Oncolytic adenovirus with hyaluronidase activity that evades neutralizing antibodies: VCN-11.

Autor: Mato-Berciano A; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Morgado S; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Maliandi MV; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Farrera-Sal M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain; Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Virotherapy and Immunotherapy Group, ProCURE Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain., Gimenez-Alejandre M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Ginestà MM; Hereditary Cancer Program, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Hereditary Cancer Program, Catalan Institute of Oncology- ICO, L'Hospitalet de Llobregat, Spain; CIBERONC, Barcelona, Spain., Moreno R; Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Virotherapy and Immunotherapy Group, ProCURE Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain., Torres-Manjon S; Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Virotherapy and Immunotherapy Group, ProCURE Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain., Moreno P; Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain., Arias-Badia M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Rojas LA; Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Virotherapy and Immunotherapy Group, ProCURE Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain., Capellà G; Hereditary Cancer Program, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Hereditary Cancer Program, Catalan Institute of Oncology- ICO, L'Hospitalet de Llobregat, Spain; CIBERONC, Barcelona, Spain., Alemany R; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain; Cancer Virotherapy Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Virotherapy and Immunotherapy Group, ProCURE Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain., Cascallo M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain., Bazan-Peregrino M; VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain. Electronic address: mbazan@vcnbiosciences.com.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2021 Apr 10; Vol. 332, pp. 517-528. Date of Electronic Publication: 2021 Mar 03.
DOI: 10.1016/j.jconrel.2021.02.035
Abstrakt: Tumor targeting and intratumoral virus spreading are key features for successful oncolytic virotherapy. VCN-11 is a novel oncolytic adenovirus, genetically modified to express hyaluronidase (PH20) and display an albumin-binding domain (ABD) on the hexon. ABD allows the virus to self-coat with albumin when entering the bloodstream and evade neutralizing antibodies (NAbs). Here, we validate VCN-11 mechanism of action and characterize its toxicity. VCN-11 replication, hyaluronidase activity and binding to human albumin to evade NAbs was evaluated. Toxicity and efficacy of VCN-11 were assessed in mice and hamsters. Tumor targeting, and antitumor activity was analyzed in the presence of NAbs in several tumor models. VCN-11 induced 450 times more cytotoxicity in tumor cells than in normal cells. VCN-11 hyaluronidase production was confirmed by measuring PH20 activity in vitro and in virus-infected tumor areas in vivo. VCN-11 evaded NAbs from different sources and tumor targeting was demonstrated in the presence of high levels of NAbs in vivo, whereas the control virus without ABD was neutralized. VCN-11 showed a low toxicity profile in athymic nude mice and Syrian hamsters, allowing treatments with high doses and fractionated administrations without major toxicities (up to 1.2x10 11 vp/mouse and 7.5x10 11 vp/hamster). Fractionated intravenous administrations improved circulation kinetics and tumor targeting. VCN-11 antitumor efficacy was demonstrated in the presence of NAbs against Ad5 and itself. Oncolytic adenovirus VCN-11 disrupts tumor matrix and displays antitumor effects even in the presence of NAbs. These features make VCN-11 a safe promising candidate to test re-administration in clinical trials.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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