedly poor prognosis. Therapeutic options are limited, and, until recently the only FDA‑approved agent for first‑line treatment of patients with LC was the multi‑kinase inhibitor sorafenib, which exhibits limited activity and an increased overall survival (OS) of only 3 months over placebo. Therefore, the development of alternative therapeutic molecules for the treatment of LC is an urgent medical need. Antibody‑drug conjugates (ADCs) are an emerging class of novel anticancer agents, which have been developed recently for the treatment of malignant conditions, including LC, and are being studied in preclinical and clinical settings. Our group has recently generated an ADC [EV20/monomethyl auristatin F (MMAF)] by coupling the HER3 targeting antibody (EV20) to MMAF via a non‑cleavable maleimidocaproyl linker. This ADC was revealed to possess potent therapeutic activity in melanoma and breast carcinoma. In the present study, using western blot and flow cytometric analysis, it was reported that HER‑3 receptor was highly expressed in LC and activated by its ligand NRG‑1β in a panel of LC cell lines, thus indicating that this receptor may serve as a suitable target for ADC therapy. A novel ADC [EV20‑sss‑valine‑citrulline (vc)/MMAF] was generated, in which the cytotoxic payload MMAF was site‑specifically coupled to an engineered variant of EV20 via a vc cleavable linker. Cytotoxicity assays were performed to investigate in vitro antitumor activity of EV20‑sss‑vc/MMAF and it was compared to EV20/MMAF, which revealed only modest activity in LC.EV20‑sss‑vc/MMAF exhibited a significant cell killing activity in several LC cell lines. Additionally, in vivo xenograft experiments revealed that EV20‑sss‑vc/MMAF inhibited growth of LC tumors. The present data indicated that EV20‑sss‑vc/MMAF is a worthy candidate for the treatment of HER‑3 positive LC.

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