Mechanism of Action of Antibodies in Migraine Therapy

Stephen Silberstein, MD: There’s really been a change in the way of approaching the treatment of headache, and everybody’s hearing today about CGRP [calcitonin gene-related peptide] and the antibodies against CGRP. What does it mean, how did we get there, and what are we doing?

A number of observations have led to this. The original observations were Peter Goadsby [MD, PhD, FAHS] and Lars Edvinsson [MD, PhD] actually measured CGRP of a patient during a migraine attack and found it would be elevated. Later, they found that giving a triptan lowered it. Messoud Ashina [MD, PhD, DMSc] in Scandinavia actually infused CGRP into patients and found that those who had migraine actually developed a migraine headache. Koch’s postulates: CGRP causes a headache; point 2, it occurs naturally; point 3, small molecules—CGRP antagonists—were developed that help migraines.

We had all of these things and this led to the concept that CGRP was intimately involved in migraine. The next ideas: what is CGRP and what are its receptors? The CGRP receptors are widely spread throughout the body, from the gut, to the nerves, to the brain. We’re getting an idea of what they were doing and the next approach was, how do you interfere with a system? There are 2 different ways of doing it. You can block the receptor—that’s where CGRP goes—or you can suck up CGRP itself. Hence, we can develop antibodies to CGRP, and antibodies to the CGRP receptor.

The next question is, what’s an antibody? What’s it doing? And how does it work? We all know about antibodies because those are the things that protect us from infection. They are very specific and they can target 1 specific part of a molecule. Their specificity means they have little if any, adverse effects that are unintended, and if they are unintended, they’re a byproduct of how the antibody works.

Number 2, they do not produce kidney or liver problems, so they’re not metabolized by the liver or excreted by the kidney. There are interesting things about antibodies. The only time in your life you can drink an antibody and it doesn’t get destroyed in the gut is when you’re 1 month or less of age. That’s how babies get their antibodies from their mother’s milk. After that, they’re chewed up in the gut.

So what do we do? How do we give an antibody? They have to be injected. And unlike most other injections we get, they don’t immediately get in the bloodstream. They’re picked up by the lymphatics and dumped into the thoracic duct. That’s why it takes about a week from the time of the injection to the time it peaks. The alternative is an IV [intravenous infusion], which gives you a rapid increase.

The next thing to think about is, how long does an antibody live? Small molecules live for at most a day or so. If you give a small molecule, half of it’s gone in a day, and after 3 days it’s out of your system. An antibody lives for about a month. Why? Antibodies are degraded in the reticuloendothelial system. When they’re taken up, they’re actually protected by the same thing that allows transport of the antibody from the mother to the baby, the neonatal fetal receptor. Antibody gets bound, it’s protected, and it’s resurfaced. In many ways antibodies are different, they’re metabolized differently, they have longer half-lives. The way they get in the body is different. And the antibodies were developed specific to CGRP and its receptor. Sound OK?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Maybe we should talk a little about what CGRP is. I don’t think we mentioned that yet.

Stephen Silberstein, MD: OK. CGRP is the short term for calcitonin gene-related peptide. What does that mean? We all know that there’s a chemical in our parathyroid called calcitonin that’s responsible for calcium metabolism. The body’s unique. It takes the same gene, so this is calcitonin, cuts it different ways, and makes a second peptide called calcitonin gene-related peptide. It’s called a neuropeptide because it’s a peptide found in neurons. So CGRP, a neuropeptide, comes from the same gene as calcitonin, hence it’s calcitonin gene-related peptide.

Deborah Friedman, MD, MPH: Very creative name, isn’t it?

Stephen Silberstein, MD: Yes, very creative.

Deborah Friedman, MD, MPH: Well, Steve, I think a lot of practitioners get a little nervous when they hear about giving people antibodies because they’re concerned about the effect on the immune system.

Stephen Silberstein, MD: It’s not antibodies that cause problems, it’s what they do for a living. And the point I’m making is, if you’re worried about antibodies, you wouldn’t be alive. We have tons and tons of antibodies in our body. So it’s what the antibody does for a living.