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 K i of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC 50 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 IC 50 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.

Wiping Out CGRP: Potential Cardiovascular Risks

“…These include CGRP-binding RNA-Spiegelmers (e.g., NOX-L41 [14]) and monoclonal humanized antibodies directed against CGRP ('nezumabs', for the nomenclature of antibodies, see [15]: ALD403; TEV-48125; LY2951742-galcanezumab) [16][17][18][19]. In addition, a fully human monoclonal antibody ([ 8 _ T D $ D I F F ] AMG 334, erenumab, a 'numab' [15]) has been developed that is targeted against the CGRP receptor [20].…”

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

“…The approach to targeting the CGRP receptor was chosen because, as the scientists who developed it, including the lead, Dr. Cen Xu, wrote, “the ligand binding site of CGRP on the calcitonin receptor–like receptor (CRLR)–receptor activity‐modifying protein‐1 (RAMP1) CGRP‐receptor complex is broad; therefore, an antibody that can span the distance between these receptor subunits can offer the most effective blockade; 2) high selectivity for the CGRP receptor complex, which shares similarities with other receptors in the family, and if these other receptors are blocked by a less selective agent, undesired side effects could arise; and 3) the prolonged serum half‐life of an antibody can permit longer dosing intervals, which are ideal for preventive therapies.”…”

Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

“…In vitro data have shown that erenumab binds to human CGRP receptors with high affinity (dissociation equilibrium constant K D  = 20 pM) and potency (IC 50  = 2.3 nM) in a competitive and reversible manner [8]. Results from single-ascending dose (SAD) and multiple-ascending dose (MAD) phase 1 studies (NCT01688739 and NCT01723514, respectively) have been reported and showed that erenumab inhibited CIDBF in healthy and migraine subjects, indicating CGRP-receptor antagonism [9] (de Hoon JN, Van Hecken A, Yan L, Smith B, Chen JS, Bautista E, et al, unpublished data).…”