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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 192-198
A High-Affinity Human Antibody That Targets Tumoral Blood Vessels
Lorenzo Tarli,
Enrica Balza,
Francesca Viti,
Laura Borsi,
Patrizia Castellani,
Dietmar Berndorff,
Ludger Dinkelborg,
Dario Neri, and
Luciano Zardi
From Institut für Molekularbiologie und Biophysik, ETH
Hönggerberg, Zürich, Switzerland; Istituto Nazionale per la
Ricerca sul Cancro, Genova, Italy; and Research Laboratories of
Schering AG, Berlin, Germany.
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 µg 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.
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