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

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Received for publication September 12, 2005.
Revised November 10, 2005.
Accepted for publication November 11, 2005.

A trimeric anti-HER2/neu ScFv and TNF-{alpha} fusion protein induces HER2/neu signaling and facilitates repair of injured epithelia

Tzu-Hsuan Huang 1* Sherie L Morrison 1

1 UCLA

* Address correspondence to: E-mail: thhhuang{at}ucla.edu

Abstract

TNF-{alpha} genetically fused to the carboxy 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 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. Additionally, fusion with TNF-{alpha} provides a novel approach to producing polymeric antibodies.


Key words: Akt, HER2/neu, MAPK, TNF-alpha, trimeric antibody, wound healing




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