Update on Neutralizing Antibodies in MS Treatment

TED PHILLIPS, MD, PhD: Hello and welcome to this update on the effects of neutralizing antibodies in the treatment of multiple sclerosis. I'm your host, Dr. Ted Phillips from the Multiple Sclerosis Center at Texas Neurology in Dallas.

I'm pleased today to be joined by Dr. Rick Munschauer, who is chairman and professor in the department of neurology at the State University of New York at Buffalo, School of Medicine and Biomedical Sciences. And, via telephone, I'd like to welcome Dr. Andrew Pachner, professor of neurosciences at the University of Medicine and Dentistry of New Jersey. Thank you both for joining me.

Beta interferons are a mainstay in the treatment of multiple sclerosis. The patients may develop antibodies that neutralize their effect and reduce clinical efficacy. As more information has become known about the effects of these neutralizing antibodies, attempts have been made at reaching a consensus on their impact. Today, we hope to provide an opportunity for neurologists to better understand the phenomenon of neutralizing antibody development and the relevance of such development to MS treatment.

So thank you both, Rick and Andy by telephone, for joining us today.

Certainly, over recent years, we've heard a lot about neutralizing antibodies, particularly regarding interferon treatment in multiple sclerosis. And I think, first, I'd like to give Dr. Andy Pachner an opportunity maybe to start us off with his thoughts on the whole concept of neutralizing antibodies. There has been, certainly, some confusion about what's a neutralizing antibody as opposed to a binding antibody, the biological relevance or not of either. And so, Andy, how could you kind of start us off on better understanding this whole phenomenon?

ANDREW PACHNER, MD: Well, the antibodies are made by the immune response, by the humeral immune system, to any outside material that's injected. This is what the immune response does. It's why we're able to protect ourselves from infection and keep down the possibility of having malignancy. So it's a really positive response for most of the time. 99% of the time, it's a necessary part of what we do, what our immune system does.

But whenever there's a therapy that's being injected, the possibility is that the antibodies that we make to anything that's injected is going to actually interfere with the ability of that therapy to work. And that's true for just about any injected agent, that there has not been an injected agent that's been made that's been absolutely 100% identical to the human product. So, because our immune system is able to detect the differences between what is human and what is not human, we all make an immune response to injected material.

And the different assays available out there are really of two sorts. One is a binding antibody assay and another is a neutralizing antibody assay. And they each have their advantages and disadvantages. The binding antibody assays are very sensitive for any antibody material made and they're very inexpensive and they can have a very short turnaround time back to the doctor. The problem with those assays is that there are many, what are called, false positives. So you can have binding antibodies at a reasonable level without having any significant negative effect on therapy.

With respect to neutralizing antibodies, those are antibodies that are almost always bad in terms of their ability to interfere with the therapy. The problem with measuring them is that they tend to be much more expensive, they tend to be harder to do. But both of these assays are very important for trying to understand how much the antibodies interfere with the response.

Finally, there's a third group of assays just being utilized now by a number of groups all over the world and that is a bioactivity assay. So there are genes that are upregulated after injection of interferon beta and we can measure those genes either by RNA or by protein assays. And that gives us an idea of how strongly the interferon beta is working. And so if you have antibody measurements and bioactivity measurements, you have a very good idea of how well the interferon beta signal is being transduced, how strongly your patient is responding to each injection of interferon beta.

TED PHILLIPS, MD, PhD: Well , Andy, we heard you comment there a couple of times about a kind of, quote-unquote, "bad" effect possible from having these neutralizing antibodies. Rick, how convinced are you or not of, at the clinical level, at the patient level, a necessarily bad effect from neutralizing antibodies? How do you view that controversy?

FREDERICK MUNSCHAUER, MD: Well, I do think that there's an emerging clarity that's coming from this. As Andy said, when a patient who's on interferon, usually for about a year, develops neutralizing antibodies (which is really an in vitro assay), where you inject interferon into somebody, and if they have these neutralizing antibodies, you don't see a biologic effect when you measure gene expression. But your point is well taken.

What evidence do we have now that says that patients who develop neutralizing antibody have an attenuated clinical response to it? And that's an emerging group of literature that I think is now persuasive. Our first patients that we injected clinically with interferon is 1996. Why is this 2005 and we're wondering about it?

And I believe that has to do with the pharmacokinetics of antibodies. It does take about a year, a year and a half to develop neutralizing antibodies and once somebody's been on interferon for a while, we have convincing evidence that, even if you stop the interferon, it's sort of like a supertanker. You still have an immune response that persists for several months after the drug is stopped. So if you were to develop neutralizing antibodies, we would probably not see a clinical effect for at least two, three, four years into interferon therapy.

And the studies that have begun to look at that now, the long-term efficacy data, I do think really support the contention that the emergence of neutralizing antibodies is associated with an attenuation of therapeutic effect.

Probably the best single study longitudinal that's out there is the Copenhagen Group, where in Denmark, everyone, whatever interferon product you're put on, must have neutralizing antibodies assayed every six months. And, indeed, they've been looking at not only exacerbation rates as a function of antibody status, but also progression and disability.

And Sorensen and his group have now published actually a number of followup studies to this, that exacerbation rate in those patients who developed neutralizing antibodies returns to a level that's significantly greater than those patients who do not develop neutralizing antibody. And, now, with some six- and even seven-year data, the Copenhagen Group has also shown statistically significant differences in disability in those patients who develop neutralizing antibodies.

And there are other studies, too, that have looked at this. I think the longer-term PRISMS data would support, although in a less-controlled way, the contention that neutralizing antibodies are indeed associated with a loss of clinical effect.

What's your take on it, Ted?

TED PHILLIPS, MD, PhD: Well, I basically agree with your viewpoint and, Andy, I want to give you an opportunity here in just a second to chime in.

It has been confusing, I think for a number of years, due to a variety of reasons, different studies, different treatment preparations, different relative immunogenicity, different assay methods used, different standards being used to determine antibody positivity or persistence. All of that has really not standardized yet in any one single way that everybody looks at the same and yet I would agree with you.

I think that, as time has gone on, that more clarity rather than less clarity is emerging from this and my take on it is that persistent antibodies, capable of neutralizing interferon biological activity at least when used to treat MS, result in a relative diminution of therapeutic effect.

Andy, how do you see this?

ANDREW PACHNER, MD: Well, I agree with everything you guys have said. I think one of the reasons it has not been clearer is because the problem is not one of black and white. It's not like one has either positive antibodies or no antibodies. The point is that there is a continuum of antibody levels in the population and we all like things simple and straightforward, but our immune system isn't built that way.

And so what we'd like to do is call a patient either antibody-positive or antibody-negative, but really there's a spectrum. So some people are very, very strongly positive. And then there are people who have almost no antibody that you can measure.

The problem is that there is a gray zone in between and some people have low levels neutralizing antibodies, so they would be considered neutralizing antibody-positive, but their neutralizing antibodies are at such a low level that they don't strongly interfere with the biomarkers that we measure. While other people have binding antibodies that are so high that they are strong enough to interfere, despite the fact that they may not have neutralizing antibodies that are clearly positive at the cutoffs that we use.

So I think that's one of the problems in the field is this desire to simplify basically a very complex process and that is the immunogenicity of these drugs. If you look at the two ends of the spectrum, the very strong neutralizing antibody positives, those are very clear. They've completely lost efficacy and they're back to their MS that they had before they started. And, in those patients, when you inject interferon, you're basically injecting normal saline, because the drug never gets to the interferon receptor.

On the other hand, people with very low antibodies are basically as if they started anew. They don't have any antibodies that interfere. But there is that gray zone in between and its variable levels of decrease in the activity of the interferon.

TED PHILLIPS, MD, PhD: Rick, in view of Andy's comments just now, do you feel that we are yet at a point that we could even begin to think about actual guidelines for clinical practice to integrate results of neutralizing antibody assays into clinical practice and management of people with MS?

FREDERICK MUNSCHAUER, MD: Well, I think we should and, in fact, many countries around the world have already done that and we, in North America, have been limited in our ability to get neutralizing antibodies, largely because of the cost involved and the availability of the assay in general.

But in a perfect world, where these antibody assays would be readily available, in the same sense that we can get ANAs, I think that we are, from a level one science point of view, at the point where, if we had antibody determination, we could construct guidelines that I think would be agreed upon by most authorities in the field for using antibodies to guide therapeutic choices.

As we mentioned before, it takes about a year to develop neutralizing antibodies and I personally feel (and this is what happens in Denmark) that neutralizing antibodies, if available, in a perfect world, should be measured in everybody after a year. However, that's not the case with us and, at our MS center in Buffalo, if somebody has been on interferon for a year and experiences evidence of disease activity with an exacerbation or a definitive disease-related progression and also if their MRI shows evidence of disease activity, then those are the kinds of people that we try to get antibody determination on.

And I think Andy stated it very well. Within the constructs of a major MS center, we can actually measure whether or not an individual has a response to an interferon injection.

We measure STAT1 or MX mRNA, but certainly you could measure MX protein, too, and get an idea. And I think that's where the field should be headed.

We should recognize that interferon, a protein biologic that's injected, is no different than all the other protein biologics that we have, ranging from insulin to the growth-stimulating factors.

When you develop neutralizing antibodies, the drug doesn't work and you lose the whole class. If I developed a neutralizing antibody against one beta interferon, it will neutralize all beta interferon preparations. And it would be nice to factor that in to our therapeutic decision-making and it really is just access issue that I see with it.

So I do think we could develop some guidelines and, around the world, others have. I think that represents a challenge to how we practice medicine.

TED PHILLIPS, MD, PhD: Yes, and as we're winding down this program, I'd like to hear from both of y'all, in view of what we have available right now, is this a cost-effective, in each of your opinions, a cost-effective maneuver now? If it is, how is it perhaps best used? If it isn't, what needs to happen in terms of perhaps new assay methods that might prove to be more cost-effective? Andy, let me ask you to comment quickly on this and then we'll finish up with comments from Rick.

ANDREW PACHNER, MD: Yes, Ted, I strongly agree with Rick. I mean, one of the problems is that the United States is way behind other countries in this whole analysis issue that, in many countries, the government will not pay for interferon if you are neutralizing antibody-positive at a high level and that's logical. Why would you want to continue to give a drug that's not working and that might actually cause problems? So I would strongly agree with Rick on the fact that we are behind European countries and Australia in this whole issue.

In terms of what can be done now. If I were to pick one time point, and there are some people who do this, -- I don't because I do have my laboratory where we can run the samples every three months or every six months -- but if you're picking one time point, I would pick a year. There are a number of physicians who do this. Screen everybody at one year for neutralizing antibodies, because you're going to miss very few people with neutralizing antibodies who might develop them later.

And you will find that many patients will have neutralizing antibodies at high levels and those people are not getting the adequate amount of interferon beta. And that's something that we, as clinicians who are treating our patients, need to know, whether the therapy that we're giving is really having an effect. And whether or not the patient is clinically doing well or clinically not doing well, we need, in my opinion, to know whether the drugs are working.

TED PHILLIPS, MD, PhD: Rick, final comments from you?

FREDERICK MUNSCHAUER, MD: Well, once again, I'd endorse what Andy and you have mentioned. It is possible to get through routine blood work a binding assay. That binding assay, an anti-interferon beta-binding assay, is what we use as a screening test. It is universally available. It's not standardized; we don't have good outcome measures with it. But, at least, it's a start for us and it is what I think is an emerging technology for us to be more concerned with therapeutic levels.

You know, what Andy said is really true. If we put the patient first and we all know that MS is, in the majority of people, a bad disease we need to make sure that our therapies are doing what we think they're doing.

TED PHILLIPS, MD, PhD: I certainly agree. We're out of time for this particular program. I want to thank my friends and colleagues, Dr. Rick Munschauer and Dr. Andy Pachner via telephone for joining us today. This remains an interesting topic of discussion and one in which there are not final conclusions reached. But, as mentioned earlier in discussion, as time has gone on, it seems as though things are perhaps becoming a bit more clear rather than less clear regarding the ultimate importance of antibodies capable of neutralizing interferon bioactivity and their, therefore, not unexpected detrimental effect to therapeutic efficacy.