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J. Biol. Chem., Vol. 279, Issue 53, 55697-55706, December 31, 2004

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Modulation of the M2 Muscarinic Acetylcholine Receptor Activity with Monoclonal Anti-M2 Receptor Antibody Fragments^*

Jean-Christophe Peter, Gerd Wallukat¶, Jean Tugler||, Damien Maurice||, Jean-Christophe Roegel||, Jean-Paul Briand, and Johan Hoebeke**

From the CNRS, Unité Propre de Recherche 9021, Institut de Biologie Moléculaire et Cellulaire, Laboratory of Therapeutical Chemistry and Immunology, F-67084 Strasbourg, France, ^¶Max Delbrück Centrum for Molecular Medicine, D-13092 Berlin, Germany, and ^||Forenap Therapeutic Discovery, Institute of Pharmacology, School of Medicine, F-67000 Strasbourg, France

Antibodies directed against the second extracellular loop of G protein-coupled receptors are known to have functional activities. From a partial agonist monoclonal antibody directed against the M2 muscarinic receptor, we constructed and produced a single chain variable fragment with high affinity for its target epitope. The fragment is able to recognize its receptor on Chinese hamster ovary cells transfected with the M2 muscarinic acetylcholine receptor to block the effect of carbachol on this receptor and to exert an inverse agonist activity on the basal activity of the receptor. The antibody fragment is also able to increase the basal rhythm of cultured neonatal rat cardiomyocytes and to inhibit in a non-competitive manner the negative chronotropic effect of carbachol. This antibody fragment is able to exert its inverse agonist activity in vivo on mouse heart activity. The immunological strategy presented here could be useful to develop specific allosteric inverse agonist reagents for G protein-coupled receptors.

Received for publication, June 28, 2004 , and in revised form, October 6, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ746180.

^* This work was supported in part by grants from the Centre National de la Recherche Scientifique and Fondation pour la Recherche Médicale. 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.

Supported by a grant from the Ministère de le Recherche et Technologies.

^** To whom correspondence should be addressed: UPR 9021 CNRS "Immunologie et Chimie Thérapeutiques," IBMC, 15, rue René Descartes, F-67084 Strasbourg, France. Tel.: 33-3-88-41-70-24; Fax: 33-3-88-61-06-80; E-mail: j.hoebeke{at}ibmc.u-strasbg.fr.

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