Engineering Protease-Specific Human Antibodies and Discovering Novel Serine Proteases Expressed in Prostate Cancer Using Phage Display

摘要

Quantitative RT-PCR and immunohistochemistry (IHC) experiments revealed that membrane-type serine protease 1 (MT-SPl), a member of the TTSP family, is specifically overexpressed in epithelial cancer cells and tissue samples. It was reported that in advanced stages of prostate, breast, and ovarian cancers MT-Spl is not regulated by its endogenous inhibitor HAI-l. MT- Spl plays diverse roles by activating pro-uPA, pro-HGF, and PAR-2. Taken together, MT-SPl may be a key upstream factor involved in the ECM remodeling plasminogen activation cascade and in signal transduction cascades involved in cell transformation. Dysregulated MT-SPl expression could promote the proteolytic activity of MT-SPl resulting in a more invasive phenotype. We postulated that inhibition of its proteolytic activity might curtail the invasive phenotype. As MT-SPl is a cell surface protein, we chose to target the protease with anti-MT-SPl single chain monoclonal antibodies (scFvs) that we isolated using phage display. These scFvs potently and selectively inhibit the protease activity of MT-SPl. Our initial in vivo studies revealed the sizes of xenografted human ovarian tumors in nude mice were significantly reduced following treatment with the inhibitory scFvs, indicating the therapeutic potential of these scFvs for the treatment of epithelial cancers in ovary, prostate and breast.