Gene Therapy of Disseminated Breast Cancer Using Adenoviral Vectors Targeted Through Immunological Methods

摘要

Targeting of adenovirus vectors, encoding for therapeutic genes, to tumor-speciflc receptors on breast cancer cells should result in specific killing of these cells. Targeting is necessary to prevent gene transfer in normal tissues resulting from the infection of normal cells by adenovirus. We have previously reported the use of an anti-knob antibody fragment (Fab), which prevents Ad infection, conjugated to folate to target adenovirus to folate receptor positive cells. In this report, the Fab has been conjugated on a large scale to an anti-EGFR antibody (425) and an anti-erbB-2 antibody (Herceptin) to yield Fab-425 and Fab-Herceptin conjugates, respectively. These conjugates were used to target adenovirus specifically to EGF and erbB-2 receptors on BT 474, MDA-MB-468, MDA-MB- 134, MDA-MB-23 1, MDA-MB-453, and SK-BR-3 breast cancer cells. In addition, the conjugates could specifically target adenovirus to the receptors in a hetergeneous cell population. In vivo studies were conducted which show that adenovirus can specifically target MDA-MB-468 cells using the Fab-425 conjugate. These results are significant in that they demonstrate that adenovirus vectors can be specifically delivered to breast cancer cells in a heterogeneous cell population and in vivo. This will be significant for treating disseminated breast cancer with adenovirus vectors.