I thought interesting, BTK as the new kid on the block should inhibit B cell activity and it should inhibit memory B cell activity. I saw the title and thought interesting and then saw the contents and its mouse EAE and at this point I sort of switched off. Because mice have different B cells and importantly it is a hard core T cell mediated disease in mice. Indeed it was shown by the company making the molecule that anti-CD20 did not inhibit the EAE model and the BTK inhibitor did and implied it was due to a microglia effect.
However this is forgotten and now it is working by B cells. Why do I say ugh when I see this in the beasties, because it shows it isn’t that great. Put fingolimod in this scenario and there would be nothing 0/12 with disease and the score is zero. Here we have essentialy all animals getting disease and the severity drops from 4 to 2.5. Look at the tissue and in the control you see lots of cells (top right) and nothing in BTK treated (Bottom right) problem this does not fit with the data on the left because the score is 2.5 and not 0 and so you would expect to see something. This is the problem when you can cherry pick your data
Then they show that BTK inhibitor blocks B cell function in mice and give preliminary data in humans. We know this is how these inhibitors work. They show that the BTK does not inhibit the number of B cells so it is going to be hard to support the memory cell hypothesis with this one, so maybe I will shut up on this one.
Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease.Torke S, Pretzsch R, Häusler D, Haselmayer P, Grenningloh R, Boschert U, Brück W, Weber MS.Acta Neuropathol. 2020 Aug 6. doi: 10.1007/s00401-020-02204-z. Online ahead of print.
Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.