Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy

• Published in: Clinical cancer research 2008-10, Vol.14 (20), p.6538-6545
• Main Authors: Ran, Yuliang, Hu, Hai, Hu, Dong, Zhou, Zhuan, Sun, Yuemin, Yu, Long, Sun, Lixin, Pan, Jian, Liu, Jun, Liu, Tong, Yang, Zhihua
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Cell Membrane - metabolism; Cell Proliferation; cell surface expression; Cytoplasm - metabolism; Derlin-1; Endoplasmic Reticulum - metabolism; Extracellular Matrix - metabolism; Female; Fluorescent Antibody Technique; Humans; Immunoconjugates - pharmacokinetics; Iodine Radioisotopes - therapeutic use; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, Nude; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; Peptide Fragments - immunology; Peptide Fragments - metabolism; Pharmacology. Drug treatments; Rabbits; Radiopharmaceuticals - therapeutic use; Tissue Array Analysis; Tissue Distribution; tumor targeting therapy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0476

Purpose: Tumor targeting therapy is one of the most promising strategies for anticancer treatment. Derlin-1 has been reported to participate in misfolded protein dislocation and integrates into the endoplasmic reticulum (ER) membrane to survey for such protein aggregates. We elucidate herein that Derlin-1 can leak to the plasmalemma from the ER in tumor cells and may have clinical application as a novel cancer target in the hope of developing a new tumor targeting therapy. Experimental Design: The cell surface expression of Derlin-1 was shown by immunofluorescence analysis of nonpermeabilized cells and Western blotting of fractional proteins of tumor cells. Derlin-1 expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and γ-scintigraphic imaging were done using 125 I-labeled Derlin-1 targeting antibody in isogenic mice models. Finally, tumor-bearing mice were treated by the anti-Derlin-1 polyclonal antibody and monoclonal antibodies. Results: Derlin-1 was expressed on various tumor cell surfaces and adopted a homodimer conformation. Robust cytoplasmic and membrane expression of Derlin-1 was detected in various types of human cancers tissues but was not correlated with any clinicopathologic features of pancreatic cancer. Derlin-1 directed antibodies specifically targeted to colon tumors and significantly suppress tumor growth in isogenic mice. Conclusions: These preclinical data show that Derlin-1 protein is a functional molecular target expressed on the tumor cell surface and is a candidate therapeutic target that may be translated into clinical applications.