ABSTRACT
Abstract ................................................................................................................. 310 Advantages of Vascular Targeting Agents .............................................................. 310
Biologic Rationale ............................................................................................. 310 Pharmacological Rationale................................................................................ 311 Technological Improvements Enabling the Identication of Novel Tumor Vascular-Specic Antigens ................................................................................ 312
Vascular Targeting Agents in Clinical Development ............................................. 313 Small-Molecule Vascular Targeting Agents ...................................................... 313 Clinical Development of Ligand-Directed Vascular Targeting Agents ............. 315
Promising Targets for Ligand-Directed Vascular Targeting Agents ....................... 316 Integrins ............................................................................................................. 316 Endoglin (CD105) ............................................................................................. 316 Robo4 ................................................................................................................ 317 Aminopeptidase N (CD13) ............................................................................... 317 Delta-Like 4 (DLL4) ......................................................................................... 317 VEGFR-2 (CD 309) .......................................................................................... 318 CXCR4 (CD184) ............................................................................................... 318 Tie2 (CD202b) .................................................................................................. 318
Future Directions ................................................................................................... 319 References .............................................................................................................. 319
KEY WORDS: vascular targeting agents, tumor vasculation, antibody-drug conjugates
Vascular targeting agents (VTAs), by denition, induce antitumor effects via rapid and selective destruction of blood vessels within established tumors, leading to collapse in tumor blood ow and tumor cell death due to ischemia and extensive hemorrhagic necrosis. VTAs can be broadly divided into two types: low-molecular-weight compounds and ligand-directed macromolecules. Both classes of compounds are designed to exploit pathophysiological differences between tumor and normal tissue endothelial cells to achieve selective targeting of tumor vessels. The clinical data generated with small molecule VTAs validated the safety and efcacy of this therapeutic strategy. Ligand-directed VTAs exploit differences in antigen expression to deliver a therapeutic agent selectively to the tumor vasculature. A variety of ligand-directed agents targeting antigens selectively expressed on tumor vasculature are being developed preclinically. Recently, the use of laser capture microdissection technology combined with gene expression proling and subtractive proteomic mapping conrmed some of the vascular targets described earlier and identied novel, tumor vascularspecic antigens. In this chapter, we review the advantages of the vascular targeting approach and summarize the preclinical and clinical data generated with this class of compounds.
