Development of inhibitors for a angiogenesis factor CTGF and its application for angiogenetic diseases

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1) As inhibitors for connective tissue growth factor (CTGF), a polyclonal antibody was raised by immunizing a synthesis CTGF fragment into rabbit. In addition, monoclonal anti-CTGF antibodies were also prepared.2) Recombinant CTGF (rCTGF) promoted the adhesion, proliferation and migration of the vascular endothelial cells and these effects were inhibited by anti-CTGF antibody.3) rCTGF markedly induced the tube formation of vascular endothelial cells, and this effect was stronger than that of basic fibroblast growth of vascular endothelial growth factor.4) Application of rCTGF to the chicken chrioallantoic membrane (CAM) resulted in gross angiogenic response and the effect was inhibited by anti-CTGF antibody. rCTGF injected with collagen gels into the back of mice induced strong angiogenesis in vivo.5) Among three cell lines (breast cancer cell line MDA231, fibrosarcoma cell line HT1080 and squamous carcinoma cell line A431), the ability to produce CTGF was highest in MDA231 and lowest in A431 and was parallel to their ability to form angiogenic tumors in nude mice. Anti-CTGF antibody inhibited tumor-induced angiogenesis in CAM.6) CTGF was present in synovial fluid in patients with rheumatoid arthritis which is an angiogenic decease.7) CTGF was expressed in the infarct zone of experimentally induced myocardial infarction in rats.8) Human anti-CTGF antibodies were raised in transgenic mice producing human type antibody. One of them inhibited bone metastasis of MDA231 tumors which produce much CTGF.These findings indicate that CTGF is a novel, potent angiogenesis factor which functions in multi-stages in physiological and pathological angiogenesis and suggest that anti-CTGF antibody can be used as an inhibitor for angiogenesis.