For more than three decades, investigators in the fields of microbiology and immunology have been working to develop safe and effective therapeutic agents to treat autoimmune diseases like multiple sclerosis (MS), inflammatory bowel disease (IBD), and lupus.
The most promising line of research has involved the targeting of CD40 ligand (CD40L), one of the most central molecules in our immune system, which was discovered in 1992 in the lab of Randy Noelle, PhD, an emeritus professor of microbiology and immunology at Dartmouth’s Geisel School of Medicine.
In his recent Perspective piece in the journal Science, and in the following Q & A, Noelle talks in detail about efforts to develop CD40L antagonists and why they are proving to be powerful autoimmune drugs that have the potential to fundamentally change the way we treat inflammatory diseases.
Q: How do you describe autoimmunity to folks in the community?
Noelle: As we age, we don’t regulate our immune system as well and it goes haywire and starts attacking the host. And this is true of mostly all of the diseases we suffer from that have inflammatory components. So, for example, MS results from the generation of immune cells that infiltrate your central nervous system (CNS) and start demyelinating (damaging) cells in your brain. Ulcerative colitis is when your immune system starts attacking your large intestine and causes disease. And in rheumatoid arthritis, your joints start getting eroded, causing stiffness, pain, inflammation, and loss of function.
Q: How have antibodies evolved as treatments for autoimmune diseases?
Noelle: For the past 15 years, the pharmaceutical industry has realized the overwhelming therapeutic potential of antibodies as drugs that can block specific molecules in your immune system and prevent inflammation.
When we developed the first antibody for CD40L to block its function back in 1995 in my lab, antibodies weren’t being used for therapy and the pharmaceutical industry thought they were never going to be sold as a drug because of the expense to produce them and the fact that they have to be injected. Now, there are over 100 antibodies approved as drugs, and they are the leading format for drug development. Their dominance in the industry is because of their therapeutic efficacy, specificity, and their overall safety.
With new technologies, antibody engineering has been revolutionary, in terms of how we can tweak them to be more effective drugs and make sure they get delivered to the right place. We’ve improved their production and longevity, and how they’re administered (using injectable pens versus syringes). Technology has also helped tremendously in sifting through the 100s of molecules as potential drug targets that regulate your immune system, so we can identify the best candidates for antibody targeted therapies.
These days, it’s become an extremely profitable and attractive pharmaceutical objective to make antibodies, as opposed to pills, because the latter can have toxicities and side effects. Antibodies, because they’re so specific, usually don’t have overt toxicities.
Q: Can you talk a little bit about CD40L and why it was such an important discovery?
Noelle: In CD40L, we found the “kingpin” of molecules that is critical for turning on your immune system. As humans we actually have two immune systems, a high-tech one (adaptive) and a more primordial one that just responds in a knee-jerk fashion (innate). CD40L is essential for triggering the high-tech one, giving us the ability to make sophisticated immune responses like high-affinity antibodies to viruses or cytotoxic T cells to tumors. However, the adaptive immune response is also the pathway that mediates the development and pathological progression of a litany of autoimmune diseases.
Given its central role of driving autoimmunity, we realized that if we could block it, we could turn off the adaptive immune response at will and prevent autoimmune disease. Around 1992, we made an antibody that successfully bound to CD40 ligand in mice—blocking its function and turning off the immune response. It was the first of many successful preclinical studies using that strategy. Virtually every autoimmune disease that we modelled in mice was arrested by treatment with anti-mouse CD40L. This set the stage for developing anti-CD40L treatments for human diseases.
Q: But then you were met with a devastating setback that you were eventually able to overcome. What happened?
Noelle: Around 1999, my lab produced an anti-human CD40L and we partnered with a company to engineer it to make it suitable for a drug to treat human disease. Clinical trials began. At the same time, another company also produced an anti-CD40L antibody, but a very unusual toxicity in the other company’s antibody caused two fatalities. That set the field back for many years—at first nobody wanted to get anywhere near CD40 ligand antibodies for fear that they might cause more deaths. Eventually, companies did move forward on targeting CD40 ligand. But instead of antibodies they used atypical, inferior drugs.
For about 10 years, we focused on trying to understand what could have caused the antibody to manifest this unusual toxicity. In 2015, we discovered the problem and strategically engineered the antibody to make it safe. ImmuNext, a company I co-founded, licensed the antibody to Sanofi in 2017 so they could develop the antibody for human therapy and initiate clinical trials in autoimmunity. Since then, the antibody, known as frexalimab, has proven to be very safe—hundreds of patients have received it in clinical trials with no severe adverse events.
Q: What makes frexalimab particularly promising?
Noelle: One of the current strategies developed by the pharmaceutical industry is to produce antibodies that actually kill specific cells that make up your immune system so these cells cannot contribute to autoimmune inflammation. These strategies can be very therapeutically effective. However, if for any reason you need to restore those cells targeted by the antibody, you need to stop therapy and allow the cells to reconstitute. This can take a long time…a year or longer perhaps.
The attractive thing about frexalimab is that it simply blocks the function of CD40 ligand and only requires a 2-3 week break if patients need to recover their adaptive immune function. It works by targeting and blocking the immune system pathways that drive autoimmunity, as opposed to depleting cells in our immune system.
Q: Where do things stand now with testing the effectiveness of your drug?
Noelle: Since licensing to Sanofil, they have completed a very successful phase II trial in MS, initiated two phase 3 clinical trials in MS, and have ongoing phase II trials in lupus and type 1 diabetes.
The phase II clinical trial data in MS with frexalimab shows that it can block acute inflammation in MS as effectively as the leading drugs for the disease, and frexalimab looks to be safer. One of the most pressing needs in treating MS is that the majority of MS patients have subtle worsening or “smoldering-associated” disease despite being treated with drugs that can effectively arrest focal inflammatory disease activity. The phase III trial will determine if frexalimab can arrest smoldering disease…we are hopeful because we believe it will block pathways critical in the progressive process.
I’m overwhelmingly hopeful for the broad therapeutic success of frexalimab in a range of autoimmune diseases because frexalimab targets pathways that are central to the development and pathological progression of autoimmune disease. I believe frexalimab will also work in other indications where there is clinical need—including lupus, type 1 diabetes, and inflammatory bowel disease.
The CD40L story is one of how basic science can provide exciting new avenues for the development of revolutionary new drugs.
