Trending Topic

Brain head human mental idea mind 3D illustration background
8 mins

Trending Topic

Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Cognitive impairment is the hallmark symptom of Alzheimer’s disease (AD); however, neuropsychiatric symptoms (NPS), including psychosis, agitation and mood disturbances, are common not only in AD but also in Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia and vascular dementia.1–5 Psychotic symptoms have been reported to be present in 12–74% of patients with AD, with […]

Therapeutic Monoclonal Antibodies for Migraine

Stephen Silberstein
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: May 20th 2015 US Neurology, 2015;11(1):64–5 DOI: http://doi.org/10.17925/USN.2015.11.01.64
Select a Section…
1

Abstract

Overview

Monoclonal antibody (mAb) treatment has revolutionized the approach to many diseases. They comprise immunoglobulin G (IgG) isotypes. Calcitonin gene-related peptide (CGRP) is important in migraine pathogenesis. Four mAbs that target either CGRP or the CGRP receptor are in development for prophylaxis of episodic migraine or chronic migraine. Preliminary data suggest that they are effective.

Keywords

Monoclonal antibodies, migraine treatment, calcitonin gene-related peptide (CGRP)

2

Article

Monoclonal antibody (mAb) treatment has revolutionized the approach to many diseases and represents a fast-growing area of drug development.1,2 They are composed of immunoglobulin G (IgG) isotypes, divided into four subclasses.3 In 1986, the US Food and Drug Administration (FDA) approved muromonab-CD3, the first mouse-derived therapeutic mAb indicated for transplant rejection.4 Human or “fully human” mAbs were later developed in 2002 that contained human heavy and light chains. How are mAb named? The stem -mAb indicates an mAb, and the substem indicates the species: murine (-omAb), chimeric (-ximAb), humanized (-zumAb), and human (-umAb).5 Antibodies can bind directly to the ligand or its receptor.6 Binding to a cell-surface receptor prevents binding of the ligand and causes downstream processes (e.g. receptor dimerization, receptor breakdown, and signal transduction).6

Monoclonal antibodies are delivered parenterally because of their large size and hydrophilicity. They are not filtered by the kidney or excreted into the urine intact. Their average serum half-life is weeks to months, allowing them to be administered monthly.7, 8

Monoclonal Antibodies in Migraine Prophylaxis
Calcitonin gene-related peptide (CGRP) is important in migraine pathogenesis.9 Recently, multiple human monoclonal antibodies that specifically target the human CGRP receptor have been generated. The inhibition of capsaicin-induced increases in dermal blood flow has been used as an in vivo pharmacodynamic model in humans and nonhuman primates during their development. Topically applied capsaicin stimulates dermal neurons to release CGRP resulting in a localized increase in dermal blood flow. The CGRP receptor mAb prevented capsaicin-induced increase in dermal blood flow in cynomolgus monkeys for up to 7 days.10

The immunochemical distribution of CGRP receptor mAb has been tested. This recognizes the functional CLR/RAMP1 receptor complex, but not its individual components. CGRP receptor complexes are expressed on multiple levels in the trigeminal vascular system of the cynomolgus monkey: 1) in the meningeal vasculature innervated by CGRP-positive nerve fibers; 2) in neurons and satellite cells in the trigeminal ganglion; and 3) in neurons in the spinal trigeminal nucleus. The CGRP receptor localization is consistent with CGRP’s role in trigeminal sensitization and suggests that interfering with CGRP receptor transmission may be beneficial for the treatment of migraines.11

Another approach is CGRP antibodies that would inhibit neurogenic vasodilation with a long duration of action. Incorporating two rat blood-flow models measuring electrically stimulated vasodilation in the skin or the middle meningeal artery, vasodilatatory responses were found largely dependent on the neurogenic release of CGRP from sensory afferents. Treatment with anti-CGRP antibodies inhibited skin vasodilation or the increase in middle meningeal artery diameter to a similar magnitude as treatment with CGRP receptor antagonists, but with a slower onset of action. The inhibition was evident 1 week after dosing. Chronic treatment with anti- CGRP antibodies had no detectable effects on heart rate or blood pressure.12

Four mAbs that target either CGRP or the CGRP receptor are currently in development for prophylaxis of episodic migraine (four to 14 headache days per month) or chronic migraine (≥15 headache days per month). LY2951742 is a humanized mAb targeted against the CGRP ligand (CGRP itself). In a phase II study of patients with episodic migraines, subcutaneous (SC) administration of LY2951742 (150 mg every 2 weeks) resulted in a reduction from baseline at week 12 of 1.2 days compared with placebo.13 In a separate phase II study, ALD403, another humanized mAb against the CGRP ligand, showed similar results at weeks 5 to 8; intravenous (IV) administration of ALD403 (1,000 mg) reduced monthly migraine headaches by 1.0 day compared with the placebo group.14 Monthly dosing (SC) of LBR- 101, a third humanized mAb against the CGRP ligand, and monthly dosing (SC) of AMG 334 are also being evaluated in phase II clinical trials. AMG 334 is unique among the novel CGRP mAbs for migraine prevention in that it is a fully human mAb that targets the CGRP receptor rather than CGRP itself. Results of the AMG 334 will be presented at the Biennial Congress of the International Headache Society, Valencia, Spain, May 14–17, 2015. Monoclonal antibodies offer advantages: high target specificity, no liver or kidney metabolism, and a long half-life. The safety and efficacy of monoclonal antibodies against the CGRP ligand or CGRP receptor are currently being investigated and will help determine the importance of these potentially new treatments for migraine prevention.

2

References

  1. Buss NA, Henderson SJ, McFarlane M, et al., Monoclonal
    antibody therapeutics: history and future, Curr Opin Pharmacol,
    2012;12:615–22.

  2. Reichert JM, Therapeutic monoclonal antibodies approved or
    in review in the European Union or United States. Available at:
    http://www.antibodysociety.org/news/approved_mabs.php
    (accessed November 15, 2014).

  3. Jefferis R, Isotype and glycoform selection for antibody
    therapeutics, Arch Biochem Biophys, 2012;526:159–66.

  4. Nelson AL, Dhimolea E, Reichert JM, Development trends
    for human monoclonal antibody therapeutics, Nat Rev Drug
    Discov, 2010;9:767–74.

  5. International Nonproprietary Names (INN) for biological
    and biotechnological substances, World Health
    Organization, 2013.

  6. Carden CPA, Arkenau HT, de Bono JS, Optimising the
    development of antibodies as treatment for cancer. In:
    Hidalgo ME, Garrett-Mayer E, Clendeninn NJ, eds, Cancer
    Drug Discovery and Development, New York, NY: Springer
    Science+Business Media, 2011.

  7. Mould DR, Sweeney KRD, The pharmacokinetics and
    pharmacodynamics of monoclonal antibodies—mechanistic
    modeling applied to drug development, Curr Opin Drug Discov
    Devel, 2007;10:84–96.

  8. Wang W, Wang EQ, Balthasar JP, Monoclonal antibody
    pharmacokinetics and pharmacodynamics, Clin Pharmacol
    Ther, 2008;84:548–58.

  9. Bell IM, Calcitonin gene-related peptide receptor antagonists:
    New therapeutic agents for migraine, J Med Chem,
    2014;57:7838–58.

  10. Zhu D, Zhang J, Zhou L, et al., A human CGRP receptor
    antagonist antibody, AA95, is effective in inhibiting capsaicininduced
    increase in dermal blood flow in cynomolgus
    monkeys, 54th Annual Scientific Meeting, American Headache
    Society, Los Angeles, CA, 2012;O22.

  11. Liu H, Xu C, Shi L, et al., Immunohistochemical localization
    of the CLR/RAMP1 receptor complex in the trigeminovascular
    system of the cynomolgus monkey, 53rd Annual
    Scientific Meeting American Headache Society, Washington
    DC, 2011;P2.

  12. Zeller J, Poulsen KT, Sutton JE, et al., CGRP function‐blocking
    antibodies inhibit neurogenic vasodilatation without affecting
    heart rate or arterial blood pressure in the rat, Br J Pharmacol,
    2008;155:1093–103.

  13. Dodick DW, Goadsby PJ, Spierings ELH, et al., Safety and
    efficacy of LY2951742, a monoclonal antibody to calcitonin
    gene-related peptide, for the prevention of migraine: a phase
    2, randomised, double-blind, placebo-controlled study, Lancet
    Neurol, 2014;13:885–92.

  14. Dodick DW, Goadsby PJ, Silberstein SD, et al., 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;13:1100–7.

  15. Foltz IN, Karow M, Wasserman SM, Evolution and emergence of
    therapeutic monoclonal antibodies: what cardiologists need to
    know, Circulation, 2013;127:2222–30.

3

Article Information

Disclosure

Stephen Silberstein, MD, serves as a consultant and/or advisory panel member and receives honoraria from Alder Biopharmaceuticals, Allergan, Inc., Amgen, Avanir
Pharmaceuticals, Inc., Dr. Reddy’s Laboratories, eNeura Inc., ElectroCore Medical, LLC, Medscape, LLC, Medtronic, Inc., Mitsubishi Tanabe Pharma America, Inc., NINDS, Supernus Pharmaceuticals, Inc., Trigemina, and Teva Pharmaceuticals. No funding was received for the publication of this article.

Correspondence

Stephen Silberstein, MD, Thomas Jefferson University, Jefferson Headache Center, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, US, E: stephen.
silberstein@jefferson.edu

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

Received

2015-02-02T00:00:00

4

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF

This Functionality is for
Members Only

Explore the latest in medical education and stay current in your field. Create a free account to track your learning.

Close Popup