Position-specific Polymeric-Coated Oncolytic Adenovirus Improves Anti-Tumor Efficacy and Evades Neutralizing Antibodies in Pancreatic Cancer Models

Enhancing the safety and efficacy of systemically administered oncolytic adenoviruses remains a significant challenge to achieve effective targeting of primary tumors and disseminated disease. Intravenous administration exposes viral particles to various blood components interfering with their therapeutic activity. To protect adenoviruses from the inactivating factors we developed a shielding strategy based on a nanoparticle formulation reactive to a specific-site in the hexon hypervariable region 1. We propose a novel coating approach based on the combination of a bioresponsive oligopeptide-modified poly(β-aminoester)s (OM-PBAE-CRRR) and an irreversible linear PEG polymer with protruding ends to shield the oncolytic adenovirus AdNuPARc-E (PEPB). The formulated virus displays a slight delay in the transduction and replicative capacity at early time points that normalizes in a few days. Interestingly, similar oncolytic efficacy to the naked virus was observed in vitro, with enhanced antitumor effect in vivo in a pancreatic cancer model. In accordance, PEPB showed significantly enhanced pharmacokinetics and increased liver and tumor transduction in the xenograft model. In the presence of neutralizing antibodies (NAbs) coated viral particles maintained the infectivity and the replication capacity. Notably, in pre-immunized immunocompetent mice, protection from NAbs resulted in a higher viral accumulation in tumors than in the liver and was associated with significant antitumor activity. In summary, our findings indicate that the proposed formulation PEPB -the oncolytic adenovirus AdNuPARc-E site-specifically shielded with OM-PBAE-CRRR/PEG - offers a promising approach to improve tumor targeting after systemic administration, even in the presence of pre-existing neutralizing antibodies.