Details

Autor(en) / Beteiligte

• 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.
• Capellà, Gabriel
• Alemany, Ramon
• Cascallo, Manel
• Bazan-Peregrino, Miriam

Titel

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

Ist Teil von

• Journal of controlled release, 2021-04, Vol.332, p.517-528

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. VCN-11, a new oncolytic adenovirus, disrupts tumor stroma by expressing hyaluronidase and evades neutralizing antibodies by shielding itself with serum albumin, thereby leading to antitumour efficacy. [Display omitted] •VCN-11 is a new oncolytic adenovirus that expresses hyaluronidase and displays an albumin-binding domain on its capsid.•VCN-11 has shown a good efficacy and safety profile in different animal models.•Hyaluronidase expression allows VCN-11 to disrupt the tumor extracellular matrix favoring viral dissemination.•An Albumin Shield (ABS) protects VCN-11 from antibody neutralization and enables effective readministration.•VCN-11 is a promising therapy to be tested under repeated administrations in cancer patients