A high-affinity human antibody that targets tumoral blood vessels.
Angiogenesis is a characteristic feature of many aggressive tumors and of other relevant disorders. Molecules capable of specifically binding to new-forming blood vessels, but not to mature vessels, could be used as selective vehicles and would, therefore, open diagnostic and therapeutic opportunities. We have studied the distribution of the ED-B oncofetal domain of fibronectin, 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 exponentially growing phase, but not in the slow-growing phase. Then we performed biodistribution studies in mice bearing a subcutaneously implanted F9 murine teratocarcinoma, using a high-affinity human antibody fragment (L19) directed against the ED-B domain of fibronectin. Radiolabeled L19, but not an irrelevant anti-lysozyme antibody fragment (D1.3), efficiently localizes in 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-dependent in the 0.7 to 10 microg range of injected antibody. The integral of the radioactivity localized in tumoral vessels over 24 hours was greater than 70-fold higher than the integral of the radioactivity in blood over the same time period, normalized per gram of tissue or fluid. These findings quantitatively show that new-forming blood vessels can selectively be targeted in vivo using specific antibodies, and suggest that L19 may be of clinical utility for the immunoscintigraphic detection of angiogenesis in patients.
Tarli
L
L
Institut für Molekularbiologie und Biophysik, ETH Hönggerberg, Zürich, Switzerland.
Balza
E
E
Viti
F
F
Borsi
L
L
Castellani
P
P
Berndorff
D
D
Dinkelborg
L
L
Neri
D
D
Zardi
L
L
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000915:Antibody Affinity; D014408:Biomarkers, Tumor / Q000276:immunology*; D005353:Fibronectins / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000276:immunology*; D020033:Protein Isoforms / Q000276:immunology
D000906:Antibodies; D014408:Biomarkers, Tumor; D005353:Fibronectins; D020033:Protein Isoforms