title: Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies.
abstract: The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC(50) of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments.
authors: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors: Christine
authors: C
authors: Kowalczyk
authors: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors: Nathalie
authors: N
authors: Dunkel
authors: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors: Laure
authors: L
authors: Willen
authors: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6010.
authors: Margret L
authors: ML
authors: Casal
authors: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6010.
authors: Elizabeth A
authors: EA
authors: Mauldin
authors: Department of Dermatology, University of Geneva, CH-1211 Geneva, Switzerland.
authors: Olivier
authors: O
authors: Gaide
authors: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors: Aubry
authors: A
authors: Tardivel
authors: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors: Giovanna
authors: G
authors: Badic
authors: Apoxis SA, CH-1004 Lausanne, Switzerland.
authors: Anne-Lise
authors: AL
authors: Etter
authors: Apoxis SA, CH-1004 Lausanne, Switzerland.
authors: Manuel
authors: M
authors: Favre
authors: Cell Essential, Boston, Massachusetts 02116; Tufts University School of Medicine, Boston, Massachusetts 02111.
authors: Douglas M
authors: DM
authors: Jefferson
authors: Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin EH25 9PS, Scotland, United Kingdom.
authors: Denis J
authors: DJ
authors: Headon
authors: Apoxis SA, CH-1004 Lausanne, Switzerland; Edimer Biotech, Ch de l'Eglise 7, CH-1066 Epalinges, Switzerland.
authors: Stéphane
authors: S
authors: Demotz
authors: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. Electronic address: pascal.schneider@unil.ch.
authors: Pascal
authors: P
authors: Schneider
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002469:Cell Separation; D002645:Chickens; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018604:Epitope Mapping / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D053338:Receptors, Ectodysplasin / Q000737:chemistry* / Q000276:immunology; D020349:Surface Plasmon Resonance; D014070:Tooth / Q000196:embryology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands; D053338:Receptors, Ectodysplasin; D014409:Tumor Necrosis Factor-alpha