Oncolytic adenovirus with hyaluronidase activity that evades neutralizing antibodies: VCN-11
| Autor: | Marcel Arias-Badia, Mireia M. Ginestà, Silvia Torres-Manjon, Sara Morgado, Martí Farrera-Sal, Ana Mato-Berciano, Marta Gimenez-Alejandre, Maria Victoria Maliandi, Luis A. Rojas, Paz Moreno, Manel Cascallo, Miriam Bazan-Peregrino, Ramon Alemany, Rafael Moreno, Gabriel Capellá |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Oncolytic adenovirus
Pharmaceutical Science Hamster Hyaluronoglucosaminidase Mice Nude 02 engineering and technology Virus Replication Virus Adenoviridae 03 medical and health sciences Mice In vivo Cell Line Tumor Cricetinae Animals Cytotoxicity 030304 developmental biology Oncolytic Virotherapy 0303 health sciences biology Chemistry 021001 nanoscience & nanotechnology Antibodies Neutralizing Xenograft Model Antitumor Assays In vitro Oncolytic virus Oncolytic Viruses biology.protein Cancer research Antibody 0210 nano-technology |
| Zdroj: | Journal of controlled release : official journal of the Controlled Release Society. 332 |
| ISSN: | 1873-4995 |
| Popis: | 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 1.2x1011vp/mouse and 7.5x1011vp/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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect