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Affilin-based retargeting of adenoviral vectors to the epidermal growth factor receptor
Frederik Wienen1, Robin Nilson1, Ellen Allmendinger1
1Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany.
Introduction:
Treatment of head and neck squamous cell carcinomas (HNSCC) by oncolytic adenoviral vectors holds promise as an efficient anti-cancer therapy. The epidermal growth factor receptor (EGFR) represents an attractive target receptor since it is frequently overexpressed in many types of HNSCC.
Methods:
To achieve EGFR-specific targeting by human adenovirus type 5 (HAdV-5) based vectors, the EGFR affinity ligand Affilin was covalently attached in a position specific manner either to the fiber or the hexon protein of the vector capsid. In vitro and in vivo studies investigated EGFR-specific cancer cell transduction, susceptibility to natural sequestration mechanisms, pharmacokinetics and biodistribution profiles of Affilin-decorated vectors.
Results:
Affilin-decorated vectors showed strongly enhanced and EGFR-specific cancer cell transduction in vitro and less susceptibility to known sequestration mechanisms of HAdV-5 particles. However, in vivo neither systemic nor intratumoral vector administration resulted in an improved transduction of EGFR-positive tumors. Comprehensive analyses indicated hampered EGFR-targeting by Affilin-decorated vectors was caused by rapid vector particle consumption due to binding to the murine EGFR, insufficient tumor vascularization and poor target accessibility for Affilin in the solid tumor caused by a pronounced tumor stroma.
Conclusion:
In vitro studies yielded proof-of-concept results demonstrating that covalent attachment of a receptor-specific Affilin to the adenoviral capsid provides an effective and versatile tool to address cancer-specific target receptors by adenoviral vectors. Regarding EGFR as the vector target, off-target tissue transduction and low receptor accessibility within the tumor tissue prevented efficient tumor transduction by Affilin-decorated vectors, rendering EGFR a difficult-to-target receptor for adenoviral vectors.
Insights
Oncolytic adenoviral vectors targeting EGFR showed promise in vitro for head and neck cancers. However, in vivo studies revealed challenges with tumor targeting and accessibility, limiting therapeutic efficacy.
Area of Science:
- Oncolytic virotherapy
- Gene therapy vectors
- Cancer biology
Background:
- Head and neck squamous cell carcinomas (HNSCC) are often treated with oncolytic adenoviral vectors.
- Epidermal growth factor receptor (EGFR) is frequently overexpressed in HNSCC, making it an attractive therapeutic target.
Purpose of the Study:
- To engineer EGFR-specific targeting of human adenovirus type 5 (HAdV-5) vectors.
- To evaluate the in vitro and in vivo efficacy of Affilin-decorated adenoviral vectors for HNSCC treatment.
Main Methods:
- Covalently attached Affilin ligand to HAdV-5 capsid proteins (fiber or hexon) for EGFR targeting.
- Investigated EGFR-specific cancer cell transduction, sequestration, pharmacokinetics, and biodistribution in vitro and in vivo.
Main Results:
- Affilin-decorated vectors demonstrated enhanced, EGFR-specific cancer cell transduction in vitro with reduced susceptibility to sequestration.
- In vivo studies showed no improved tumor transduction with systemic or intratumoral administration.
- Hampered in vivo targeting was attributed to rapid vector consumption by murine EGFR, poor tumor vascularization, and limited Affilin accessibility due to tumor stroma.
Conclusions:
- Covalent attachment of Affilin to adenoviral capsids is a versatile tool for targeting specific receptors in vitro.
- EGFR remains a challenging target for adenoviral vectors in vivo due to off-target binding and poor accessibility within solid tumors.
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