title: Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor.
abstract: Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with [(125)I]-CGRP binding to the human CGRP receptor, with a Ki of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (>5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Licheng
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Dawn X D
authors.initials: DX
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Smith
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: David C
authors.initials: DC
authors.lastname: Immke
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Wild
authors.affiliation: Department of Neuroscience (L.S., S.G.L., D.X.D.Z., H.S., J.Z., D.C.I., K.D.W., C.X.), Department of Global Biostatistical Science (B.P.S.), Amgen Inc., Thousand Oaks, California cenx@amgen.com.
authors.forename: Cen
authors.initials: C
authors.lastname: Xu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001667:Binding, Competitive / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008881:Migraine Disorders / Q000517:prevention & control; D011817:Rabbits; D051381:Rats; D018003:Receptors, Calcitonin / Q000187:drug effects / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018003:Receptors, Calcitonin; D000242:Cyclic AMP; C000605816:erenumab; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin