An oncolytic HAdV-5 with reduced surface charge combines diminished toxicity and improved tumor targeting

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Human adenovirus type 5 (HAdV-5)-based oncolytic viruses hold significant promise for anti-cancer therapy. However, poor tumor-targeting and off-target organ transduction after systemic administration limit their therapeutic efficacy. Additionally, the strong liver tropism of HAdV-5-based vectors poses the risk of hepatotoxicity. By genetic modification of the major capsid protein Hexon we generated a HAdV-5-based oncolytic vector (HAdV-5-HexPos3) with reduced negative surface charge. Coxsackie- and adenovirus receptor (CAR) binding-ablated (ΔCAR) HAdV-5-HexPos3_ΔCAR exhibited superior and CAR-independent transduction of various cancer cell lines in vitro, further enhanced in the presence of HAdV-5 naïve murine plasma. Upon intravenous administration into tumor-bearing immunodeficient NSG mice, replication-deficient HAdV-5-HexPos3_ΔCAR vector particles showed significantly reduced off-target organ tropism in all tissues analyzed, including the liver. Moreover, we detected a significantly increased intratumoral vector load for HAdV-5-HexPos3_ΔCAR, leading to a 29-fold elevated tumor-to-liver ratio compared to a control vector with unmodified Hexon. Intravenous injection of a conditionally replicating Hexon-unmodified control vector induced severe hepatotoxicity in tumor-bearing NSG mice, while a conditionally replicating HAdV-5-HexPos3_ΔCAR vector was well tolerated and resulted in intratumoral vector presence for up to 56 days. HAdV-5-HexPos3_ΔCAR represents a promising vector platform for the generation of HAdV-5-based oncolytic viruses with reduced systemic toxicity and improved therapeutic efficacy.