title: Anti-repulsive Guidance Molecule C (RGMc) Antibodies Increases Serum Iron in Rats and Cynomolgus Monkeys by Hepcidin Downregulation.
abstract: High levels of hepcidin, the main regulator of systemic iron metabolism, lead to various diseases. Targeting hepcidin and lowering its concentration is a possible form of intervention in order to treat these diseases. High turnover rate of hepcidin is a major drawback of therapies directly targeting this peptide. We developed two monoclonal antibodies ABT-207 and h5F9-AM8 which inhibit hemojuvelin/repulsive guidance molecule C (RGMc) and downregulate hepcidin. We conducted single-application and dose response studies to understand the antibodies' mechanism and subchronic toxicology studies to exclude safety-related concerns. Investigation was carried out at different biological levels through qPCR, Affymetrix, liquid chromatography coupled with mass spectrometry (LC-MS/MS), histopathology, serum iron, unsaturated iron binding capacity (UIBC), and drug concentration measurements. After a single application of these antibodies, hepcidin expression in liver and its serum protein levels were reduced. Serum iron increased for several weeks. The RGMc antibodies show a pronounced dose response relationship in rats with h5F9-AM8 having an IC50 (UIBC) of approximately 80-fold higher than ABT-207. When hepcidin levels were downregulated, iron deposition in the liver was visible histologically 1 week post application. These antibody-mediated iron depositions were not associated with any adverse toxicologically relevant effect at the doses and time points evaluated. Iron depositions seen after 14 weekly treatments with ABT-207 were reversible in rats and in cynomolgus monkeys. Due to their long-lasting effects and excellent safety profile, both RGMc-blocking antibodies ABT-207 and h5F9-AM8 are favorable clinical candidates for diseases characterized by high serum hepcidin levels like anemia of chronic disease.
authors.affiliation: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen, Germany.
authors.forename: Preethne
authors.initials: P
authors.lastname: Böser
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seemann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Liguori
authors.forename: Leimin
authors.initials: L
authors.lastname: Fan
authors.forename: Lili
authors.initials: L
authors.lastname: Huang
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.forename: Andreas
authors.initials: A
authors.lastname: Popp
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Mueller
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D064451:Hepcidins / Q000097:blood / Q000235:genetics*; D020128:Inhibitory Concentration 50; D007501:Iron / Q000097:blood*; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D064451:Hepcidins; D008565:Membrane Proteins; D007501:Iron