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Multiple Sclerosis: Biologics Treatment

By Dr. Shafiq Qaadri, MD

What is meant by ‘treatment with a biologic drug?’
A biologic is a product, like a protein, that is made by a living cell. For example, the biologics used in MS are made by a genetically-engineered E. coli bacteria or by cell cultures…Monoclonal antibodies are also a good example of biologics, and so his human insulin that is manufactured by bacteria.

How do these biologics differ from the typical molecules in the medications that we prescribe?
The differences are variable. But biologics have the potential for inducing the development of antibody resistance.

How have biologics changed the face of medicine?
The change is significant, adding a major therapeutic dimension, because the biologics are the ultimate in designer drugs…Cell receptors can be very specifically targeted.

But there are also some added challenges and difficulties. For example, in studies of the biologic erthyropoetin, antibodies that developed against the biologic also reacted against your own native erthyropoetin. Those antibodies that react with the drug also react against your own protein. This situation would severely impair your ability to manufacture red blood cells, leading to aplastic anemia.

Why is it that there is so much cross-application with the biologics, meaning a drug developed for one disease can be used for another disease?
It’s true, and there are multiple receptor effects. For example, Antegren, one of the new MS drugs coming down the pipeline, was originally developed for Crohn’s disease.

There have been other drugs for MS that were originally developed for rheumatoid arthritis. The interferons were, of course, used in other situations, especially as antivirals for hepatitis…Therapies that are developed for autoimmune diseases seem to have this quality.

What is the significance of ‘neutralizing antibodies?’
As the biologics are proteins, they can induce an antibody response. For example, there are antibodies that can attach to various parts of a molecule. Some just bind, but the molecule still is functional.

Neutralizing antibodies attach to various moieties of the biologic, but they happen to bind to a critical part, a part that interferes with receptor attachment. Then the protein can no longer act, no longer function, and is neutralized.

It should also be noted that this is not an all-or-none phenomenon. There will be varying degrees of antibody production to different biologics, and the relative antigenicity of the different biologics is a key consideration in MS management.

In MS, for example, the therapeutic effect of the biologic therapies is modest. It’s certainly not a cure, though we can affect relapse rates and so on. And if the already modest effect is further diminished because of the presence of these neutralizing antibodies, that impacts therapy…We don’t want to be in the situation in which we’re using expensive medications that are doing nothing.

What factors influence which MS patients end up with neutralizing antibodies?
Any of the biologic agents can lead to antibody production, although each product has its own rate of production. But there’s more to it than just the molecule itself. For example, the actual beta-interferon 1a molecule that you have naturally is the same as the biologic medicine, so you would think there would be no antibody production.

But when the medication is given the way it is, in a specific formulation, that makes a difference. So the question then arises, what is it in the formulation that leads to antibodies—and that is a tough question, the focus of a great deal of research…It’s still an unsolved problem. For example, after you discontinue one MS biologic, the antibodies come down rapidly, whereas with another biologic the antibodies persist at high levels…There’s a lot of tweaking going on now trying to develop a cleaner product—a biologic with lower immunogenicity.

How are these neutralizing antibodies identified?
The measure is indirect, measuring the biological effect of a drug. For example, the one that is most used is called the MxA protein, which is one of the proteins that gets generated by the cell, a marker of biologic activity.

If your biologic is relatively clean and functioning well, with low immunogenicity, the level of the MxA protein should rise above baseline. Again, it’s a marker of biological effect.

On the other hand, with the ongoing delivery of an interferon, if there is no rise of the MxA protein, then there is no biological activity of the drug. The only thing we can then blame that on is the neutralizing effect of the antibodies.

Another approach is the measure of an individual’s serum’s ability to kill viruses, which is one of the abilities of interferon. So serum is added to cell cultures with active viruses. The viruses will then kill the cells, unless there’s something to stop them—the interferon in the patient’s serum. So the more viral death and the more remaining cells, the more active the interferon, and thus the less neutralizing antibodies.
Again, this is another indirect measure. But the problem with these tests is that it’s not the same as just measuring the level of a drug.

Can neutralizing antibodies be prevented, either at the level of manufacture, or administration of the drug, or during ongoing therapy?
This is an area that upsets me. Neutralizing antibodies were known since at least 2001. It was known that these would have an impact on the efficacy of these drugs.

From then till now there’s been this rhetoric about how important these antibodies are—are they a little bit important, moderate, or very important? They’ve been asking, ‘How high is high?’

In this time, not enough has been done. For example, once you have patients on these products, you have to measure everyone, you have to measure the levels of neutralizing antibodies in everyone every 6 months, and then you have to deal with them.

But because this question was left, antibody levels were not routinely measured early on, the question of what you do once you have them is still not solved…There have been improvements, though. For example, research led to formulation changes, which reduced the immunogenicity of Avonex from 20-25% positivity down to 1-5% positive for antibodies.

Are patients affected by these neutralizing antibodies?
It depends. In a clinical trial, patients will inject placebo, get no antibodies, and thus have no effect. With medium antibody production, they will still get some benefit from the biologic agent. But if you lose half the drug’s effect, you’re really losing a lot.

There’s really no problem with the antibody itself—it doesn’t do anything to the person; it just interferes with drug efficacy.

Do all MS biologics have the same risk for neutralizing antibodies?
No. It’s very product-specific. Betaseron has the highest rate of production, roughly around 30%. An interesting issue is that if you stop this drug, the biological effect will actually continue for a further 6 to 8 months.

If you take Interferon beta-1a, known as Rebif, the higher dose of the drug actually causes a lower rate of antibody production, about 15 to 20%. But if you stop this drug, the antibodies might persist for up to 3 years, if nothing else is done.

Avonex has an antibody production of, on average, 3%, which is quite good for a biologic.

What can be done for patients who have developed neutralizing antibodies?
This is a real problem. I wish we had more information, and at least partial answers.
If you use intermittent steroids, such as high dose prednisone, you may get a slight reduction over a period of time.

But other than changing the drug formulation, for example going to a pre-filled syringe or changing the pH, there’s really nothing else so far that will change the course of the development of these antibodies.

How has all this impacted your patient care?
Substantially. I monitor neutralizing antibodies in all my patients, even though some neurologists do not. If the levels are high, I’ll repeat the measurement subsequently. If the levels stay high, I’ll stop the drug. But then the question arises, the big problem is—what do I do with my patient?

Dr. Shafiq Qaadri is a Toronto family physician and Continuing Medical Education lecturer. www.doctorQ.ca

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