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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 15, 2005; DOI: 10.1124/jpet.105.095513

0022-3565/06/3163-983-991$20.00
JPET 316:983-991, 2006
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CELLULAR AND MOLECULAR

A Trimeric Anti-HER2/neu ScFv and Tumor Necrosis Factor-{alpha} Fusion Protein Induces HER2/neu Signaling and Facilitates Repair of Injured EpitheliaFormula

Tzu-Hsuan Huang, and Sherie L. Morrison

Department of Microbiology, Immunology and Molecular Genetics (T.-H.H., S.L.M.) and the Molecular Biology Institute (S.L.M.), University of California, Los Angeles, Los Angeles, California

Tumor necrosis factor (TNF)-{alpha} genetically fused to the carboxyl terminus of a single-chain Fv (ScFv) antibody specific for the human HER2/neu (anti-HER2/neu ScFv-TNF-{alpha}) forms a homotrimeric structure that retains both TNF-{alpha} activity and the ability to bind HER2/neu. In contrast to anti-HER2/neu IgG3, anti-HER2/neu ScFv-TNF-{alpha} induces potent HER2/neu signaling, activating the downstream mitogen-activated protein kinase (MAPK) and Akt pathways in SKBR3 cells. Activation of MAPK and Akt by anti-HER2/neu ScFv-TNF-{alpha} inhibited the apoptosis of SKBR3 cells induced by actinomycin D. Remarkably, anti-HER2/neu ScFv-TNF-{alpha} facilitated the repair of injured epithelia. Accelerated wound healing required binding to HER2/neu but not TNF-{alpha} activity since anti-HER2/neu ScFv-TNF-{alpha} (S147Y), containing a mutant TNF-{alpha} with significantly decreased biological activity, demonstrated equivalent ability to facilitate wound healing and soluble HER2/neu inhibited the effect. These results suggest that trimeric anti-HER2/neu ScFv has the potential to facilitate wound healing. In addition, fusion with TNF-{alpha} provides a novel approach to producing polymeric antibodies.

Received September 9, 2005; accepted November 11, 2005.

Address correspondence to: Dr. Tzu-Hsuan Huang, Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Box 951489, Los Angeles, CA 90095-1489. E-mail: thhhuang{at}ucla.edu






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