Eptinezumab-related information introduction

Eptinezumab is a monoclonal antibody directed against CGRP infused every 3 months for the preventive treatment of migraine in adults.

Eptinezumab is a fully-humanized IgG1 antibody manufactured using yeast (Pichia pastoris) and developed by Lundbeck Seattle Biopharmaceuticals.^[7]

Eptinezumab has been specifically designed to bind to both alpha and beta forms of the human calcitonin gene-related peptide (CGRP).

It was approved by the FDA in February 2020 for the preventive treatment of migraine headaches in adults.^[7]

>Eptinezumab|Heavy

EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGINGATYYA

SWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVTVSSASTKGPSVF

PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV

TVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTHTCPPCPAPELLGGPSVTLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVL

TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLSLSPGK

>Eptinezumab|Light

QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDASTLASGVP

SRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL

SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Eptinezumab is a fully-humanized IgG1 antibody manufactured and designed specifically to bind both alpha and beta forms of the human calcitonin gene-related peptide (CGRP).^{[1][2][3][5][8]}

Studies since 1985 have demonstrated that CGRP levels increase during acute migraine attacks in migraine-suffering patients but normalize after efficacious sumatriptan therapy.^[4] Moreover, research has also shown that intravenous administration of CGRP can induce migraine-like attacks in migraine-suffering patients.^[4] For all these reasons, the binding of CGRP to interfere with its activity was specifically designed to be the form and mechanism of action for Eptinezumab. The binding of Eptinezumab to natural endogenous CGRP subsequently interferes with its activities, such as its binding to CGRP receptors, for example.

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin-receptor-stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha (α-CGRP or CGRP I), and CGRP beta (β-CGRP or CGRP II). α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

CGRP is produced in both peripheral and central neurons. It is a potent peptide vasodilator and can function in the transmission of nociception. In the spinal cord, the function and expression of CGRP may differ depending on the location of synthesis. CGRP is derived mainly from the cell bodies of motor neurons when synthesized in the ventral horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. Conversely, CGRP is derived from dorsal root ganglion when synthesized in the dorsal horn of the spinal cord and may be linked to the transmission of pain. In the trigeminal vascular system, the cell bodies on the trigeminal ganglion are the main source of CGRP. CGRP is thought to play a role in cardiovascular homeostasis and nociception. In the heart, CGRP acts as a chronotrope by increasing heart rate.  Apart from these attributes, CGRP is known to modulate the autonomic nervous system and plays a role in ingestion.

CGRP has moderate effects on calcium homeostasis compared to its extensive actions in other areas, such as the autonomic nervous system.

CGRP mediates its effects through a heteromeric receptor composed of a G protein-coupled receptor called calcitonin receptor-like receptor (CALCRL) and a receptor activity-modifying protein (RAMP1). CGRP receptors are found throughout all the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., respiratory, endocrine, gastrointestinal, immune, and cardiovascular). The extracellular loop number 2 is fundamental for ligand induced activation, with key interactions of R274/Y278/D280/W283.

CGRP receptor is found in myelinated A-fibers axon which is required for ligand specificity and function of the receptor. The CGRP receptor has three subunits: receptor activity-modifying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP).[18] The complex central receptor is the G protein-coupled receptor calcitonin receptor-like receptor (CALCRL) which is necessary for CGRP and adrenomedullin (AM receptors). For function CGRP, CALCRL must coincide with RAMP1 where the ligand-binding domain of CGRP is located. It also includes two cytoplasmic proteins that associate with the CALCRL-RAMP1 to form signal transduction. CALCRL contains the Gα subunit, which activates adenylyl cyclase and cAMP-dependent signaling pathways. Receptor-mediated transduction elevates in intracellular cAMP activate protein kinase A, which results in the phosphorylation of multiple targets, including potassium- sensitive ATP channels (KATP channels), extracellular signal-related kinases and transcription factors such as cAMP-responsive element-binding protein (CREB). In smooth muscle of neurovascular region, the elevation of cAMP upon CGRP activation results in vasodilation of the blood vessel. Chronic exposure to CGRP causes degradation of lysosomes.

Fig 1 Structure of the human calcitonin receptor-Gs complex (Quoted from https://en.wikipedia.org/wiki/Calcitonin_gene-related_peptide#Medicines)

Reference

[1] Pellesi L, Guerzoni S, Pini LA: Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date. Clin Pharmacol Drug Dev. 2017 Nov;6(6):534-547. doi: 10.1002/cpdd.345. Epub 2017 Apr 14. 

[2] Benemei S, Cortese F, Labastida-Ramirez A, Marchese F, Pellesi L, Romoli M, Vollesen AL, Lampl C, Ashina M: Triptans and CGRP blockade - impact on the cranial vasculature. J Headache Pain. 2017 Oct 10;18(1):103. doi: 10.1186/s10194-017-0811-5. 

[3] Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J: Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014 Nov;13(11):1100-1107. doi: 10.1016/S1474-4422(14)70209-1. Epub 2014 Oct 5. 

[4] Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, Vigneri S, Edvinsson L, Maassen Van Den Brink A: Blocking CGRP in migraine patients - a review of pros and cons. J Headache Pain. 2017 Sep 25;18(1):96. doi: 10.1186/s10194-017-0807-1. 

[5] Vollbracht S, Rapoport AM: New treatments for headache. Neurol Sci. 2014 May;35 Suppl 1:89-97. doi: 10.1007/s10072-014-1747-z. 

[6] EconoTimes Business Article: Alder BioPharmaceuticals® New Data Demonstrated Eptinezumab Increased Migraine-Free Intervals (Up to 32.5 days) and Improved Quality-of-Life Outcomes in Patients with Episodic Migraine.

[7] FDA Approved Drug Products: Vyepti (Eptinezumab-jjmr) for intravenous injection.

 

[8] Presentation on CGRP, MONOCLONAL ANTIBODIES AND SMALL MOLECULES (-GEPANTS).