Neovascular targeting with cyclic RGD peptide (cRGDf-ACHA) to enhance delivery of radioimmunotherapy

Radioimmunotherapy (RIT) has been hampered by delivery of only a small frac tion of the administered dose of radiolabeled MAb to tumor. A strategy for creating and controlling tumor vascular permeability would enable more effe ctive 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 mo dels, apoptosis of neovascular endothelial cells has been demonstrated afte r treatment with alpha v beta 3 antagonists. Since this apoptotic effect co uld 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 pha rmacokinetic study of an immunospecific MAb given after an alpha v beta 3 a ntagonist was performed in nude mice bearing human breast cancer xenografts . The alpha v beta 3 antagonist, cyclic RGD pentapeptide (c-RGDf-ACHA; cycl e arginine glycine aspartic acid D-phenylalanine -1 amino cyclohexane carbo xylic acid), inhibits alpha v beta 3 binding to its vitronectin ligand at n anomolar levels. Cyclic RGD peptide (250 mu g i.p.) given I hour before In- 111-ChL6MAb resulted in a 40 - 50% increase in tumor uptake (concentration) , when compared to the control tumor uptake, of MAb 24 hours after administ ration. When cyclic RGD peptide was given as a continuous infusion (17.5 ug /hr)for I or 24 hours before In-111-ChL6, tumor uptake of In-111-ChL6 was i ncreased less, and, these data were not statistically different from the co ntrol data. There were no differences for any of the groups in the concentr ations of In-111-ChL6 in normal organs or blood when compared to the contro l group. The results suggest that cyclic RGD peptide provided a temporary, selective increase in tumor vascular permeability, that allowed a larger fu nction of the In-111-ChL6 to accumulate in the tumor.