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

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.