title: Identification, characterization, and targeting of IL-4 receptor by IL-4-Pseudomonas exotoxin in mouse models of anaplastic thyroid cancer.
abstract: Thyroid cancer is a rapidly increasing endocrine cancer. Since interleukin-4 receptor (IL-4R) is overexpressed in human solid cancer, we examined expression of IL-4R in 50 cases of anaplastic thyroid cancer (ATC), 37 well-differentiated papillary cancer (WDPC), 35 well-differentiated follicular cancer of thyroid (WDFC), and 37 normal thyroid specimens by immunohistochemistry (IHC) and in-situ hybridization (ISH) techniques. We demonstrated that IL-4Rα was overexpressed in 36/50 (72%) ATC, 20/35 (57%) WDFC, and 11/37 (30%) WDPC tumors. Other two subunits of IL-4R, interleukin-13 receptor α1 (IL-13Rα1) and interleukin-2 receptor gamma (IL-2RγC), were either weakly expressed or absent. As ATC is a highly aggressive cancer with higher incidence of IL-4Rα expression, we characterized IL-4R in 3 ATC cell lines. RT-qPCR and IFA results showed that IL-4Rα is overexpressed while IL-13Rα1 is weakly expressed. Control human umbilical vein endothelial cell line (HUVEC) showed weak expression of IL-4Rα. Binding and competition studies with 125I-IL-4 in ATC cell lines demonstrated that IL-4 specifically bound to IL-4Rα on cell surface. ATC cell lines were highly sensitive to a chimeric fusion cytotoxin consisting of circularly permuted IL-4 and truncated Pseudomonas exotoxin (IL-4-PE), which killed them in a concentration dependent manner. IL-4-PE also blocked colony formation of ATC cell lines in clonogenic assays. IL-4-PE mediated a significant antitumor activity in mouse models of ATC. Intratumoral administration of IL-4-PE caused significant regression of established tumors in a dose dependent manner and increased the overall survival without any visible toxicity. Thus, IL-4Rα in ATC may represent a novel therapeutic target and IL-4-PE may serve as an investigational therapeutic option for ATC.
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Toshio
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Leland
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Varrichio
authors.affiliation: Office of Biostatistics and Epidemiology, Mayo Clinic, Minnesota, MN 55905, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Lababidi
authors.affiliation: Department of Pathology, Mayo Clinic, Minnesota, MN 55905, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lloyd
authors.affiliation: Department of Otolaryngology, Mayo Clinic, Minnesota, MN 55905, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Kasperbauer
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology*; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D037521:Virulence Factors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D015847:Interleukin-4; D053662:Interleukin-4 Receptor alpha Subunit; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508598:IL4 protein, human; C504000:IL4R protein, human