Will the mechanistic SH1 ever stick? or will we have more failed MS studies?

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Today is hard core science day. We can learn a bit together. You can learn a lot for the human experiment, which is the clinical trial. Success of trial points the finger at something important, but failure can too.

We thought what works in arthritis (MS of the Joint) would work in MS (arthritis of the brain). That was until we tried tumour necrosis factor (TNF) inhibitory activity. It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as T helper cells and others.

Prof (Sir) Marc Feldmann was the person who introduced me to ProfG and he had the patent on this approach and was the first example where someone have moved an immunological from the bench into the clinic and he and his clinical College won the Lasker Prize (just abit below the Nobel Prize) and I guess got minted in the process. Interestingly I filed a patent of anti-MS with Prof Feldman for MS….The closest I got to being minted, was a packet of “polos”

Polo (confectionery) - Wikipedia

Although I believed you had to get the TNF blockade into the CNS for it to work…and still do..It wasn’t done that way. The drug was given intravenously into the blood and rather than the millions, it was a disaster zone as it seemed to make MS worse. Not satisfied with one failure another TNF inhibitor was tried and it failed.

I recently wondered if this was because it augmented memory B cell activity (See below), however I now think it must be more complex than that, and wonder if it has something to do with the B cell follicles that occur in MS brain and arthritis joints. In arthritis the anti-TNF gets rid of follicles but does touch MS brains as the antibody won’t get in. This study (below) complicates the picture as it can get in the brain.

However, it was worse than just augmenting MS in drug-treated people, it seemed that anti-TNF triggered demyelinating disease. Understanding this phenomenon will provide important clues in understanding MS.

It looks like we may have another failure from arthritis, which seems to trigger demyelinating disease. These are JAK inhibitors.

Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway.

JAK–STAT pathway targeting for the treatment of inflammatory bowel disease  | Nature Reviews Gastroenterology & Hepatology

They were initially named “just another kinase” 1 and 2 (since they were just two of many discoveries screens of kinases), but were ultimately published as “Janus kinase”. The name is taken from the two-faced roman god (Janus) of beginnings, endings and duality, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other inhibits the kinase activity of the first.

There are 4 JAK proteins: JAK1JAK2JAK3 and TYK2. Signal transducer and activator of transcription (STATprotein family are intracellular transcription factors that mediate many aspects of cellular immunityproliferationapoptosis and differentiation. They are primarily activated by membrane receptor-associated Janus kinases (JAK).

The first JAK inhibitor to reach clinical trials was tofacitinib. Tofacitinib is a specific inhibitor of JAK3 (IC50 = 2 nM) thereby blocking the activity of IL-2IL-4IL-15 and IL-21. Hence Th2 cell differentiation is blocked and therefore tofacitinib is effective in treating allergic diseases.

Should alarm bells be ringing for MS, if Th2 are important inhibitors of MS?. I think however they are bad for MS, just as Th1 or Th blah blah will be unwelcome.

However, Tofacitinib to a lesser extent also inhibits JAK1 (IC50 = 100 nM) and JAK2 (IC50 = 20 nM) which in turn blocks IFN-γ and IL-6 signalling and consequently Th1 cell differentiation. One mechanism (relevant to psoriasis) is that the blocking of Jak-dependent IL-23 reduces IL-17 and the damage it causes. So you can see people will have their sights set on blocking-JAK as MS is mediated by CD4 TH17 cells.

JAK3 (Janus Kinase 3) deficiency is an recessive form of severe combined immune deficiency (SCID). It is characterized by lack of circulating T and NK (Natural Killer) cells and normal number of B lymphocytes. So JAK kinase inhibitors should affect T cells.

What does it to to MS? It seems that Tofacitinib, which is approved for arthritis can trigger demyelination just like anti-TNF. Is there a similar mechanism?. It may not be MS but a demyelinating event as it went away when drug-treatment stopped

Cellular responses to TNF are initiated by either of two cell surface receptors, the type 1 TNF receptor (TNFR1) and the type 2 TNF receptor (TNFR2). Although neither receptor contains an intrinsic protein tyrosine kinase, such activity has been implicated in TNF action. Indeed TNF induces the tyrosine phosphorylation and activation of the intracellular Janus tyrosine kinases. So anti-TNF would inhibit JAK kinase.

Alarm Bells should be ringing

Although Tofacitinib provides a good treatment for RA, it also causes several severe side effects, such as anaemia and neutropenia, which are possibly caused by the inhibition of JAK2. Tofacitinib, baricitinib and upadacitinib are the first 3 JAK inhibitors. To date, they have demonstrated comparable efficacy to tumour necrosis factor (TNF) inhibitors in terms of American College of Rheumatology (ACR) response rates and disease activity (DAS28) scores.

JAK1 can associate with TNF activity and JAK3 protein was also detected in immature B cell lines. The data suggest that the regulation of JAK3 expression and activity is likely to be important in B cell development and function. Indeed, Tofacitinib has a direct impact on human naive B-lymphocytes, independently from its effect on T lymphocytes, by impairing their development into plasmablasts and immunoglobulin secretion. Tofacitinib predominantly affects naive B lymphocytes, while its effect on total peripheral B cells containing …….memory B cells is less pronounced. Inhibition of BAFF receptors target naive B cells and plasma cells but dont inhibit MS. There is a relative increase of B-cells 8–12 weeks after tofacitinib treatment with maintained subpopulation distribution, so it can increase memory B cells………….

Alarm Bells perhaps should be really ringing.

In this study the issues developed many years after treatment on so the triggering event is going to be a rare event that triggers the problems. So it is going to be more complicated and a chance event.

CNS demyelination during tofacitinib therapy: First report

Fathi Massoud, Ismail Ibrahim Ismail Dr., Jasem Y. Al-Hashel, Hesham AbboudDOI: https://doi.org/10.1016/j.msard.2020.102568

Iatrogenic demyelination is a distinct clinical subtype of central nervous system (CNS) inflammatory disorders. The Janus kinase inhibitor, tofacitinib, is an oral disease-modifying antirheumatic drug that has shown contradictory effects on multiple sclerosis in animal models. In this report, we describe a novel case of reversible multifocal CNS demyelination in a patient with seropositive rheumatoid arthritis on tofacitinib. Although the mechanism is not completely understood, activation of T17 cells by tofacitinib and the subsequent increased production of interleukin-17 could be the cause. Moreover, a link between TNF-α and JAK/STAT pathways has been suggested, which may further explain the occurrence of iatrogenic demyelination in this case.

Although the mechanism is not completely understood, activation of T17 cells by tofacitinib and the subsequent increased production of interleukin-17 could be the cause. This idea is based on mice, however as the IL-23 pathway is inhibited IL-17 should be reduced as as seen in humans.

So if and when this is tried in MS, I suspect we should be prepared for failure

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MouseDoctor

6 comments

  • …Inhibition of BAFF receptors target naive B cells and plasma cells but dont inhibit MS.

    What do you mean by target here? Does it mean kill? So a drug that inhibit BAFF its able to kill plasma cells?

    Thanks

    • There were a number of BAFF receptor inhibitors used in Lupus and as BAFF (Bcell activating factor) is a growth factor for naive and plasma B cells, block this and they are inhibited. However a molecule that blocks BAFF receptor and APRIL made MS worse. They also increase memory B cells. So simply trying to inhibit B cell activity does not give you a huarenteed MS drug.

      • What if that drug is used on top of anti cd20? No naive b cells to be tured into memory B cells, no memory B cells around because there is the anti cd20, only plasma cells left to be hit.

        • I doubt will get there…because they wont do one on top of the other to start…In MS the memory B cells have already turned before you start treating

  • Oh yes, the alarm bells should be ringing! They are ringing pretty loudly in my head right now. I am following where your train of thought is going.

  • One domain exhibits the kinase activity, while the other inhibits the kinase activity of the first.

    Feedback loop inhibition

    🙂

    Nice post

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