3. Monoclonal antibodies 5
Monoclonal antibodies are manufactured in laboratories, and are derived from an identical group of cells (clone) that are designed to attack a specific cancer antigen. Some proteins of the tumor vascular endothelium become particularly active during the tumor growth process, and can serve as antigens for monoclonal antibodies. These proteins include fibronectin extra-domain B, tenascin-c, integrin-alpha-beta, VEGF, prostate-specific membrane antigen, endoglin, and CD44.
Peptides are protein fragments, some of which have the capability to bind to receptor sites on vascular endothelium. Therefore, they serve as targeting moieties. Through genetic engineering, these "homing" peptides are added to the surface proteins of bacteriophages. Phages are viruses that naturally infect bacteria. This approach can lead to the development of targeted delivery of chemotherapeutic drugs by attaching a drug to a peptide.
5. Radiation-induced drug targets
Radiation therapy activates a biochemical signaling pathway in tumors that make the endothelial cells resistant to radiation. Interestingly, this activation results in the formation of receptors on the vascular endothelium that can serve as drug targets. This understanding can lead to the development of VSAs that work in concert with radiation to destroy tumors.
An experimental VSA consists of liposomes (fatty molecules) coated with fibrinogen antibody. 4 This agent binds to a fibrinogen receptor on the endothelium. This fibrinogen receptor was activated by radiation of the tumor vascular system. The binding resulted in an 85% reduction of blood flow through the vessel. Another approach uses inhibitors of the enzyme phosphatidylinositol 3-kinase/Akt. 2 This enzyme is an essential component of the radiation induced biochemical signaling pathway.
6. Vascular endothelial growth factor (VEGF)
The monoclonal antibody bevacizumab acts against VEGF receptors. It is marketed as Avastin by Genetech for cancer therapy. VSAs are also under studies which combine VEGF with diphtheria toxin or a plant toxin. 7
7. Tissue Factor
Tissue factor is the major initiator of the coagulation cascade that results in blood clot formation. Tissue factor is normally absent within the blood vessels, but is present in tissues outside the blood. A modified form of tissue factor was prepared that by itself was inactive in the blood. A VSA was prepared by combining this modified tissue factor with an antibody that was directed to a specific antigen on the tumor epithelium. After binding to the epithelium, tissue factor was activated leading to clot formation and blocking of blood flow through the vessel.
