Identification of a monoclonal antibody, TV-1, directed against the basement membrane of tumor vessels, and its use to enhance the delivery of 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 basement membrane antigen that is found in all tissues but that is accessible only in tumor vessels, making it an alternative vehicle for the delivery of biologically active peptides to tumors. A panel of 30 monoclonal and polyclonal antibodies was screened by immunohistochemistry on sections of human tumors, normal vascular endothelium, and connective tissues. Five antibodies were chosen for in vivo evaluation, including two antifibronectin antibodies (TV-1, HFN 7.1), one anti-basic fibroblast growth factor antibody (anti-BFGF), and two antibodies reactive with a mesenchymal cell antigen (TP-1, TP-3). Three nude mouse tumor models characterized by varying degrees of vascularization (low to high) were used. After chemical conjugation to interleukin 2 (IL-2), these antibodies were used to pretreat tumor-bearing nude mice 3 h before injection with a radiolabeled mAb directed to the transplanted tumors. Pretreatment with TV-1/IL-2 or HFN 7.1/IL-2 produced a 3-fold higher 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 compared with the specific vasoconjugate (Lym-1/IL-2) as a pretreatment in the Raji lymphoma model, which has low vascularization, TV-1/IL-2 yielded approximately 60% of the tumor uptake seen with Lym-1/IL-2. In comparison, pretreatment with TV-1/IL-2 in the LS174T colon carcinoma model, which has high vascularization, yielded approximately the same tumor uptake seen with the B72.3/IL-2 vasoconjugate, which directly targets the tumor cells. These studies demonstrate that a mAb directed against fibronectin in the endothelial subcellular matrix can be used to deliver vasoactive agents to tumors.
Epstein
A L
AL
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Khawli
L A
LA
Hornick
J L
JL
Taylor
C R
CR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002196:Capillaries / Q000473:pathology; D002460:Cell Line; D004337:Drug Carriers; D006801:Humans; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000008:administration & dosage* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D004337:Drug Carriers; D000922:Immunotoxins; D007376:Interleukin-2; D008565:Membrane Proteins