Radioimmunotherapy (RIT) has been hampered by delivery of only a small fraction of the administered dose of radiolabeled MAb to
tumor. A strategy for creating and controlling
tumor vascular permeability would enable more effective RIT. The alpha v
beta 3 integrin receptor is an appealing target for strategies designed to enhance permeability of
tumor vessels because it is highly and preferentially expressed in most
tumors. In human
tumor mouse models, apoptosis of neovascular endothelial cells has been demonstrated
after treatment with alpha v beta 3 antagonists. Since this apoptotic effect could transiently increase permeability of
tumor blood vessels, radiolabeled
antibodies (MAb) circulating during this period would have increased access to extravascular
tumor. To determine if this hypothesis was correct, a pharmacokinetic study of an immunospecific MAb given after an alpha v beta 3 antagonist was performed in nude mice bearing human
breast cancer xenografts. The alpha v beta 3 antagonist,
cyclic RGD pentapeptide (
c-RGDf-ACHA; cyclo
arginine glycine aspartic acid D-
phenylalanine -1 amino
cyclohexane carboxylic acid), inhibits alpha v beta 3 binding to its
vitronectin ligand at nanomolar levels.
Cyclic RGD peptide (250 micrograms i.p.) given 1 hour before 111In-ChL6 MAb resulted in a 40-50% increase in
tumor uptake (concentration), when compared to the control
tumor uptake, of MAb 24 hours after administration. When
cyclic RGD peptide was given as a continuous infusion (17.5 micrograms/hr) for 1 or 24 hours before 111In-ChL6,
tumor uptake of 111In-ChL6 was increased less, and, these data were not statistically different from the control data. There were no differences for any of the groups in the groups in the concentrations of 111In-ChL6 in normal organs or blood when compared to the control group. The results suggest that
cyclic RGD peptide provided a temporary, selective increase in
tumor vascular permeability, that allowed a larger fraction of the 111In-ChL6 to accumulate in the
tumor.