The immune system protects our bodies from foreign invaders, but sometimes, when it malfunctions, it can result in life-threatening autoimmune disorders. But what if the immune system could be regulated to counter these diseases? Immunometabolism, an emerging field in therapeutics, aims to rein in autoimmunity altogether.
According to Neil Weir, chief executive officer (CEO) of British biotech Sitryx, there are unmet treatment needs that patients with inflammatory conditions like idiopathic pulmonary fibrosis (IPF) struggle with, and so, there is all the more reason to expand treatment options. The disease, which results in scarring of the lungs that can cause fatal side effects, has no cure, as of yet. There are only two drugs that have been given the go-ahead from the U.S. Food and Drug Administration (FDA) – pirfenidone and nintedanib – which are both anti-fibrotic therapies. While these medicines help relieve symptoms, not only do they come with side effects like nausea and fatigue, but more importantly, they do not address the root cause of the disease.
That’s where the mechanism behind immunometabolism could potentially come into play. As metabolic changes in immune cells can drive the development of diseases like autoimmune conditions and even cancer, intervening in cell metabolism can potentially reverse inflammation and cure diseases.
Immunometabolism is essentially the overlap between metabolic pathways and how cells synthesize molecules like proteins, key to the functioning of the immune system, explained Weir. Along with a team of researchers at Sitryx, Weir was able to identify how the immune system uses metabolic pathways to assist it in making key decisions around balance of activity and effector function.
Immunometabolism: Sitryx pioneers an emerging class of drugs
“The immune system uses key control points and metabolic pathways to assist in controlling that (the immune system), that it stands to reason that there’s a form of control over the immune system around metabolism and energy supply… because it’s a highly energy dependent activity. But it is much, much more than that,” said Weir. “It’s actually an act of regulation that the immune system uses these metabolic pathways to do.”
This sets the tone for the kind of therapies that companies like Sitryx are developing. Since different groups of cells in the immune system are linked to various diseases, each type of cells can be targeted by interfering at specific points of metabolism, to tackle a specific disease.
For instance, in conditions like multiple sclerosis, psoriasis, atopic dermatitis, rheumatoid arthritis and fibrosis, inflammatory macrophages, pan-inflamm T-cells and stromal cells are inhibited. Whereas, in a second profile for treating inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, hidradenitis suppurativa and diabetic nephropathy, the company is looking to target inflammatory macrophages and pan-inflamm T-cells but augment T reg cells. For treating the third group of diseases, which includes indications like systemic lupus erythematosus (SLE), atopic dermatitis, psoriasis, ankylosing spondylitis and myasthenia gravis, the following cells are deterred: pan-inflamm T-cells, Th1 cells, Th17 cells and B cells, while T reg cells are amplified. Similarly, other diseases like IPF, asthma, Sjogren’s disease and chronic obstructive pulmonary disease can be treated by downregulating immune cells.
Currently, the company has three drugs in lead optimization stages, for treating atopic dermatitis (eczema), pulmonary fibrosis and IBD, which it aims to take to the clinic with the help of its additional series A funding worth £32 million ($39 million) that the biotech received last month.
Moreover, it has also partnered with American multinational giant Lilly on bringing cures for multiple sclerosis and SLE to the market, which are in preclinical and lead optimization phases respectively. The preclinical candidate for multiple sclerosis is based on the process of post translational modification. This is a process by which a chemical group is added to an amino acid in a protein, after the protein has been synthesized. In multiple sclerosis, post translational modifications of proteins are key features in identifying biomarkers, according to a research paper published in PubMed. Weir explained that proteins that have cysteine, a sulfur- and thiol-containing amino acid, can respond to metabolic intermediates that can modify the system.
“So, it’s a sort of real time control on quite a wide range of different proteins that the immune system has adopted itself,” said Weir.
As the immune system upregulates an enzyme that makes this metabolite, immunomodulatory therapies are designed to boost this. “We’re essentially just trying to impose further activity across that wider range of regulatory proteins. And, we also know it’s the type of mechanism that has shown potential impact across a number of therapeutic indications,” said Weir.
How are immunometabolism-based therapies different from immunotherapies?
While immunometabolism-based therapies are similar to immunotherapies in terms of dealing with the immune system in both cases, they are not quite the same. Weir pointed out that the former is “a natural means by which the immune system regulates itself.” To add to that, immunometabolism drugs allow for a more selective approach to the type of cells that you want to suppress.
And, as a result, they are much more inclined to be potent in cells that are in inflamed environments, while they have much less effect on immune cells that are not undergoing the kind of proliferation that is associated with the inflamed environment.
Furthermore, immunometabolism drugs can have an effect across a broad range of inflammatory mediators, be it cytokines, tumor necrosis factor (TNF) or interferons, unlike certain immunotherapies which are designed to target only one type of cell. In the case of immunometabolism, they’re leveraging the means by which the immune cell modulates the inflammatory process itself.
“So, that gives you an opportunity to have a more profound impact across a wider range of patients, because you’re ticking off a wider range of inflammatory activities that are associated with the disease process,” said Weir.
ImmunoMet taking cancer on
Meanwhile, in cancer care, Texas-based ImmunoMet is developing its lead immunometabolism-based candidate lixumistat, for a number of indications. These include pancreatic cancer, BRAF mutant malignant melanoma, glioblastoma multiforme, castrate-resistant prostate cancer and gastrointestinal stromal tumor. The candidate is designed to target a particular metabolic pathway in the mitochondria. The candidate is presently in phase 1B trials.
The OXPHOS process in the mitochondria has been associated with the growth of cancer cells, and the overstimulation of the pathway can lead to tumor microenvironment hypoxia – a situation wherein the tumor cells are stripped of oxygen supply – which prevents tumor cells from being killed, and limiting the effect of immunotherapies. This is where immunometabolism drugs could come to the rescue.
By targeting this hyperactive metabolism, lixumistat can attack any immune cell type that employs the OXPHOS pathway when cancer cells invade the body. Through the same mechanism, lixumistat is also being investigated for IPF in phase 2 trials, as cells linked to fibrosis tend to adapt an OXPHOS-dependent metabolism for fibroblasts to be converted to myofibroblasts in IPF.
Tackling challenges
Although recent immunometabolism research has led to companies like Sitryx and ImmunoMet cropping up in 2018 and 2015, as well as anti-rheumatic drugs like methotrexate – an immunosuppressant that reduces swelling – having received the green signal from the FDA several decades ago, there aren’t a lot of contenders in the field just yet. Earlier this year, American pharmaceutical Rheos Medicines bowed out of the immunometabolism space after it had inked a multi-million dollar deal with Swiss multinational Roche, four years ago. Although it was on track to advance its MALT-1 inhibitor in chronic graft-versus-host disease, rheumatoid arthritis and psoriasis, according to internet archives, much isn’t known about why Rheos called it quits.
While we can’t speculate why Rheos backed out, the area of research is not without its challenges.
“It’s a complex area full of promise, but it’s not a straightforward area,” said Weir. “One of the most obvious questions we’re often asked is: is metabolism not just so key to the life and well being of the cell that if you use drugs to modify metabolic pathways, does it not almost automatically manifest as a more toxic effect on the individual?”
Weir explained that they intend to address this by choosing the right target. As the immune system is heavily interconnected, there are “opportunities to go down different routes and come back in again.” “The cell is actually remarkably capable of being plastic and reorganizing, so. So, in fact, we’re working on cells that have already reorganized their pathways.”
However, this is no easy task as the culture media would aid in the growth of a vast number of cells. This means that the cells would not work in a way that is representative of the environment of depleted nutrients.
“I think one of the tricks is you have to understand the pharmacology in the appropriate metabolic environment,” said Weir.
If drug developers don’t get it right, it could result in a swarm of toxicities. For example, when inhibiting a kinase that is an inflammatory mediator, the approach would be to single out the particular type of kinase – as there are three isoforms in the kinase family – to avoid inducing side effects.
“As with all small molecules, unless you have the right selectivity profile and the correct target… then, you always have a chance of potentially detrimental side effects versus beneficial effects. But that’s no different to pretty much all drug discovery.”
Yet, the need for these drugs remain as there is a huge gap in terms of bringing patients into remission. Despite drugs like anti-TNFs to treat rheumatoid arthritis creating a worthy impact, there are still around 30% to 40% of patients who do not gain complete remission, according to Weir.
“So, I think we are working in areas where there’s real, significant unmet need remaining,” said Weir. “I would really like to bring forward drugs that do something more towards resolving the disease and correcting that disease, rather than accepting the ongoing disease, and just suppressing the inflammatory consequences of the disease.”
Although it might take a while for these drugs to hit the market, and maybe even to ensure that a certain candidate is the right fit for treating cancers and inflammation, this relatively untapped field could possibly bring a new era to cancer and autoimmune medicine.