B lymphocytes are currently of great importance for therapy research in MS. They are a central element in the pathogenesis of MS, on the one hand as important antigen-presenting cells, on the other hand as precursor cells in antibody production.
Drugs that change or impair the functionality of B cells are currently very successful in MS therapy – especially the cell-depleting monoclonal antibodies such as Ocrelizumab or the precursor substance Rituximab. With the concept of B-cell depletion, relapsing MS – especially in the early stages of the disease – can be controlled very well, but also patients in later progressive disease phases can benefit from it.
To mediate this effect, cell-depleting antibodies bind directly to the surface of the target cells (i.e., the B cells) with their recognition region after infusion. At the end opposite the binding region, these antibodies are equipped with a signal system that activates the body’s own defense mechanisms (the so-called complement system and natural killer cells). These unspecific body’s own defense mechanisms are signaled that the B cell is a foreign body that must be eliminated. This results in all B cells currently in the bloodstream and recognized by the therapeutic monoclonal antibodies being eliminated by the body’s own (innate) immune system.
This mechanism of action is very fast – just a few hours after the infusion, all B cells in the peripheral blood are depleted. Accordingly, these therapies must also be given with concomitant medication with (anti-inflammatory) cortisone and fever-reducing agents – because the rapid destruction of a large number of cells results in the release of messenger substances that give the body a general feeling of illness. Without concomitant medication, the therapy is not tolerated as well.
Now, with all the successes of B-cell depletion, it should be critically noted that the approach is relatively “brutal”. It would be much smarter to not just decimate this important cell population but to preserve it and inhibit its function. Because not only in times of the Corona pandemic it was repeatedly questioned whether it makes sense to deplete such an important immune cell population in the long term.
Another point of criticism is that the depleting antibodies, due to their sheer size (they are high molecular weight protein molecules), cannot penetrate efficiently into many tissues. Especially in the central nervous system, where the main disease process of MS (especially in late stages of the disease) takes place, these drugs have only marginal effects at best.
The goal is thus the development of drugs that are capable of impairing the functionality of B cells without having to deplete them, and that exert this effect not only on B cells in the periphery but also on inflammatory cells in the central nervous tissue. With the development of BTK inhibitors, this goal has been significantly advanced.
The abbreviation BTK stands for Bruton Tyrosine Kinase. This is an intracellular enzyme that is downstream of the B cell receptor, among other things, and is therefore of great importance for the activation and proliferation of B cells. BTK inhibitors are now the focus of most major pharmaceutical companies. Primarily, they were used and approved in cancer therapy, but the first Phase II studies on their effects in MS have already been conducted. Last year, the results of a Phase II study with Evobrutinib (a BTKi from Merck) were published (Montalban et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019 Jun 20;380(25):2406-2417). And on 23.04.2020, Sanofi released a press release about the results of the Phase II study with their BTKi SAR442168 (www.sanofi.com/en/media-room/press-releases/2020/2020-04-23-07-00-00).
The results of these first “proof of concept” studies are quite promising and justify the further development of this class of substances in MS – and this is quite hopeful. Because BTKi not only play a role in the activation of B cells, they are also important in the activation of microglial cells. Microglia are important resident immune cells in the brain that probably maintain inflammation in the CNS, especially in (secondary) chronic progressive MS. Unlike other MS drugs, BTKi are CNS permeable and can therefore work at the site. This could indeed be associated with a significant therapeutic advance (also for longer ill MS patients).
