title: Fsn0503h antibody-mediated blockade of cathepsin S as a potential therapeutic strategy for the treatment of solid tumors.
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 in vitro. 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 in vivo activity of Fsn0503h against a colorectal tumor xenograft model, with a 10 mg/kg three times a week intravenous schedule being optimal. In conclusion, Fsn0503h not only inhibited the invasiveness of cancer cells in vitro, but also exerted antitumor effects both in vitro and in vivo. These findings validate Cat-S as a therapeutic target, and support the development of Fsn0503h for the therapy of solid tumors.
authors.affiliation: Oncology Therapeutic Development, 100 rue Martre, 92110 Clichy, France; Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 19 Via Giuseppe La Masa, 20156 Milan, Italy. Electronic address: ramirobioq@hotmail.com.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Vázquez
authors.affiliation: Oncology Therapeutic Development, 100 rue Martre, 92110 Clichy, France; INSERM U728, Department of Medical Oncology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Astorgues-Xerri
authors.affiliation: Oncology Therapeutic Development, 100 rue Martre, 92110 Clichy, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bekradda
authors.affiliation: Fusion Antibodies Ltd, Springbank Industrial Estate, Pembroke Loop, BT17 0QL Belfast, Northern Ireland, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Gormley
authors.affiliation: Fusion Antibodies Ltd, Springbank Industrial Estate, Pembroke Loop, BT17 0QL Belfast, Northern Ireland, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Buick
authors.affiliation: Fusion Antibodies Ltd, Springbank Industrial Estate, Pembroke Loop, BT17 0QL Belfast, Northern Ireland, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Kerr
authors.affiliation: Oncology Therapeutic Development, 100 rue Martre, 92110 Clichy, France.
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
authors.affiliation: INSERM U728, Department of Medical Oncology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 19 Via Giuseppe La Masa, 20156 Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Laboratory of Anti-tumor Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 19 Via Giuseppe La Masa, 20156 Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.affiliation: Oncology Therapeutic Development, 100 rue Martre, 92110 Clichy, France.
authors.forename: María E
authors.initials: ME
authors.lastname: Riveiro
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002403:Cathepsins; C028217:cathepsin S
keywords: Cathepsin S; Cathepsin S blockade; Cell invasiveness; Colo-205 xenografts; Fsn0503h antibody