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Mol Cancer Ther. 2005;4:1801-1809
© 2005 American Association for Cancer Research

Human single-domain neutralizing intrabodies directed against Etk kinase: a novel approach to impair cellular transformation

Keren Paz, Laura A. Brennan, Michelle Iacolina, Jacqueline Doody, Yaron R. Hadari and Zhenping Zhu

Departments of Antibody Technology and Protein Science, ImClone Systems, New York, New York

Requests for reprints: Keren Paz, Department of Antibody Technology, ImClone Systems, 180 Varick Street, New York, NY 10014. Phone: 201-645-1405; Fax: 212-645-2054. E-mail: keren.paz{at}imclone.com

Etk, the 70-kDa member of the Tec family of nonreceptor protein tyrosine kinases, is expressed in a variety of hematopoietic, epithelial, and endothelial cells and was shown to be involved in several cellular processes, including proliferation, differentiation, and motility. In this study, we describe a novel approach using a human single-domain antibody phage display library for the generation of intrabodies directed against Etk. These single-domain antibodies bind specifically to recombinant Etk and efficiently block its kinase activity. When expressed in transformed cells, these antibodies associated tightly with Etk, leading to significant blockade of Etk enzymatic activity and inhibition of clonogenic cell growth in soft agar. Our results indicate that Etk may play a role in Src-induced cellular transformation and thus may represent a good target for cancer intervention. Furthermore, our single-domain antibody-based intrabody system proves to be an excellent tool for future intracellular targeting of other signaling molecules.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 2/05; revised 8/17/05; accepted 8/30/05.




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Copyright © 2005 by the American Association for Cancer Research.