Tregalizumab is currently the only known antibody that selectively activates the immunomodulatory subpopulation of regulatory T cells. The antibody acts early in the inflammatory cascade and as such represents a novel therapeutic approach to the relief and treatment of inflammatory processes.
Tregalizumab acts as an agonist and is a humanized anti-CD4 monoclonal antibody. Unlike other molecules in its class, it binds to CD4 in a specific and unique manner to activate regulatory T cells.
Regulatory T cells are essential for maintaining peripheral immune tolerance; they suppress autoreactive T cells (i.e. cells targeted against the body’s own structures) and thereby prevent the excessive activation of T lymphocytes seen in autoimmune diseases.
Therefore, Tregalizumab has the potential to help treat a wide variety of autoimmune diseases and conditions associated with the signs and symptoms of chronic inflammation.
Milestones and lessons learned
First milestones passed
Tregalizumab has already undergone intensive scientific and clinical studies on autoimmune diseases and has reached the Phase II clinical trial stage. In parallel, its mode of action has also been tested in preclinical studies using in vitro models and human cells. In addition, tregalizumab has been tested in eight clinical trials thus far: two in healthy volunteers, two in psoriasis vulgaris (plaque psoriasis)
and four in rheumatoid arthritis. Phase IIa studies on the indications of psoriasis and rheumatoid arthritis showed promising effects with no unexpected safety concerns.
In addition, in vitro testing of tregalizumab on cells from patients with allergic asthma has revealed a very promising immunomodulatory potential for this therapeutic indication.
The development of tregalizumab for the indication of rheumatoid arthritis was completed with the Phase IIb T-Cell Regulating Arthritis Trial 2b (TREAT2b) in 2015. The primary endpoint was not achieved. A retrospective analysis suggested interactions of tregalizumab with disease-modifying methotrexate therapy that may have had a negative impact on tregalizumab efficacy.
The next milestone
T-Balance Therapeutics announces that the German regulatory authority, the Paul-Ehrlich-Institut, has approved a Phase 2a clinical trial for the use of tregalizumab in the treatment of allergic asthma.
The Phase IIa trial on the efficacy and safety of tregalizumab in allergic asthma is planned for the beginning of 2021.
‘Lead indication’: allergic asthma
Bronchial asthma is a heterogeneous disease characterized by chronic inflammation of the lungs. Global figures show that about 350 million people suffer from asthma.1 This number is expected to rise to an estimated 400 million by the year 2025.2 Worldwide, some 495,000 people die from asthma every year.3
Two types of asthma can be distinguished: allergic asthma and non-allergic asthma. In allergic asthma, the body reacts to a typically harmless substance with an unbalanced excessive immune reaction shifted towards TH2 lymphocytes. This, in turn, leads to an increase in eosinophils and the secretion of pro-inflammatory cytokines. Allergic asthma often begins in childhood or adolescence.
Tests using in vitro models have shown that tregalizumab balances the immune response of patients with allergic asthma towards TH1 signalling, thereby indicating a potential for the reduction of inflammation. In the planned Phase IIa TREGULAIRE study, the efficacy and safety of the active substance in the indication allergic asthma will be investigated. The current database indicates tregalizumab could be a promising targeted therapeutic option in allergic asthma.
1 GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 2017; 5:691-706.
2 Masoli et al, The global burden of asthma: executive summary of the GINA Dissemination Committee Report, Allergy 2004:59 469-478.
3 Global, regional and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392:1736-88.
With its unique mechanism of action, tregalizumab has a potential for use in therapeutic indications across a wide variety of diseases involving chronic inflammatory processes.
Autoimmune diseases and other diseases with chronic or excessive inflammation
Worldwide, about 50 million people4 are affected by one of the more than 80 currently recognized autoimmune diseases. These include type 1 diabetes, multiple sclerosis, lupus, rheumatoid arthritis, plaque psoriasis and psoriatic arthritis, ankylosing spondylitis, atopic dermatitis and celiac disease. Other examples of serious chronic or excessive inflammatory diseases are Crohn’s disease and ulcerative colitis. Anti-inflammatory drugs, immunosuppressants and biologicals are used to treat these medical conditions. For these indications alone, biologicals have a market value of €75 billion. With its novel mode of action, tregalizumab has the potential to achieve a high market value.
Common to all these diseases is the overreactive immune system, in which self-tolerance is lost and autoimmune responses are initiated. In the healthy body, this immune tolerance is regulated and maintained by regulatory T cells (Tregs).
Tregalizumab acts precisely at this point: the monoclonal antibody activates regulatory T cells in a highly specific manner to help interrupt the pathogenic overreaction of the immune system and restore immune tolerance.
4 7th International Conference on Infectious Diseases, Bacteriology and Antibiotics. October 12-13, 2020 Prague, Czech Republic. Abstract of Autoimmune Disease Session. URL: https://infectiousdiseases.annualcongress.com/events-list/autoimmune-disease. Cited: 5 June 2020