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CELLULAR AND MOLECULAR

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

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)- genetically fused to the carboxyl terminus of a single-chain Fv (ScFv) antibody specific for the human HER2/neu (anti-HER2/neu ScFv-TNF-) forms a homotrimeric structure that retains both TNF- activity and the ability to bind HER2/neu. In contrast to anti-HER2/neu IgG3, anti-HER2/neu ScFv-TNF- 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- inhibited the apoptosis of SKBR3 cells induced by actinomycin D. Remarkably, anti-HER2/neu ScFv-TNF- facilitated the repair of injured epithelia. Accelerated wound healing required binding to HER2/neu but not TNF- activity since anti-HER2/neu ScFv-TNF- (S147Y), containing a mutant TNF- 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- provides a novel approach to producing polymeric antibodies.

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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