Antibody-guided AAV vectors for antigen-specific delivery of suicide genes

Gene Ther. 2025 Oct 24. doi: 10.1038/s41434-025-00570-5. Online ahead of print.

ABSTRACT

Antibody-drug conjugates (ADCs) are a promising class of targeted cancer therapeutics, but their efficacy is often limited by off-target toxicity caused by payload leakage after internalization into tumor cells. To overcome this, we developed an ADC alternative using an antibody-guided adeno-associated virus (AAV) vector system that delivers suicide genes specifically to cancer cells. By displaying Protein A on the AAV VP2 capsid, we enabled IgG binding and stable complex formation on the capsid, leading to efficient antibody-guided transduction under our assay conditions. This modular platform allows flexible retargeting specific tumor-associated antigens simply by changing the antibody, without genetic re-engineering of the capsid. Using an AAV2 heparan sulfate binding knockout (HBKO) background to minimize nonspecific infection, we achieved antigen-specific transduction for multiple targets including CD20, EGFR, PSMA, CEA, and CD5 (with varying levels of enhancement depending on the target). In vitro, the system successfully directed EGFP expression and, upon delivery of the pro-apoptotic gene BAX, induced selective apoptosis in target-positive cells. Unlike conventional ADCs, this strategy is designed to minimize the risk of extracellular payload leakage and to confine cytotoxicity primarily to transduced cells, thereby supporting more selective tumor targeting. Our approach may offer a versatile alternative for targeted cancer therapy, with the potential for further development into customizable and precision-guided gene-based treatments.

PMID:41298904 | DOI:10.1038/s41434-025-00570-5