No MS-ing Around: How monoclonal antibodies are revolutionising multiple sclerosis treatment

Imagine your immune system turning against your brain. That's what it's like for patients with multiple sclerosis. But what if we could get the immune system to stand down with laser-like precision? Welcome to Pathways Gone Wild, where we untangle big questions in medical science with clarity, curiosity, and zero yons. Good morning everybody and welcome to the podcast. I'm Natalie German and this podcast is part of the Biomedical Science Degree at Monash University. Today we're taking you through one of the most transformative areas in modern medicine. If you're wondering if this podcast is for you, if you're curious about science and medicine, you are in the right place. Today's topic, no emescing around. How monoclonal antibodies are revolutionising multiple sclerosis treatment. So emescing condition wants to find by disability, but now treatable facts to some truly remarkable discoveries. We'll kick off today with a quick look at the emes disease. Then we'll take a moment to explore the state of treatment before monoclonal antibodies were introduced. Next, we'll break down what monoclonal antibodies are and why they're so powerful. And then we'll dive into the Natalazuma, the first monoclonal antibody to treat emes. Finally, we'll look at what the future of monoclonal antibody therapy might hold. This podcast is for educational purposes only and doesn't replace professional medical advice. Let's kick things off with some intros. I'm here with my two mates from Monash Biomedical Science. We're all in the same molecular class. Welcome Ethan and Prio. Hey Natalie. And Natalie, good to be here. Awesome. So emes is an autoimmune disease. It's lifelong and I'm sure a lot of people know someone who's affected by it. My younger cousin was diagnosed with fees ago and I was pretty big shock for the family. One to two Australians who diagnosed with MS every day and close to three million people worldwide are affected. So it's a pretty big issue. So yeah, let's start with auto immunity. What is it? Yeah, so autoimmune diseases can happen when the body's immune system mistakenly attacks its own healthy cells. And this is because the body's immune system thinks that they're foreign invaders in a way. And because the immune system is really powerful and also really, really good at its job, it can result in lifelong information and also damage to tissues like the joints or the skin and even organs, which all depends on the condition involved. So what kind of autoimmune conditions are you talking about here? Like what other parts of the body can be affected? So we can have a whole array of autoimmune diseases. Let's take for example, arthritis that affects the joints. We also have alopecia causing hair loss and even type one diabetes, which affects someone's ability to make insulin. And with multiple sclerosis being an autoimmune disease, what occurs is that the immune system attacks the central nervous system, which we can call the CNS, which includes our brain and spinal cord and our operative nerve connected to our eyes. Okay, and so this MS just come out of the blue. So unfortunately it does come out of nowhere for patients and just like all other autoimmune conditions, it can result from a combination of both genetic and environmental factors. Okay, and so before we go deeper here, can you explain for our listeners how the nervous system actually works and how MS affects it? So we definitely, so think of the nervous system as like a really big natural electricity grid, which transmit signals around the body about how to move to acts or think. Yeah, so what you're saying is that we can kind of think of nerves as like cables within our house that have insulation around them that our own nerves also have an insulating layer wrapped around them called my limb. And what this helps is conduct the signal electrical signals more quickly, helping it travel along our nerve fibers. So in MS what basically happens is that the patients only mean cells can start to attack the malign and there are lots of different processes involved and some of these are really complicated, but one of them is when the patients own immune cells cross into the brain where they wouldn't really normally be apt. And once they're there, they can start to get confused and attack the malign because they think that they're like a foreign pathogen or a harmful bacteria that shouldn't be in the brain. Yeah, and unfortunately the inflammatory damage from MS can be pretty major and this process is called demialation. And what that leads to is the body trying to repair the damage, but instead of fully restoring the original tissue, it leads behind a scar like tissue, which will form lesions. Okay, and so the bodies attempting to repair itself, what kind of function is left? The problem is that the malign repair process is not 100% efficient. Think of it like getting a scar on your skin. It covers and protects the area, but it doesn't have the same pores, it can't sweat or act like normal skin. It's just there doing the bare minimum. And so the more more scar in that presence in MS patients over time, the less functional that their nerves become. Yeah, and a fun fact of why we call MS multiple sclerosis is because sclerosis means heartening in ancient Greek. So it's many heartenings which manifest as lesions which you're missing within the brain. Okay, and so it's this like hardening or scarring that is why it's considered a degenerative disease. Yeah, yeah, absolutely correct. So degenerative meaning symptoms get progressively worse over time. The lesions just don't want to go away. Okay, all right. So there's four types of MS. What can you tell me about the main one, which is what we're going to focus on today. So relapsing, remitting MS is the main one. And it actually counts for 85% of diagnoses. Relapses are these periods of symptomatic attacks that essentially damages the patient's nerves. And then this is forward forward by a period of remission where the patient can partially recover from these symptoms. So preo general talk more about what this means for patients to have MS. Yeah, yeah, of course. So the relapses happen about every two years in most patients. And what happens with our treatment is that the nerves keep taking hits. Well, really matters between each relapse is how much someone actually bounces back and the recovery kind of sets the tone for what their daily life looks looks like moving forward. So what happens over time is that the pattern usually shifts from just these occasional flare ups, this low steady decline. Patients might start dealing with things like let's say numbness, weakness, even constant fatigue. And worst of all trouble with just moving around from the day to day lives. Okay, so with you. So let's summarize. In MS, the immune system mistakenly attacks the protective myelin around nerves in the brain and spinal cord. This leads to inflammation, which then causes scarring and gradual nerve damage. And then the most common form relapsing remitting MS causes flare ups followed by a period of partial recovery, but without treatment, it can lead to progressive symptoms like fatigue, weakness and mobility issues. So after MS, a condition driven by the body's own immune system going rogue, damaging the brain and spinal cord and causing symptoms that can be unpredictable and debilitating. But here's the thing, while the disease has been around for a long time, the way we treat it has changed big time coming up next will take a quick look back at the early treatments for MS, why they fell short and how a new kind of therapy changed the game, monoclonal antibodies stay with us. Let's rewind for a moment and look at what life was like before monoclonal antibodies came on the scene. Found this great article by Ranzahoff and colleagues that walked through treatments and back then treatment was more like damage control for relapses, but it didn't do much to slow disease progression. Doctors kind of had two main tools, they could use steroids to put out the fire during a relapse or they could use broad immunosuppressants to try and prevent the next relapse from happening. So what was like the main issue or problem with this approach? Well neither option did much to stop the disease from getting worse and both came with some pretty serious downsides. So steroids were a short term fix, they could reduce inflammation during a relapse, but over time they kind of lost their punch and came with side effects like high blood pressure, which is not ideal for something you might need again and again. And then there were the immunosuppressants, so these aim at the root of the problem, like the overactive immune system, but they're not precise. So they shut down the whole system, not just the part misfiring in the brain and that leaves patients open to picking up infections from bacteria or viruses, or while they're still dealing with their MS. Yeah, so what kind of ended up happening was doctors were trying to start trying to balance whether they could suppress the disease enough without leaving the patients too vulnerable to infection. High doses weren't very well tolerated and the benefits were kind of limited. Okay, so tell me about why monoclonal antibodies are so much better. So monoclonal antibodies are a way to be really specific and they can help leave the rest of the immune system to do its normal functions. So maps are basically lab made versions of proteins, which are made in our body to find infections and these are called antibodies. So these proteins are made by cells. which we call B cells and they're really precise. So basically what happens is that each one of them can lock them to a specific target, which is called an antigen. - And just to explain, an antigen might be something let's say on a virus, like the spike protein on COVID-19, or a feature of a cancer cell that just isn't on normal cells. So antigen are just proteins that can identify things from self and non-self. - Yeah, right, right. Okay, and so what are antibodies? Well, antibodies are just like the keys built for any specific lock. Each antibody is unique to each antigen. - So this is essentially what makes maps so powerful of medicine. We can basically design them to target any specific thing in the body that we want them to bind to. And we can also attach different drugs or tags to them, which can block or kill what they bind to. So this means that the right credit action occurs exactly what's needed in the body. And in terms of MS, that's targeting those defective immune cells, which mistakenly attacked the brain and causes MS-related symptoms. - Okay, so let's recap. Older MS treatments either reduce inflammation, short term, or broadly suppress the immune system, but with limited precision and low effectiveness and tough side effects. On the other hand, monoclonal antibodies change the game by allowing targeting off specific parts of the immune system causing damage. So treatment happens exactly where it's needed without shutting everything down. It's kind of poetic, right? Like one of the most powerful treatments for MS is made by B-cells, one of the very cells causing the problem in the first place. Coming up next, we'll have a look at Natalzoomab, the first map created to treat MS. Don't go anywhere. ♪ Your favorite TV shows are capturing ♪ ♪ I know my schedule right ♪ ♪ My schedule back in the fight ♪ ♪ This ♪ - Welcome back. Okay, so now we're diving into a study on Natalzoomab. And so what researchers are looking at here is, instead of broadly suppressing the whole immune system, what if the treatment could just block the immune cells that get into the brain and cause all the damage? So tell me about the study. Here, so a study in 2006 by Paulman and colleagues was published in the New English Journal of Medicine. And this was on Natalzoomab, which is also known as the OGMab. It basically helps to show why maps are such a big deal for treating MS and reducing those MS related symptoms. So in the study, which was a clinical trial, the researchers compared Natalzoomab against a placebo. So they recruited almost a thousand patients and that consisted of roughly 600 getting Natalzoomab and then the rest just got the placebo. So what they saw is that Natalzoomab treatment resulted in a 90% reduction in brain lesions and then it also helped cut the relapse rate by 68%. And they also saw that the drug reduced the risk of disability getting worse or progressing by a further 42%, which was compared against the placebo. So as we can see here, these are some really, really amazing results. And then there was also a cult study in 2023 by a management and colleagues, which basically shows that Natalzoomab and maps in general improve cognition more for patients than when they want other MS treatments. - Okay. And since it was so effective, how does it actually work? - So Natalzoomab essentially binds to immune cells and locks them out of the brain. - And essentially does this by blocking a special key on immune cells from working, which is needed for these cells to access the brain. - So, okay, it stops the key from working, but what does that actually mean? - Yeah, so Natalzoomab binds to proteins, which are known as integrins and these are located on the surface of immune cells, such as T cells. This protein is basically the key that unlocks the cartilage that surrounds and protects the brain. - And so this cartilage you're referring to, which helps protect the brain from a truce, is what doctors are like to call the blood brain barrier. - Yeah, exactly. And by altering this key, T cells aren't able to access the brain or damage the body anymore. - Right, right. Okay, so this all sounds really good, but is it a cure like everything solved? - Yeah, so Natalzoomab isn't actually cure for MS. A cure would mean stopping all of the immune cell confusion so that they don't target our own body. - Yeah, so Natalzoomab only helps to minimize or manage the damage that this cloud of confusion causes. - But, okay, still a lot of good data that Natalzoomab reduces disability. Did you guys have some data on like more of the indirect outcomes like how these translates to improving patient lives? - Yeah, so one of the main impacts that MS has on patients is that it stops people from going to work. - Yeah, that's right. And a 2022 study in a really prominent journal, so that's the journal of Newrology, Neurosurgery and Psychiatry by Chen colleagues, basically saw that the odds of losing work proctorie. So that's the data that patients are completely away from work and also the data that they are at work, but they're really struggling with those MS symptoms where much lower patients when they're on Natalzoomab compared to when they were using other treatments. So what this shows us is that Natalzoomab has been revolutionary at least in one way because it allows patients to head back to work more quickly and this helps improve the overall quality of life. - Okay, so just to recap, in a segment we looked at the ground breaking 2006 study on Natalzoomab, the first map used to treat MS, it showed revolutionary results, significantly reducing relapses and brain lesions and overall slowing disability progression by 42%. Wow, and we broke down how it works. So explaining it locks in me and sells out of the brain. And then we looked at how Natalzoomab also significantly improved the lives of MS patients by allowing them to return to work quickly, improving their quality of life. Coming up next, we'll finish with a final study that's more recent. It shows another map and gives us an idea of what the future of monoclonal antibody therapy might hold. Okay, we're looking ahead at some of the most exciting breakthroughs in monoclonal antibodies for MS here. And we talked about how far treatments have come with Natalzoomab, but now we're adding into research that's kind of the next generation of therapies. So what do we find? - So for a really long time, the thinking was that MS was mostly a T cell German disease. So thinking that these cells were the main culprits in a way. And then came along Steve and Halzo who really challenged this idea. And after 20 years of research, he helped prove that B cells also played a really, really important role in disease progression. And he actually said a $3 million prize for his work. - Okay, and so how is his theory actually tested? - Well, it's great that you asked because one of the more important studies that I wanted to chat about was published in 2020 with a monoclonal antibody called or was a Fatemoo map. And this trial compared a treatment that targeted only B cells with a traditional immune treatment called Terrafor Numeid, which affects both B and T cells. And what was most important is that a Fatemoo map selectively decreased these B cells by buying to a special protein called CD20. - Okay, and so I guess the main thing that we're hoping to discover was how often patients had relapses, right? - Yeah, and that's what they're able to achieve with a Fatemoo map coming out on top. So patients taking a Fatemoo map had about half as many MS relapses as those taking the traditional treatment. It also did better slowing down disability. So feel people on Fatemoo maps saw their MS get worse over time. Let's take for example, up to three months, 10.9% of Fatemoo map patients had disability progression compared to 15% on Terrafor Numeid. And these results with statistically significant. - Yeah, okay. And so anything else worth mentioning from the study? - Yeah, so brain MRIs and blood tests also showed less disease activity in the Fatemoo map group. - So this shows that MS isn't just a T cell problem. It's more complex and as we keep learning, scientists are able to create even more targeted models on antibodies. And it's not an exaggeration to say that MS have completely reshaped how we treat MS. - Right, and so to conclude, that's the power of targeted therapy, potent and effective results. First, it was blocking immune cells from entering the brain with Natal Zoom app. And now with the Fatemoo map, it's wiping out the B cells doing long term damage. Both of these treatments are also much more effective than steroids and broad immunosuppressants, which have many downsides. And this is just the beginning. New monoclonal antibodies are being developed every month and are paving the way for well-personalized treatments of MS, offering new hope to patients. So that's it for today. Thanks so much for joining us as we walk through the basics of MS all the way to the clinical trials of monoclonal antibody treatment. If you liked what you heard, you can check out the show notes for links to the studies we talked about and how to reach us by email. We love your fake act.