Abstract
Degradation of extracellular matrix components is a key step in tumor progression, facilitating invasion, angiogenesis, and metastasis. The lysosomal cysteine protease cathepsin S (Cat-S) is a prominent player in this process. We evaluated the antitumor activity of Fsn0503h, the first Cat-S-antagonistic humanized monoclonal antibody, in a panel of cancer cell lines and in human colon carcinoma xenografts. Cat-S was expressed in 11 out of 36 solid tumor-derived cell lines. Fsn0503h significantly reduced the invasive capacity of all Cat-S-expressing cell lines invitro. This was confirmed by the Cat-S small-molecule inhibitor Z-FL-COCHO, validating the importance of this protease in tumor cell invasiveness. Interestingly, Fsn0503h displayed antiproliferative effects in Cat-S positive and some Cat-S-negative cell lines. We provide the first demonstration of invivo activity of Fsn0503h against a colorectal tumor xenograft model, with a 10mg/kg three times a week intravenous schedule being optimal. In conclusion, Fsn0503h not only inhibited the invasiveness of cancer cells invitro, but also exerted antitumor effects both invitro and invivo. These findings validate Cat-S as a therapeutic target, and support the development of Fsn0503h for the therapy of solid tumors.
Published Version
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