Our immune system serves as the body’s main line of defense against harmful invaders. But what happens when this powerful defense mechanism activates its own host, launching an attack on healthy cells and tissues? For millions of people battling autoimmune diseases, it can greatly impact their lives. However, advances in immunotherapy have revolutionized this way autoimmune disease treated.
The first immunotherapy, approved by the US Food and Drug Administration (FDA) in 1986, was the anti-tumor cytokine interferon-alpha 2 (IFN-a2). The therapy is able to stimulate an immune response by regulating cytokines, and was originally used to treat hairy cell leukemia (HCL).
Since then, immunotherapy has been considered a powerful tool in the treatment of cancer, and has become an integral part in the fight against solid tumors. Driven by its success in cancer research, immunotherapy has become a standard of care for treating autoimmune and inflammatory diseases, over the past decades.
Immunotherapy company Revolo Biotherapeutics’ approach to targeting autoimmune and inflammatory diseases
Eosinophilic esophagitis (EoE) is one of the inflammatory diseases targeted through immunotherapy. EoE occurs when the esophagus reacts badly to allergens such as food or pollen, which causes white blood cells known as eosinophils to proliferate and trigger inflammation, damaging and injuring the lining of the esophagus. People with EoE often have difficulty swallowing (dysphagia), stomach pain, and heartburn.
For the treatment of this debilitating disease, Revolo Biotherapyheadquartered in the UK, has developed a peptide drug, 1104. Candidate binds to monocytes – which mature into dendritic cells – and modifies regulatory signals that cause them to activate regulatory dendritic cells, regulatory T cells and regulatory B cells – all of which protect our immune system from overdrive.
As part of the proof of concept study for the EoE trial, patients were given three doses of the drug over a two-week period. There is an arm with 4 mg of 1104, an arm with 8 mg, and a placebo. The candidate was found to be safe and well tolerated. In addition, the drug is cleared from the systemic circulation within 24 hours, indicating a relatively short pharmacokinetic exposure. But the pharmacodynamic effects last for weeks, and maybe even months, explains Jonathan Rigby, CEO of Revolo Biotherapeutics.
“We are pleased with the data, in which we demonstrated that we met our primary end point, which was histological reduction of primary inflammatory cells, especially eosinophils. And when you measure these eosinophils by flow cytometry, we show a statistical increase in the reduction of eosinophils, compared to placebo,” said Rigby.
The patient also filled out a dysphagia questionnaire, as a tool for self-monitoring of symptoms, and according to the results, significant improvement was observed.
“So even in a short study, we know that the drug has a huge impact on the lives of these patients, and that’s incredible. And then also, we showed a significant increase of T regulatory cells and B regulatory cells, and some other key immune cells,” said Rigby, who added that the company is preparing for a phase 2A proof-of-concept trial for 1104 for the treatment of food allergies.
Rheumatoid arthritis: an immunotherapy candidate gaining support
In addition to EoE, Revolo Biotherapeutics is making advances in immunotherapy for rheumatoid arthritis, a chronic autoimmune disease that affects 1.5 million people in the US alone. The drug candidate 1805 is a modified analogue of the endogenous immune-binding protein immunoglobulin (BiP), which, like 1104, generates regulatory dendritic cells.
To better understand the therapeutic potential of 1805, a study with 24 patients who did not respond well to biologic drugs, was conducted several years ago. The trials demonstrated remission of the disease, which lasted the entire trial period – 12 weeks. Furthermore, 1805 showed decreased correlation in inflammatory biomarkers of rheumatoid arthritis.
Recently, a study was conducted to further investigate the effectiveness of 1805. Comparative blood analysis between healthy volunteers and rheumatoid arthritis sufferers was performed to observe the reversal of genes associated with rheumatoid arthritis. While no gene changes were observed in people who did not have rheumatoid arthritis, 1805 has shown promise for people with autoimmune diseases.
“We see thousands of reversed genes in patients who have rheumatoid arthritis,” said Rigby. He explains that unlike biologic drugs, which come in a black box warning about the risks of infection and certain types of cancer associated with the drug, 1805 doesn’t suppress the immune system to the point where the body can’t fight off other diseases.
Managing inclusion body myositis
As biotech seeks to manage autoimmune diseases, it is based in the US Abruro devoted to developing therapies for inclusion body myositis (IBM). A rare condition that affects 10-112 people per million population, IBM is prevalent in people over 50 years of age. It is a progressive disease characterized by muscle atrophy – which is the wastage of muscle mass – in the arms, knees and those involved in swallowing, and can even lead to premature death.
Because highly cytotoxic T cells attack muscle in IBM, Abcuro’s ABC008 is a monoclonal antibody that binds to these cells, targeting them through cell-mediated immune defense mechanisms. After being awarded the Orphan Drug Designation by the FDA in 2020, ABC008 successfully completed a phase 1 study where it demonstrated long-lasting, dose-dependent depletion of cytotoxic T cells. Earlier this year, the company announced it had started a phase 2/3 trial of registration ABC008 for the IBM treatment.
“We are excited by the evidence of the interesting mechanisms observed with ABC008 to date in the first human study of IBM patients,” said Steven Greenberg, founder and senior scientific advisor to Abcuro. “These data promise the ability of ABC008 to potentially selectively deplete highly cytotoxic T cells without affecting important protective T cell populations, distinguishing ABC008 from previous widespread T cell depletors and an important step forward for discovering a potential treatment for IBM.”
Lupus Research: CAR-T Therapy to win?
Meanwhile, advances in lupus research have been in the news lately. And, in particular, chimeric antigen receptor (CAR) T-cell therapy could change the game for people with systemic lupus erythematosus. Lupus is caused by an overactive immune system that attacks its own tissues, causing inflammation and symptoms that include fatigue, rashes, skin lesions and, in drastic cases, kidney failure.
The trial was conducted by researchers at the Friedrich Alexander University Erlangen-Nuremberg in Germany, on five patients who were unresponsive to standard lupus medications. T cells are extracted and engineered to express CAR – which can bind to B cells – before being reinfused into the patient.
It was observed that the number of B cells had decreased, which spurred remission of the disease. What’s more, despite B-cell recovery, symptom reduction was maintained throughout the follow-up period.
While acknowledging that the scale of this study does not approach clinical trials consisting of much larger cohorts, it paves the way for possible alternatives to current treatment measures for people who do not respond well to immunosuppressive treatment.
Startups aim to breakthrough autoimmune therapy
As CAR-T therapy is hailed as a triumph for lupus research, breakthroughs in the treatment of multiple sclerosis and ulcerative colitis are eagerly awaited. Various startups are developing immune-related therapies, including those based in the US Atara Biotherapy And Landslide Biopharma.
The drug candidate forming ATA188, currently in phase 2 trials, is designed to kill cells that have been infected with the Epstein-Barr virus (EBV). An increasing number of studies point to EBV as a major cause of multiple sclerosis. When the immune system attacks the central nervous system, specifically the myelin sheath – the insulating layer that forms around nerve cells – it can cause damage to nerve fibers, affecting mobility, vision and bladder function – all manifestations of disease.
Intended to stop disease progression, ATA188 contains T cells – from healthy donors previously infected with EBV – that have been modified to recognize EBV proteins, in order to trigger an attack on the infected cells.
Last year, the candidate was given fast-track designation by the US FDA, and a phase 1 trial looked at symptom relief, and found the drug to be well tolerated. Currently, ATA188 is being investigated in a phase 2 clinical study.
In addition, Landos Biopharma is developing a therapy for ulcerative colitis. The candidate NX-13 is a small orally administered molecule that targets the mitochondrial-associated receptor NLRX1 to regulate immune responses. Since this disease is exacerbated by inflammation resulting from an immune system attack on the tissues in the intestine, NX-13 aims to decrease the production of inflammatory cytokines in the intestine.
The company is also developing therapies for multiple sclerosis and rheumatoid arthritis, both of which are in preclinical stages.
“We have to find ways to not suppress the immune system because we need it, we need it to do its job. We need to get it from this imbalanced pro-inflammatory state to a regulated homeostatic state, so we don’t cause autoimmune disease, but instead allow the immune system to fight these bacteria, viruses, and cancers.
Jonathan Rigby, CEO of Revolo Biotherapeutics
Addressing the challenge of immune suppression
As research into autoimmune diseases expands, Rigby reveals that the key to fighting autoimmune diseases is not suppressing the immune system. He points out that unlike high-dose steroids, drug candidate Revolo Biotherapeutics still enables the body to fight bacteria and viruses, according to data from studies in animal models.
“Your immune system can be your best friend and it can be your worst enemy. We fight millions and millions of bacteria, viruses and cancer every day. So we do all of this without our knowledge… But when it gets out of balance, it becomes a problem.
Excited to partner on the rheumatoid arthritis program after completing its more important phase 3 trial, Rigby said: “We have to find ways to not suppress the immune system because we need it, we need it to do its job. We need to get it from this imbalanced pro-inflammatory state to a regulated homeostatic state, so we don’t cause autoimmune disease, but instead allow the immune system to fight these bacteria, viruses, and cancers. So that’s our goal – we’re not suppressing the immune system… And being optimistic here, but this – we’re resetting the immune system and bringing it back to this tolerogenic homeostatic state.”
New technologies related to immunotherapy for autoimmune diseases