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J. Biol. Chem., Vol. 279, Issue 42, 43780-43788, October 15, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/42/43780    most recent M401803200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, W. Articles by Lee, D. H. S. Search for Related Content PubMed PubMed Citation Articles by Li, W. Articles by Lee, D. H. S. Social Bookmarking                      What's this?

A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin^*

Weiwei Li, Lee Walus, Sylvia A. Rabacchi, Adrienna Jirik, Ernie Chang, Jessica Schauer, Betty H. Zheng, Nancy J. Benedetti, Betty P. Liu, Eugene Choi, Dane Worley, Laura Silvian, Wenjun Mo, Colleen Mullen, Weixing Yang, Stephen M. Strittmatter, Dinah W. Y. Sah, Blake Pepinsky, and Daniel H. S. Lee¶

From the Biogen Idec, Inc., Cambridge, Massachusetts 02142 and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06150

The Nogo66 receptor (NgR1) is a neuronal, leucinerich repeat (LRR) protein that binds three central nervous system (CNS) myelin proteins, Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein, and mediates their inhibitory effects on neurite growth. Although the LRR domains on NgR1 are necessary for binding to the myelin proteins, the exact epitope(s) involved in ligand binding is unclear. Here we report the generation and detailed characterization of an anti-NgR1 monoclonal antibody, 7E11. The 7E11 monoclonal antibody blocks Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein binding to NgR1 with IC₅₀ values of 120, 14, and 4.5 nM, respectively, and effectively promotes neurite outgrowth of P3 rat dorsal root ganglia neurons cultured on a CNS myelin substrate. Further, we have defined the molecular epitope of 7E11 to be DNAQLR located in the third LRR domain of rat NgR1. Our data demonstrate that anti-NgR1 antibodies recognizing this epitope, such as 7E11, can neutralize CNS myelin-dependent inhibition of neurite outgrowth. Thus, specific anti-NgR1 antibodies may represent a useful therapeutic approach for promoting CNS repair after injury.

Received for publication, February 18, 2004 , and in revised form, July 13, 2004.

^* 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.

^¶ To whom correspondence should be addressed: Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142. Tel.: 617-679-2563; Fax: 617-679-3200; E-mail: Daniel_Lee{at}biogenidec.com.

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