A Compelling Way to Restore Immune Tolerance by Inactivating Mycobacteria Through A Novel Process
A Breakthrough Tolerysing Therapy Discovered at the Institut Pasteur
Dr Gilles Marchal, a Tolerys adviser, and his research team from the Institut Pasteur, discovered a unique tolerysing effect of mycobacteria through a novel inactivation method.
The corresponding Extended Freeze-Drying (EFD) inactivation process entails a unique lyophilization cycle. Unlike current sterilization processes, e.g heat killing, with EFD, mycobacteria are killed without denaturation of macromolecules. The resulting preparation of inactivated mycobacteria containing immunoactive proteins presents strong skills to regulate pathologic inflammation, which is devoid of any counterbalancing effect of live bacteria that can inhibit the innate immune system directed against infection.
A Mechanism of Action Based on the Restoration of Immune Tolerance
The therapeutic manipulation of CD4+CD25+FoxP3+ regulatory T cells (Tregs) has recently gained prominence, as these cells are attracted to the site of inflammation, where they have the capacity to restore immune homeostasis through a combination of mechanisms including the secretion of anti-inflammatory cytokines, cell contact-mediated regulation via the T cell receptor, costimulatory molecules, and cytolytic activity.
Preclinical research on our lead product EFD01B, also named EFD BCG, led to the discovery of a crucial interplay between tolerogenic plasmacytoid dendritic cells and a population of nonspecific Tregs, both producing the immunoregulatory cytokine IL-10. The expansion and activation of the latter cells drive persistent effects preventing Th1, Th2 and Th17 proinflammatory responses. The anti-inflammatory effect induced by EFD01B lasts up to three months. This prolonged duration of action supports the idea that treatment regimen will be easier to follow for patients.
Proof-of-Efficacy of EFD01B was shown in several models of allergic disorders (i.e., allergic asthma, atopic dermatitis, food allergy) and other chronic inflammatory diseases (i.e., inflammatory colitis, multiple sclerosis, atherosclerosis).
An Unexpected Beneficial Effect Obtained with Inactivated Mycobacteria
Bacillus Calmette-Guérin (BCG) a live attenuated vaccine against tuberculosis that has been administered to more than 3 billion newborns and young children over the last 90 years with very low rates of severe side effects according to the World Health Organisation.
Live attenuated BCG vaccine was the first human medicinal product for which a surprising protective effect was reported on childhood allergic conditions at the end of 90s. This effect is nevertheless limited since contradictory results were obtained in subsequent studies.
Preliminary efficacy studies in a model of allergic asthma showed an outstanding preventive effect after EFD01B treatment while live BCG was associated with a slightly improved lung function. In contrast, heat-killed BCG administration induced a pro-inflammatory effect.
In addition to the positive efficacy results, no side effect has been associated with EFD01B during in vivo studies and, noticeably, no interference was reported with live preparations of BCG as a vaccine against tuberculosis.
The Manufacturing Process Defines a Biotherapy
The EFD technology is simple and practical utilizing widely-available equipment, with a moderate operating cost and without major safety risks of the manufacturing process. The EFD process has a high percentage yield of active pharmaceutical ingredient. As a result, the manufacturing process developed by Tolerys will allow the production of large commercial batches of EFD products for the treatment of allergic diseases.
The EFD inactivation method is patented but a strong know-how is required for the manufacturing process. In addition, as a biological product we use our own BCG strain. As a consequence, we consider that our products will be well protected against biosimilar competition.