This is about a B-cell inhibitor called Frexalimab. It is still in the pipeline and is being tested against MS. When it comes to new therapeutic strategies for the treatment of multiple sclerosis, the influence on B cells currently plays a key role. Just as a reminder: B cells are immune cells that produce antibodies but also act as so-called antigen-presenting cells in the immune response and thus also play an important role in autoimmune diseases such as MS. Most new MS therapies or the therapeutic agents that are currently in a promising development stage aim at reducing or decreasing the activation of B cells.
Thus, the B-cell-depleting antibodies ocrelizumab, ofatumumab, and (soon) ublituximab (see also DocBlog Ublituximab – a new B-cell-depleting antibody and amsel.de Ublituximab approved in Europe) reduce the number of B cells in peripheral blood and so-called Bruton tyrosine kinase inhibitors (BTKi – see also DocBlog MS-Docblog – Details about the new class of active substances of the BTKi), which are currently being tested by many pharmaceutical companies for the treatment of MS, aim at preventing the activation of B cells.
Frexalimab: new B-cell inhibitor against MS?
A new interesting approach, which also decreases B-cell activation, now joins these concepts: an antibody against the surface molecule CD40L (L = ligand, also referred to as CD154 in the literature) called Frexalimab. Frexalimab blocks the costimulatory connection of CD40 and CD40L, which is necessary for communication between T and B lymphocytes but also plays a role in the activation of cells of the innate immune system, such as macrophages and dendritic cells, without the cells being destroyed.
The results of a phase II study with Frexalimab were recently communicated at an international MS meeting. The antibody was safe and was well tolerated by the study patients, no serious side effects were reported. Frexalimab – given as an infusion – led to a significant reduction of new Gd-absorbing T1 lesions in the MRI (in the high-dose group, reduction by 89% compared to placebo). After 24 weeks of observation time, 96% of the study participants in the high-dose Frexalimab arm were free from new Gd-absorbing T1 lesions in the MRI. Also interesting is a significant reduction of plasma NfL (neurofilament light chains) levels in both Frexalimab dosages compared to placebo after 12 weeks of observation time.
The results of these first randomized, controlled phase-2 data for a CD40L inhibitor in MS thus point to the potential for further development of this concept. Anyone interested in viewing the original data for themselves, the poster is freely available online (https://drive.google.com/file/d/1L54B_i_8Dh5zRdjUqcTpWj0UGYu4B8x5/view).
Why is the CD40 activation pathway interesting for the treatment of autoimmune diseases and specifically for the treatment of MS? Ultimately, at first glance, it is also “just” a modulation of the peripheral immune system – so an approach that underlies many of the currently available MS therapies. This interest is likely to do with the role of the Epstein-Barr virus (EBV) in the development of multiple sclerosis.
Connection between EBV and CD40L
EBV infects B lymphocytes and alters their activation. This interaction with B lymphocytes can have far-reaching effects on the host’s immune response and lead to the development of certain B-cell-associated diseases. The Epstein-Barr virus can also establish a latent infection in B lymphocytes, which means that the virus rests in the cells and no longer shows active virus production.
Older basic scientific work was able to show that EBV-infected B cells express CD40L, unlike non-infected cells (Imadome et al. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7836-40). This erroneous CD40L expression can increase the ability of EBV-infected B cells to present antigens/autoantigens. Blocking CD40L by Frexalimab could impair the B-cell antigen presentation of EBV-infected B cells. Therefore, the effect of anti-CD40L may be related to influencing EBV-associated mechanisms, which is of great interest in the context of current discussions about the significance of EBV for MS – and that is why the phase II study is also worth a comment on DocBlog.
