title: Generation and characterization of rendomab-B1, a monoclonal antibody displaying potent and specific antagonism of the human endothelin B receptor.
abstract: Endothelin B receptor (ETBR) is a G protein-coupled receptor able to bind equally to the three identified human endothelin peptides. It is expressed primarily on vascular endothelial cells and involved in various physiological processes including vascular tone homeostasis, enteric nervous system development, melanogenesis and angiogenesis. Furthermore, overactivation or overexpression of ETBR have been associated with the development of various diseases such as cardiovascular disorders and cancers. Therefore, ETBR appears to be relevant target for the therapy or diagnosis of highly prevalent human diseases. In this study, we report the in vitro characterization of rendomab-B1, a monoclonal antibody (mAb) obtained by genetic immunization, which selectively recognizes the native form of human ETBR (hETBR). Rendomab-B1 is the first-reported mAb that behaves as a potent antagonist of hETBR. It recognizes an original extracellular conformational epitope on the receptor, distinct from the endothelin-1 (ET-1) binding site. Rendomab-B1 not only blocks ET-1-induced calcium signaling pathway and triggers rapid receptor internalization on recombinant hETBR-expressing cells, but also exerts pharmacological activities on human vascular endothelial cells, reducing both cell viability and ET-1-induced hETBR synthesis. In addition, binding experiments using rendomab-B1 on different melanoma cell lines reveal the structural and functional heterogeneity of hETBR expressed at the surface of these cancer cells, strongly suggesting the existence of tumor-specific receptors. Collectively, our results underscore the value of rendomab-B1 for research, therapeutic and diagnostic applications dealing with hETBR.
authors.affiliation: CEA, iBiTecS, SPI, Laboratoire d'Ingénierie des Anticorps pour Santé, Gif sur Yvette, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Allard
authors.forename: Anne
authors.initials: A
authors.lastname: Wijkhuisen
authors.forename: Aurélie
authors.initials: A
authors.lastname: Borrull
authors.forename: Frédérique
authors.initials: F
authors.lastname: Deshayes
authors.forename: Fabienne
authors.initials: F
authors.lastname: Priam
authors.forename: Patricia
authors.initials: P
authors.lastname: Lamourette
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ducancel
authors.forename: Didier
authors.initials: D
authors.lastname: Boquet
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Couraud
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000276:immunology*; D016466:CHO Cells / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000008:administration & dosage; D065131:Endothelin B Receptor Antagonists; D005260:Female; D057809:HEK293 Cells / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007114:Immunization; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D044023:Receptor, Endothelin B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D065131:Endothelin B Receptor Antagonists; D044023:Receptor, Endothelin B; D043562:Receptors, G-Protein-Coupled; D004247:DNA