A high-affinity human antibody that targets tumoral blood vessels

Angiogenesis is a characteristic feature of many aggressive tumors and of o ther relevant disorders. Molecules capable of specifically binding to new-f orming blood vessels, but not to mature vessels, could be used as selective vehicles and would, therefore, open diagnostic and therapeutic opportuniti es. We have studied the distribution of the ED-B oncofetal domain of fibron ectin, a marker of angiogenesis, in four different tumor animal models: the F9 murine teratocarcinoma, SKMEL-28 human melanoma, N592 human small cell lung carcinoma, and C51 human colon carcinoma. In all of these experimental models we observed accumulation of the fibronectin isoform containing the ED-B domain around neovascular structures when the tumors were in the expon entially growing phase, but not in the slow-growing phase. Then we performe d biodistribution studies in mice bearing a subcutaneously implanted F9 mur ine teratocarcinoma, using a high-affinity human antibody fragment (L19) di rected against the ED-B domain of fibronectin. Radiolabeled L19, but not an irrelevant anti lysozyme antibody fragment (D1.3), efficiently localizes i n the tumoral vessels. The maximal dose of L19 accumulated in the tumor was observed 3 hours after injection (8.2% injected dose per gram). By virtue of the rapid clearance of the antibody fragment from the circulation, tumor -to-blood ratios of 1.9, 3.7, and 11.8 were obtained at 3, 5, and 24 hours, respectively. The tumor targeting performance of L19 was not dose-dependen t in the 0.7 to 10 mu g range of injected antibody. The integral of the rad ioactivity localized in tumoral vessels over 24 hours was greater than 70-f old higher than the integral of the radioactivity in blood over the same ti me period, normalized per gram of tissue or fluid. These findings quantitat ively show that new-forming blood vessels can selectively be targeted in vi vo using specific antibodies, and suggest that L19 may be of clinical utili ty for the immunoscintigraphic detection of angiogenesis in patients. (C) 1 999 by The American Society of Hematology.