The TWEAK receptor Fn14 is a therapeutic target in melanoma: immunotoxins targeting Fn14 receptor for malignant melanoma treatment.

Abstract

Fibroblast growth factor-inducible protein 14 (Fn14), the cell surface receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is overexpressed in various human solid tumor types and can be a negative prognostic indicator. We detected Fn14 expression in ∼60% of the melanoma cell lines we tested, including both B-Raf WT and B-Raf(V600E) lines. Tumor tissue microarray analysis indicated that Fn14 expression was low in normal skin, but elevated in 173/190 (92%) of primary melanoma specimens and in 86/150 (58%) of melanoma metastases tested. We generated both a chemical conjugate composed of the recombinant gelonin (rGel) toxin and the anti-Fn14 antibody ITEM-4 (designated ITEM4-rGel) and a humanized, dimeric single-chain antibody of ITEM-4 fused to rGel (designated hSGZ). Both ITEM4-rGel and hSGZ were highly cytotoxic to a panel of different melanoma cell lines. Mechanistic studies showed that both immunotoxins induced melanoma cell necrosis. In addition, these immunotoxins could upregulate the cellular expression of Fn14 and trigger cell-signaling events similar to the Fn14 ligand TWEAK. Finally, treatment of mice bearing human melanoma MDA-MB-435 xenografts with either ITEM4-rGel or hSGZ showed significant tumor growth inhibition compared with controls. We conclude that Fn14 is a therapeutic target in melanoma and the hSGZ construct appears to warrant further development as a therapeutic agent against Fn14-positive melanoma.

• Authors: Hong Zhou, Suhendan Ekmekcioglu, John W Marks, Khalid A Mohamedali, Kaushal Asrani, Keeley K Phillips, Sharron A N Brown, Emily Cheng, Michele B Weiss, Walter N Hittelman, Nhan L Tran, Hideo Yagita, Jeffrey A Winkles, Michael G Rosenblum
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 133 Issue 4 Pg. 1052-62 (Apr 2013) ISSN: 1523-1747 [Electronic] United States
• PMID: 23190886 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Immunologic Factors
• Immunotoxins
• NF-kappa B
• Receptors, Tumor Necrosis Factor
• TNFRSF12A protein, human
• TWEAK Receptor
• Tnfrsf12a protein, mouse

Topics

• Animals
• Cell Death (drug effects)
• Cell Line, Tumor
• Drug Design
• Female
• Humans
• Immunologic Factors (genetics, immunology, pharmacokinetics)
• Immunotoxins (genetics, immunology, pharmacokinetics)
• Melanoma (drug therapy, immunology)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Protein Binding (immunology)
• Receptors, Tumor Necrosis Factor (immunology, metabolism)
• Signal Transduction (drug effects, immunology)
• Skin Neoplasms (drug therapy, immunology)
• TWEAK Receptor
• Up-Regulation (drug effects, immunology)
• Xenograft Model Antitumor Assays