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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1659-1665
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Enhancement of the antitumor properties of interleukin-2 by its
targeted delivery to the tumor blood vessel extracellular
matrix
Barbara Carnemolla,
Laura Borsi,
Enrica Balza,
Patrizia Castellani,
Raffaella Meazza,
Alexander Berndt,
Silvano Ferrini,
Hartwig Kosmehl,
Dario Neri, and
Luciano Zardi
From the Laboratory of Cell Biology and Laboratory of
Immunopharmacology, Istituto Nazionale per la Ricerca sul Cancro,
Genoa, Italy; Institute of Pathology, Friedrich Schiller University,
Jena, Germany; and Department of Applied Biosciences of the Swiss
Federal Institute of Technology (ETH), Zürich, Switzerland.
Angiogenic processes depend on the precise coordination of
different cell types and a complex exchange of signals, many of which
derive from new specific components of the provisional, angiogenesis-related, extracellular matrix (ECM).
Angiogenesis-associated ECM components thus represent appealing targets
for the selective delivery of therapeutic molecules to newly forming
tumor vessels. Results of a previous study indicated that a high
affinity recombinant antibody (L19) to ED-B, a domain contained in the
angiogenesis-associated isoform of fibronectin (B-FN), selectively and
efficiently targets tumor vessels. The present study shows that a
fusion protein between L19 and interleukin 2 (L19-IL-2) mediates the
selective delivery and concentration of IL-2 to tumor vasculature,
thereby leading to a dramatic enhancement of the therapeutic properties
of the cytokine. By contrast, IL-2 fused to an irrelevant recombinant antibody used as a control fusion protein showed neither accumulation in tumors nor therapeutic efficacy. Tumors in mice treated with L19-IL-2 were significantly smaller compared to those in animals treated with saline, the control fusion protein, or IL-2 alone (P = .003, .003, and .002, respectively). Moreover, no
significant differences in size were observed among the tumors from the
different control groups (using the control fusion protein, a mixture
of IL-2 and L19, or saline alone). Immunohistochemical analysis of tumor infiltrates demonstrated a significantly higher number of T
lymphocytes, natural killer cells, and macrophages, as well as
increased interferon- (IFN-) accumulation, in tumors from animals
treated with L19-IL-2 compared to tumors from control groups. The fact
that ED-B is 100% homologous in human and mouse, thus ensuring that
L19 reacts equally well with human and murine antigen, should
ultimately expedite transfer of this reagent to clinical trials.
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