Log In

Forgot Password?

OR

Not a member? Continue as a nonmember.

Become a Member

By becoming a member of the AAN, you can receive exclusive information to help you at every stage of your career. Benefits include:

Join Now See All Benefits

Loading... please wait

Abstract Details

Eptinezumab:CGRP Complex Structure and Characterization of the Ligand Binding Interface
Headache
Headache Posters (7:00 AM-5:00 PM)
059
Eptinezumab is a humanized monoclonal antibody that selectively and potently inhibits CGRP, demonstrating rapid engagement of the target ligand and reliable duration of action. 
To delineate the molecular binding mode of eptinezumab to CGRP by solving the crystal structure of the unbound eptinezumab Fab fragment and its complex with CGRP.
Eptinezumab Fab fragments—alone and in complex with a-CGRP peptide (hereafter, CGRP)—were purified, concentrated, and screened for crystallization. The tridimensional structure of the complex and the unbound Fab fragment were determined by X-ray diffraction data. Molecular dynamics simulations were performed to analyze the transition between unbound and bound states.
The atomic resolution tridimensional eptinezumab:CGRP complex molecular structure reveals that CGRP binds in a deep, narrow pocket formed by eptinezumab Fab heavy and light chains. There is extensive contact between all 6 complementarity-determining regions of eptinezumab and CGRP. Eleven of 12 CGRP amino acids visible in the crystal structure are in contact with eptinezumab Fab. The complex has high ligand-binding surface area dominated by aromatic residues, likely driving interaction selectivity and specificity. Eptinezumab contains a disulfide bond in L3, which stabilizes this loop, contributes surface area to the binding pocket, and provides van der Waals contacts. Comparison of unbound and complex structures reveals key motion near the binding cleft: heavy chain CDR loops H2 and H3 are displaced by ~1.4–2.0 Å; residue H-Tyr33 changes conformation; and CDR loop H1 is stabilized such that it is visible in the co-structure. These conformational changes create a “latch-and-lock” mechanism for binding CGRP and preventing dissociation.
Unique attributes of the eptinezumab molecular structure Fab region shed light on the specificity, durability, and strength of binding to CGRP. Details of the eptinezumab:CGRP complex structure and comparison to the unbound structure significantly advance our understanding of eptinezumab’s mechanism of action.
Authors/Disclosures
Kira Misura
PRESENTER
Kira Misura has received personal compensation for serving as an employee of Lundbeck Seattle Biopharmaceuticals. Kira Misura has received personal compensation for serving as an employee of Alder Biopharmaceuticals. Kira Misura has received stock or an ownership interest from Alder Biopharmaceuticals.
Laurent David (H. Lundbeck A/S) Laurent David has nothing to disclose.
Michelle Scalley-Kim (Seattle Genetics) Michelle Scalley-Kim has received personal compensation for serving as an employee of Alder Biopharmaceuticals. Michelle Scalley-Kim has received personal compensation for serving as an employee of Lundbeck . Michelle Scalley-Kim has received personal compensation for serving as an employee of Seattle Genetics. Michelle Scalley-Kim has received stock or an ownership interest from Seattle Genetics. Michelle Scalley-Kim has received stock or an ownership interest from Alder Biopharmaceuticals.
Andrea Olland (Xtal BioStructures) Andrea Olland has a non-compensated relationship as a author on a submitted abstract with Alder Bio (now Lundberg) that is relevant to AAN interests or activities.
Andre White (XTAL BioStructures) Andre White has a non-compensated relationship as a contributing scientist and Director with XTAL BioStructures that is relevant to AAN interests or activities.