Binding, internalization, and transgene expression of an adenoviral vector retargeted to HER3/4

Sheena H MacLeod
Adenoviruses (Ads) have been well studied for use in cancer gene therapy. However, low levels of the primary receptor, coxsackie-adenovirus receptor (CAR), in tumor cells has been shown to be a factor in low transgene expression. To increase Ad infection of breast cancer cells we constructed a human Ad5 targeted to HER3/4 receptors by the insertion of the HER3/4 ligand, the HRG EGFlike domain. These growth factor receptors are overexpressed on breast cancer, as well as other cancer cells. Here,
more » ... cancer cells. Here, we have shown higher transgene expression levels after infection of breast cancer cells expressing high levels of HER3/4 by the modified virus, compared to the wild-type binding virus. Furthermore, we have shown expanded tropism of the modified virus to Chinese hamster ovary cells that are refractory to infection by the wild-type binding virus. Competition with either the HRG EGF-like domain or soluble Ad virus fiber knob supported these results. However, gene transfer to a breast cancer xenograft model was not improved by the addition of the heregulin (HRG) EGF-like domain. We compared binding and internalization of the modified virus to that of the wildtype binding virus. As expected, the wild-type virus bound and was taken up into CAR+ cells within 10 min. The modified virus was similar in CAR+ cell lines.
doi:10.7939/r3vd6pb6p fatcat:qe432agdpjhxxiua54dpktw7la