title: A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio.
abstract: Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the fight against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv-FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells.In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymph node metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio.Mol Cancer Ther; 16(6); 1102-13. ©2017 AACR.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chang
authors.affiliation: Department of Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chan
authors.initials: YC
authors.lastname: Chang
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Tsung-Ching
authors.initials: TC
authors.lastname: Lai
authors.affiliation: Center for Immunity, Inflammation, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Derek V
authors.initials: DV
authors.lastname: Chan
authors.affiliation: Center for Immunity, Inflammation, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. d001089012@tmu.edu.tw mhsiao@gate.sinica.edu.tw.
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, Taiwan. d001089012@tmu.edu.tw mhsiao@gate.sinica.edu.tw.|Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|The PhD Program for Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D053222:Fas Ligand Protein; D006023:Glycoproteins; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D019014:fas Receptor; C047052:tumor-associated antigen 72