IDENTIFICATION OF A MONOCLONAL-ANTIBODY, TV-1, DIRECTED AGAINST THE BASEMENT-MEMBRANE OF TUMOR VESSELS, AND ITS USE TO ENHANCE THE DELIVERYOF MACROMOLECULES TO TUMORS AFTER CONJUGATION WITH INTERLEUKIN-2
Al. Epstein et al., IDENTIFICATION OF A MONOCLONAL-ANTIBODY, TV-1, DIRECTED AGAINST THE BASEMENT-MEMBRANE OF TUMOR VESSELS, AND ITS USE TO ENHANCE THE DELIVERYOF MACROMOLECULES TO TUMORS AFTER CONJUGATION WITH INTERLEUKIN-2, Cancer research, 55(12), 1995, pp. 2673-2680
mAbs reactive with epitopes expressed on tumor vessels were evaluated
as universal delivery agents of peptides with vasoactive properties to
enhance the uptake of macromolecules in tumors. Unlike other reported
approaches to target tumor vessels, a mAb designated TV-1 targets a b
asement membrane antigen that is found in all tissues but that is acce
ssible only in tumor vessels, making it an alternative vehicle for the
delivery of biologically active peptides to tumors, A panel of 30 mon
oclonal and polyclonal antibodies was screened by immunohistochemistry
on sections of human tumors, normal vascular endothelium, and connect
ive tissues. Five antibodies were chosen for in vivo evaluation, inclu
ding two antifibronectin antibodies (TV-1, HFN 7.1), one anti-basic fi
broblast growth factor antibody (anti-BFGF), and two antibodies reacti
ve with a mesenchymal cell antigen (TP-1, TP-3), Three nude mouse tumo
r models characterized by varying degrees of vascularization (low to h
igh) were used. After chemical conjugation to interleukin 2 (IL-2), th
ese antibodies were used to pretreat tumor-bearing nude mice 3 h befor
e injection with a radiolabeled mAb directed to the transplanted tumor
s. Pretreatment with TV-1/IL-2 or HPN 7.1/IL-2 produced a 3-fold highe
r tumor uptake of radiolabel compared to control mice pretreated with
mAb alone. The other three vasoactive immunoconjugates failed to show
significant increases in these tumor models, When TV-1/IL-2 was compar
ed with the specific vasoconjugate (Lym-1/IL-2) as a pretreatment in t
he Raji lymphoma model, which has low vascularization, TV-1/IL-2 yield
ed approximately 60% of the tumor uptake seen with Lym-1/IL-2. In comp
arison, pretreatment with TV-1/IL-2 in the LS174T colon carcinoma mode
l, which has high vascularization, yielded approximately the same tumo
r uptake seen with the B72.3/IL-2 vasoconjugate, which directly target
s the tumor cells, These studies demonstrate that a mAb directed again
st fibronectin in the endothelial subcellular matrix can be used to de
liver vasoactive agents to tumors.