The immune system has an extraordinary capacity to distinguish “self” from “non-self”. This means foreign invaders are eliminated effectively while maintaining tolerance to the body’s own cells and tissues (“self-tolerance”). Autoimmune diseases occur when the immune system confuses the body's own cells and tissues with foreign intruders. This breakdown in self-tolerance leads to chronic inflammation and tissue damage and has serious health implications for patients. Autoimmune diseases include over 150 types of conditions with severity ranging from relatively benign to potentially life-threatening. Examples of autoimmune diseases include systemic lupus erythematosus; type 1 diabetes; Crohn’s disease; and rheumatoid arthritis.
Traditional treatments involve reducing or suppressing the entire immune system, leaving patients vulnerable to all sorts of pathogens, and increasing the risk of cancer.
Novel approaches are focused on specifically targeting the downstream pathways and cells mediating autoimmune diseases without weakening the protective immune response. An improved understanding of the immune system and technological advances are driving the development of these next-generation therapies for autoimmune diseases. Below we’ll discuss a few of these novel therapies.
Cell therapies
Chimeric Antigen Receptors (CARs) have transformed the field of cancer therapy. By genetically modifying the antigen receptor of a patient’s T cells, malignant cells can be targeted effectively to tumour cells. Researchers realised that this principle could be extended to autoimmune diseases. This has resulted in a boom of biotech companies developing cell therapies for autoimmune diseases.
Chimeric Autoantibody Receptor T cells (CAAR)
Instead of targeting cancer cells, chimeric autoantibody receptor (CAAR) T cells express an autoantigen, an normal particle of the body that is mistakenly recognised as non-self by the immune system, to lure and eliminate autoreactive B cells, while sparing normal B cells critical to human health. Put simply, CAAR T cells recognise and bind to target autoantibodies, i.e., antibodies that react with the autoantigen, expressed on autoreactive B cells via the specific antigen and subsequently destroy them.
A phase 1 study of Autologous Desmoglein 3 Chimeric Autoantibody Receptor T Cells (DSG3-CAART) in Mucosal Pemphigus Vulgaris, a rare skin disorder, is currently recruiting patients after encouraging preclinical results. More studies using CAAR T cells for all sorts of autoimmune diseases are certainly to follow.
CAR Treg cells
Regulatory T cells, or Treg cells, are a specialised subset of suppressive T cells. They act as the immune system’s peacekeepers and ensure immune homeostasis and self-tolerance by suppressing excessive activation and proliferation of autoreactive immune cells.
In autoimmune diseases, the balance between Treg cells and effector T cells is disrupted, leading to a relative deficiency of Treg cells and/or impaired suppressive function. Consequently, effector T cells run unchecked and cause inflammatory damage. This contributes to the development and progression of autoimmune diseases.
CAR Treg therapy aims to restore the Treg/Teffector balance by directing Treg cells to areas affected by autoreactive immunity. At these locations, they exert their regulatory function by directly suppressing the activity of autoreactive immune cells, such as effector T cells and B cells. Additionally, Treg cells can release immunosuppressive molecules like interleukin-10 and transforming growth factor-beta (TGF-β), further dampening the immune response.
Research published in the Lancet earlier this July2023, suggests mRNA CAR T cell therapy targeting B cell maturation antigen found on the surface of plasma cells may decrease symptoms in Myasthenia Gravis patients, a rare autoimmune disease. We’ll need to await the phase 2b study to see how the treatment performs in a control trial, but these early results are certainly promising!
Several biotech companies focussing on Treg cell therapies have launched in recent years, including Sonoma Biotherapeutics and GentiBio. Established pharma players are starting to enter the field too. One notable example is the UK-based Quell Therapeutics, which recently entered into an agreement with AstraZeneca to develop, manufacture, and commercialise engineered Treg cell therapies for type I diabetes and inflammatory bowel disease using Quell’s proprietary multi-modal Treg cell engineering.
Innovators will be able to leverage lessons learned from conventional CART cell therapies to tackle manufacturability, scaling, and delivery challenges, which will undoubtedly accelerate getting these therapies to the clinic. However, several challenges remain. These include identifying the right autoantigens and ensuring infused Treg cells don’t shift the immune balance too much towards immune dampening. At this stage it is also unclear how long Treg cells will be able to persist, and whether they are a curative therapy for autoimmune diseases.
With respect to IP, the different stages of developing a cell therapy come with different challenges and opportunities, see our blog here on this topic.
Small molecules
Small molecules are low molecular weight organic compounds that selectively interact with specific proteins, enzymes, or pathways. Small molecule-based therapies offer several advantages over traditional drugs, including intracellular targeting due to their cell-permeability, oral administration, and ease of manufacturing.
Small molecule-based therapies can be divided into three main groups: (i) Kinase inhibitors, such as BTK inhibitors and JAK/STAT kinase inhibitors; (ii) nucleic acid sensing antagonists and inhibitors; such as NLRP3 inflammasome inhibitors and cGAS inhibitors; and (iii) cytokines and cytokine receptor complexes.
This is a crowded space with several biopharmaceutical companies developing drugs to the same or similar targets. For example, many biopharmaceutical companies, including biotech companies such as NodThera, Jecure (a Genentech company); Olatec, IFM Tre (a Novartis company) are focussing on drugs that target the NLRP3 inflammasome, a key driver of inflammation.
With competition this fierce, carefully drafted claims to specific patient sub-groups, drug dosing, and combination therapies can significantly improve market positioning.
Therapeutic immunisation
Traditionally, vaccines are prophylactic therapies, preventing the disease from occurring in the first place. However, vaccines are increasingly used to treat established diseases, including autoimmune disease. These therapeutic vaccines aim to re-educate the immune system to recognise an autoantigen as “self” and prevent the generation of an immune response against the autoantigen. This involves switching antigen-presenting dendritic cells to induce immune tolerance, a state in which immune cells are made unresponsive to self-antigens. In turn, the dendritic cell sends ‘tolerogenic’ signals to naïve T cells, preferentially inducing Treg differentiation (as opposed to T effector differentiation) or kill or switch off the effector T cell.
Inducing a tolerogenic T cell response can be achieved in several ways, including using tolerogenic peptides that that mimic the naturally processed autoantigen; co-delivery of immunomodulatory peptides with specific autoantigens; or nanoparticle-based antigen delivery.
Another tactic for inducing self-tolerance involves targeting glycans, complex sugar molecules on the surface of cells and proteins that play important roles in cell signalling and immune recognition. Autoimmune diseases are believed to have unique glycan signatures characterized by the site-specific relative abundances of individual glycan structures present on immune cells and extracellular proteins, especially the site-specific glycosylation patterns of the different Ig classes and subclasses (often referred to as the “altered glycan theory of autoimmunity”). The immune system mistakenly recognises these changes in glycosylation as foreign invaders and mounts an immune response against them.
Apart from using these glycan signatures as biomarkers for autoimmune disease, innovators are looking at targeting these glycans to induce tolerogenic immune responses. For example, Gro Biosciences are using precise placement of glycan-containing non-standard amino acids on the protein surface to reset the immune system to treating an autoantigen as “self”.
A phase III trial testing antigen-specific immunotherapy for the preservation of endogenous insulin in type I diabetes patients is currently ongoing, so these therapies may well hit the clinic sooner than thought.
Conclusion
Cell therapies, small molecules, and immunisation therapies are just a few of the ground-breaking approaches transforming the landscape of autoimmune disease treatment. As research and development continue to progress, we can look forward to more effective and targeted therapies for autoimmune diseases.
