Oncolytic adenovirus with hyaluronidase activity that evades neutralizing antibodies: VCN-11
2021
Mato-Berciano, Ana | Morgado, Sara | Maliandi, María V. | Farrera-Sal, Martí | Gimenez-Alejandre, Marta | Ginestà, Mireia M. | Moreno, Rafael | Torres-Manjon, Silvia | Moreno, Paz | Arias-Badia, Marcel | Rojas, Luis A. | Capellá, Gabriel | Alemany, Ramon | Cascallo, Manel | Bazan-Peregrino, Miriam
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.
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