Early Development of the Icon Molecule for Gene Therapy of Cancer and Macular Degeneration | Biomedgrid

I conceived the Icon strategy for cancer immunotherapy in 1996 after reading a paper showing that Tissue Factor (TF) is expressed on the surface of vascular endothelial cells and tumor cells in invasive breast cancer but not in benign breast cancer [1]. Although it was not tested in this paper, I assumed TF also is not expressed on the surface of vascular endothelial cells in normal tissues and it might provide a specific marker for the tumor vasculature. TF is a cell-surface transmembrane receptor containing an extracellular domain that binds factor VII (fVII) with high affinity and specificity, initiating the blood coagulation pathway [2] (Figure 1). TF exists as an integral membrane protein in the intact wall of normal blood vessels, preventing contact with fVII circulating in the blood, in contrast to tumor blood vessels in which the vessel wall is damaged and leaky [3], exposing TF to fVII. Thus, TF could serve as a specific molecular target and fVII as a specific targeting molecule for the pathological neovasculature (PNV). Accordingly, I designed the Icon as a heavy-chain VH immunoconjugate antibody [4] composed of factor VII as the targeting domain attached either to a mouse or human Fc domain (Figure 2), similar to a Camelid antibody composed of heavy-chain dimers devoid of light chains [5]. A mutation was introduced into the active site of fVII to inhibit the initiation of the blood coagulation pathway, which might result in pathological blood clots [6].