TY - JOUR
T1 - EV20-sss-vc/MMAF, an HER-3 targeting antibody-drug conjugate displays antitumor activity in liver cancer
AU - D'Agostino, Daniela
AU - Gentile, Roberta
AU - Ponziani, Sara
AU - Vittorio, Giulia D.I.
AU - Dituri, Francesco
AU - Giannelli, Gianluigi
AU - Rossi, Cosmo
AU - Marzullo, Liberato
AU - Giansanti, Francesco
AU - de Laurenzi, Vincenzo
AU - Iacobelli, Stefano
AU - Ippoliti, Rodolfo
AU - Capone, Emily
AU - Sala, Gianluca
N1 - Funding Information:
This project was funded by Fondazione AIRC (Italian Association for Cancer Research) (GS ID:18467; VDL ID: 20043). EC is the recipient of an AIRC fellowship. The PhD program of SP is funded by the Italian Ministry of Instruction, University, and Research under the national project PON ricerca e innovazione 2014-2020.
Publisher Copyright:
© 2021 Spandidos Publications. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Antibody-drug conjugates
KW - HER-3
KW - Liver cancer
KW - Monomethyl auristatin F
KW - Targeted therapy
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UR - http://www.scopus.com/inward/citedby.url?scp=85098635688&partnerID=8YFLogxK
U2 - 10.3892/or.2020.7893
DO - 10.3892/or.2020.7893
M3 - Article
AN - SCOPUS:85098635688
VL - 45
SP - 776
EP - 785
JO - Oncology Reports
JF - Oncology Reports
SN - 1021-335X
IS - 2
ER -