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Published on: November 24, 2014
Oncolytic adenovirus with hyaluronidase activity that evades neutralizing antibodies: VCN-11
Ana Mato-Berciano1, Sara Morgado1, María V Maliandi1
1VCN Biosciences, Sant Cugat del Vallès, Barcelona, Spain.
Abstract:
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.
Insights
VCN-11, a novel oncolytic adenovirus, effectively targets tumors and spreads within them, even when patients have neutralizing antibodies. This virus demonstrates significant antitumor activity and a favorable safety profile, suggesting potential for re-administration in clinical trials.
Area of Science:
- Oncolytic virotherapy
- Viral oncology
- Gene therapy
Background:
- Effective tumor targeting and intratumoral virus spread are critical for oncolytic virotherapy success.
- Novel oncolytic adenoviruses are being developed to overcome challenges like neutralizing antibodies.
Purpose of the Study:
- To validate the mechanism of action and characterize the toxicity of VCN-11, a novel oncolytic adenovirus.
- To assess VCN-11's tumor targeting, spreading, and antitumor efficacy, particularly in the presence of neutralizing antibodies.
Main Methods:
- VCN-11's replication, hyaluronidase (PH20) activity, and human albumin binding were evaluated.
- Toxicity and efficacy were assessed in mouse and hamster models, including studies with neutralizing antibodies.
- Tumor targeting and antitumor activity were analyzed in various tumor models.
Main Results:
- VCN-11 exhibited significantly higher cytotoxicity in tumor cells (450-fold) compared to normal cells.
- PH20 activity and albumin binding for neutralizing antibody evasion were confirmed both in vitro and in vivo.
- VCN-11 demonstrated effective tumor targeting and antitumor activity in the presence of neutralizing antibodies, unlike a control virus lacking the albumin-binding domain.
- VCN-11 showed a low toxicity profile, permitting high-dose and fractionated administrations.
Conclusions:
- VCN-11 effectively disrupts tumor matrix and exerts antitumor effects, even in the presence of neutralizing antibodies.
- Its safety profile and ability to evade immune responses make VCN-11 a promising candidate for further clinical investigation, including re-administration studies.
