Abstract
Calcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology. Aimovig (erenumab; erenumab-aooe in the United States) is the only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) therapy against the CGRP receptor (CGRPR) for the prevention of migraine. Aimovig is also the first FDA-approved mAb against a G-protein-coupled receptor (GPCR). Here, we report the architecture and functional attributes of erenumab critical for its potent antagonism against CGRPR. The crystal structure of erenumab in complex with CGRPR reveals a direct ligand-blocking mechanism, enabled by a remarkable 21-residue-long complementary determining region (CDR)-H3 loop, which adopts a tyrosine-rich helix-turn tip and projects into the deep interface of the calcitonin receptor-like receptor (CLR) and RAMP1 subunits of CGRPR. Furthermore, erenumab engages with residues specific to CLR and RAMP1, providing the molecular basis for its exquisite selectivity. Such structural insights reveal the drug action mechanism of erenumab and shed light on developing antibody therapeutics targeting GPCRs.
Highlights
Migraine is a prevalent and highly debilitating neurological condition that affects more than 10% of the world’s population (Robbins and Lipton, 2010)
The 21-amino-acid-long complementary determining region (CDR)-H3 (Figure 1C) loop exhibits a distinct secondary structure at the tip that appears to be buried deep into a pocket formed by the calcitonin receptor-like receptor (CLR)/receptor-activity-modifying protein-1 (RAMP1) interface (Figure 1B)
Results indicate that most of the buried paratope into calcitonin-gene-related peptide receptor (CGRPR) comes from the heavy chain (HC) with 1,086 A 2, the light chain (LC) buries 256 A 2
Summary
Migraine is a prevalent and highly debilitating neurological condition that affects more than 10% of the world’s population (Robbins and Lipton, 2010). Aimovig (erenumab; erenumab-aooe in the United States), a human monoclonal antibody (mAb) against the calcitonin-gene-related peptide receptor (CGRPR), was approved by US Food and Drug Administration (FDA) in 2018 for the prevention of migraine in adults. Small-molecule CGRPR antagonists, such as olcegepant and telcagepant, have shown clinical efficacy (Connor et al, 2009; Ho et al, 2008; Olesen et al, 2004), providing pharmacological and clinical validation for the use of CGRPR antagonists as migraine therapies. None of the smallmolecule agents, have been approved for clinical use due to poor pharmacokinetic properties and off-target liver toxicity concerns (Hewitt et al, 2011). Monoclonal antibodies offer unique advantages for preventive therapy, as they possess desirable pharmacokinetic and safety profiles, including longer plasma half-life, lower off-target toxicity, and minimum drugdrug interactions (Gerber, 2008; Hansel et al, 2010)
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