Connective Tissue Growth Factor (CTGF) is a member of the CCN family of proteins, which regulates biological processes including stimulation of cell proliferation, migration, and adhesion. Five of the known six CCN family members have been implicated or directly regulate angiogenic responses in specific disease models, and many are over-expressed in various tumors of diverse tissue origin. In many cases the degree of CCN over-expression has been highly correlated with the stage of tumor progression in humans. CTGF and Cyr61 are the most highly studied and exhibit the highest correlations in pancreatic, breast and glial tumors. In several published reports, over-expression of CTGF and Cyr61 has been causally linked with tumor invasiveness and metastasis, particularly metastasis to bone.

FibroGen has developed proprietary assays and identified preclinical candidates, including biopharmaceuticals and small molecule inhibitors, that interfere broadly with both CTGF, Cyr61 and CCN function. These candidates and that can be further optimized and developed as potential therapeutics.

In the area of biopharmaceuticals, FibroGen has identified monoclonal antibodies within our anti-CTGF HuMab library that cross-react with Cyr61. This provides a means to simultaneously neutralize both CTGF and Cyr61 in tumor progression models. By comparing single versus dual-reactive HuMabs, we can determine the individual role and contribution of CTGF and Cyr61 to tumor progression in several tumor disease models.

With regard to small molecules designed to inhibit CCN function, FibroGen employs a proprietary assay that measures the capacity of CCN family members, including CTGF, to directly elevate expression of extracellular matrix genes including type I collagen. The assay was optimized to a high throughput format and used to screen more than 200,000 compounds, which led to the identification of both pan-CCN and CTGF-specific small molecule inhibitors that block induction of collagen. Lead candidates are being further explored to determine their utility as inhibitors of fibrosis as well as inhibitors of tumor progression in models where CTGF and Cyr61 enhance tumor growth. As described above for anti-CCN biopharmaceuticals, single, dual and pan-inhibitory small molecules will be tested to determine the role and contribution of CTGF, Cyr61 and other CCN members on tumor progression and metastasis in several tumor disease models.