Inhibition of angiogenesis by a monoclonal antibody to kininogen as well as by kininostatin which block proangiogenic high molecular weight kininogen

Abstract

High molecular weight kininogen (HK) exhibits two activities with respect to angiogenesis after cleavage by plasma kallikrein. Cleaved HK (HKa) and its cell-binding domain 5 (D5), kininostatin, are potent antiangiogenic polypeptides. They inhibit endothelial cell migration, proliferation and tube formation. HKa and D5 inhibit angiogenesis in the chicken chorioallantoic membrane (CAM) assay. D5 stimulates apoptosis and interferes with the cell cycle. In contrast, intact HK is proangiogenic by liberating bradykinin. A monoclonal antibody to HK can inhibit angiogenesis in the CAM assay, human colon carcinoma growing as a xenograft in nude mice, and murine hybridomas growing in syngeneic hosts. Not only are the tumors decreased in volume and weight to isotype controls but the mean vascular density is decreased. Thus, both D5 and its constituent peptide and monoclonal antibody have potential for inhibiting angiogenesis and tumor growth in human therapy.