Specific Occlusion of Murine and Human Tumor Vasculature by VCAM-1–Targeted Recombinant Fusion Proteins

• Published in: JNCI : Journal of the National Cancer Institute Vol. 97; no. 10; pp. 733 - 747
• Main Authors: Dienst, Ariane, Grunow, Andrea, Unruh, Maike, Rabausch, Berit, Nör, Jacques E., Fries, Jochen W. U., Gottstein, Claudia
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 18.05.2005; Oxford Publishing Limited (England)
• Subjects: Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Blood Coagulation Tests; Carcinoma, Small Cell - blood supply; Carcinoma, Small Cell - drug therapy; Circulatory system; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Experimental tumors, general aspects; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; Hodgkin Disease - drug therapy; Hodgkin Disease - pathology; Humans; Immunohistochemistry; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Medical sciences; Mice; Microcirculation - drug effects; Necrosis; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Other treatments; Proteins; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Research Design; Rodents; Surface Plasmon Resonance; Transplantation, Heterologous; Treatment. General aspects; Tumors; Vascular Cell Adhesion Molecule-1 - drug effects; Human; Vascular cell adhesion molecule 1; Rodentia; Cell adhesion molecule; Induced occlusion; Malignant tumor; Vertebrata; Mammalia; Cancerology; Treatment; Mouse; Animal; Blood vessel; Recombinant protein; Fusion protein
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/dji130

Background: The tumor vasculature is increasingly recognized as a target for cancer therapy. We developed and evaluated recombinant fusion proteins targeting the coagulation-inducing protein soluble tissue factor (sTF) to the luminal tumor endothelial antigen vascular cell adhesion molecule 1 (VCAM-1, CD106). Methods: We generated fusion proteins consisting of sTF fused to antibody fragments directed against mouse or human VCAM-1 and characterized them in vitro by flow cytometry, surface plasmon resonance, and two-stage coagulation assays. Their therapeutic effects were tested in three human xenograft tumor models: L540rec Hodgkin lymphoma, Colo677 small-cell lung carcinoma, and Colo677/HDMEC small-cell lung carcinoma with human vasculature. Toxicity was analyzed by histologic examination of organs and determination of laboratory blood parameters. Results: The fusion proteins bound VCAM-1 with nanomolar affinities and had the same coagulation activity as an sTF standard. Xenograft tumor–bearing mice treated with fusion protein (FP) alone or in combination with lipopolysaccharide (FP/L) or doxorubicin (FP/D) exhibited tumor-selective necrosis (L540rec tumors: 74% tumor necrosis [95% confidence interval {CI} = 55% to 93%] with FP/L versus 13% tumor necrosi1s [95% CI = 4% to 22%] with vehicle; Colo677 tumors: 26% [95% CI = 16% to 36%] with FP versus 8% [95% CI = 2% to 14%] with vehicle); tumor growth delay (Colo677/HDMEC: mean tumor weights after 3 days = 42 mg in FP-treated mice versus 71 mg in vehicle-treated mice, difference = 29 mg, 95% CI = 8 to 100, Mann–Whitney P = .008); and some tumor regressions (one of seven FP-treated Colo677 tumor–bearing mice and two of seven FP/D-treated mice). The fusion protein was well tolerated. Conclusions: Recombinant tissue factor–based fusion proteins directed against an intraluminal tumor endothelial cell marker induce tumor-selective intravascular coagulation, tumor tissue necrosis, and tumor growth delay.