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

• Published in: Molecular cancer therapeutics Vol. 16; no. 6; pp. 1102 - 1113
• Main Authors: Chien, Ming-Hsien, Chang, Wei-Min, Lee, Wei-Jiunn, Chang, Yu-Chan, Lai, Tsung-Ching, Chan, Derek V., Sharma, Rahul, Lin, Yuan-Feng, Hsiao, Michael
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.06.2017
• Subjects: Animals; Antibodies, Monoclonal, Humanized - genetics; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - pharmacology; Antibody-Dependent Cell Cytotoxicity - immunology; Antigens, Neoplasm - immunology; Apoptosis; Biocompatibility; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic - metabolism; Cytotoxicity; Disease Models, Animal; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; fas Receptor - metabolism; FasL protein; Fusion protein; Glycoproteins; Glycoproteins - antagonists & inhibitors; Glycoproteins - immunology; Humans; Invasiveness; Keratinocytes; Ligands; Lymph nodes; Matrix metalloproteinases; Metastases; Mice; Mouth Neoplasms - drug therapy; Mouth Neoplasms - immunology; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Oral squamous cell carcinoma; Patients; Prognosis; Protein Binding; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; Signaling; Single-Chain Antibodies - genetics; Single-Chain Antibodies - immunology; Single-Chain Antibodies - pharmacology; Squamous cell carcinoma; Tissues; Toxicity; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0314

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.