T reg enhancers is this the future?

T

ProfG suggested that companies were looking away from simply depleting CD20 B cells and he was correct. It seems that most companies in the MS field are making Brutons tyrosine kinase inhibits that don’t deplete B cells but block their signalling.

However, I must say that on first glance, the results of BTK inhibitors in MS were less impressive than CD20 depletion. Evobrutonib inhibited gadolinium enhancng lesions in the beta-interferon range and the treatment effect of SAR442168 at the 60mg dose was 85% relative reduction of new Gd-enhancing T1 hyperintense lesions…..but not the about 95% inhibition seenbut with ocrelizumab and ofatumumab. However some will say. “That’s OK it’s not the real MS”

However, I am sure it will be claimed that BTK inhibitors work because they inhibit T cell function:-)

Xia, S., Liu, X., Cao, X. et al. T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia. Cell Mol Immunol (2019). https://doi.org/10.1038/s41423-019-0270-9

However, T cell immunology is still going strong and the T cell immunologists have suceeded to persuade Pharma that T-regulatory cells are still the bees-knees and interleukin-2 the target.

Interleukin 2 (IL-2) is critical to the activation, growth, and survival of T cells and natural killer (NK) cells, and maintains the delicate balance between auto-immunity and anti-cancer surveillance. High IL-2 doses have clear anti-tumor capabilities, but also have severe side effects that limit its clinical use. Side effects include the vascular leak syndrome (VLS), which results in lung oedema and liver damage. Therefore, a new version of IL-2 that does not induce organ toxicity would improve IL-2-based immunotherapy.

Chen X, Ai X, Wu C, et al. A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2. Cell Death Dis. 2018;9(10):989 conducted a systematic screening by changing one amino acid at a time at the interaction area of IL-2 with its receptor IL-2R to select one particular mutant IL-2, FSD13, in which the proline at position 65 was substituted by lysine (P65L). FSD13 had a greater ability than wild-type IL-2 in stimulating CD4+ T, CD8+ T, and NK cell proliferation, enhancing the expression of CD69, CD183, CD44, and CD54 in these cells, and triggering cancer cell apoptosis. FSD13 had three-time lower than wild-type IL-2 in inducing CD4+ T to Tregs. Compared with wild-type IL-2, FSD13 greatly limited the growth, invasion into adjacent tissues, and metastasis of melanoma metastatic into the lung. In contrast to wild-type IL-2, high dose of FSD3 did not alter structures and induce any pathogenic changes in the liver and lung.

But you can make alternative variants

Peterson LB, Bell CJM, Howlett SK, et al. A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease. J Autoimmun. 2018;95:1-14. Susceptibility to multiple autoimmune diseases is associated with common gene polymorphisms influencing IL-2 signaling and Treg function, making Treg-specific expansion by IL-2 a compelling therapeutic approach to treatment. As an in vivo IL-2 half-life enhancer we used a non-targeted, effector-function-silent human IgG1 as a fusion protein. An IL-2 mutein (N88D) with reduced binding to the intermediate affinity IL-2Rβγ receptor was engineered with a stoichiometry of two IL-2N88D molecules per IgG, i.e. IgG-(IL-2N88D)2. The reduced affinity of IgG-(IL-2N88D)2 for the IL-2Rβγ receptor resulted in a Treg-selective molecule in human whole blood pSTAT5 assays. Treatment of cynomolgus monkeys with single low doses of IgG-(IL-2N88D)2 induced sustained preferential activation of Tregs accompanied by a corresponding 10–14-fold increase in CD4+ and CD8+ CD25+FOXP3+ Tregs; conditions that had no effect on CD4+ or CD8+ memory effector T cells.

Effect of IL-2 in monkeys

Humanized mice had similar selective in vivo responses; IgG-(IL-2N88D)2 increased Tregs while wild-type IgG-IL-2 increased NK cells in addition to Tregs. These results describe a next-generation immunotherapy using a long-lived and Treg-selective IL-2 that activates and expands functional Tregsin vivo. Patients should benefit from restored immune homeostasis in a personalized fashion to the extent that their autoimmune disease condition dictates opening up the possibility for remissions and cures

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Ghelani A, Bates D, Conner K, et al. Defining the Threshold IL-2 Signal Required for Induction of Selective Treg Cell Responses Using Engineered IL-2 Muteins. Front Immunol. 2020;11:1106.

There are other variants

An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice Khoryati et al. Science et al. 2020 They demonstrate that administration of this IL-2 mutein resolved ongoing diabetes in nonobese diabetic mice. This proof-of-principle study raises the possibility that engineered human IL-2 muteins could be used in the treatment of autoimmune diseases.

Will it ever get used in MS? Blocking interleukin 2 and reducing T regs with daclizumab inhibited MS, but caused other problems like skin condistions and liver and brain adverse events leading to withdrawal of the drug. What will augmenting T regs do? Will it block relapsing disease even in EAE. Will this be given in remission to see if it stops relapse (Give us a call).

However memory B cells express the interleukin 2 receptor and in all the preliminary data, B cells have not got a mention, T regulatory cells are augmented, T memory cells less so….but what happens to B memory cells? In our rush for controlling T cells have we forgotten about B cells and what would happen if this variant augmented memory B cells? They would not appear in the humanised mice studies as they do not make adequate B cell responses.

However we know that pharma hunts in packs and do the same thing and AMG-592 has got there already with their variant and are in trials for systemic lupus erythematosus (SLE) (NCT03451422), and rheumatoid arthritis (NCT03410056).  However 2020 annual Report says “Phase 1b study in rheumatoid arthritis (RA) was stopped due to insufficient benefit-risk for the use with standard of care therapy in active RA patients”. Low dose interleukin-2 is in trial in diabetes (EudraCT 2017-002126-20).

So if enhancing T regs doesn’t hit the spot, the T cellers will look for a new mechanism to control autoimmunity…..Bets B regulatory cells which is what my Boss used to say in 1980 when I started immunology, will we go in a circle.

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MouseDoctor

7 comments

  • Nice post

    Question :

    If all things are in equilibrium one goes up the other come down, what happen when you get to much t reg around?

    Cancer go up?, immune surveillance would be the same ?

    Obrigado

  • Don’t to BTK inhibitors also exert an effect on the innate immune system? And isn’t there some indication that they penetrate the blood brain barrier more effectively than the current crop of MS drugs?

    I did read some promising phase 2 results on masitinib. When used in progressive MS patients, the drug seems to not only stop progression but also decrease disability scores. Of course, only phase 2, but promising.

    Interestingly, the drug is currently used to treat veterinary mast cell cancers, and is only available in Europe. Makes me wish I was a German Shepherd in London.

    I’ve crossed the threshold of desperation with my disease progression that I’ve considered trying to knick some of the stuff from Internet providers. My neuro has had to talk me off the ledge…

    • Yes BTK inhibitors do work on the innate immune system and at least one of the latest crop was selected to cross into the CNS, I suspect we will see this info at the late breaking session at ACTRIMS2020.

      Mastinib is a tyrosine kinase inhibitor, this is different from the a Brutons tyrosine kinase they are a different target.

      If you were a german shepherd in London you would have tote Schafe as there is no grass as it has been so f..ing hot….alternatively you’ld be suffering from hip dysplasia:-)

      Glad you were talked off the ledge

      • Thanks for the response, MD. Interesting that masitinib is a TK but not BTK inhibitor. I’ll have to go down the rabbit hole and research this some more.

        If I were a German Shepherd in London, you’d have to sneak me into a pub so we could grab a pint. As for the hip dysplasia, what with my Avascular Necrosis I think I’ve already checked that box. My bomb sniffing days are behind me…

        • With covid-19 and anosmia (loss of smell) I guess many peoples sniffing days are done. Unlucky for the drug dealers or if you are going in to a US airport fruit smugglers (Fruit dogs) dogs dont get it that well, cats on the other hand, another matter…tigers and lions get it…more useless papers- don’t people know tigers and lions can’t read:-)

      • Thanks for noticing, Luis.I’ve been laying low, quite disgruntled with the state of MS research and the world in general. Trying to spare the Internet from what could be a constant stream of vitriol should I choose to raise my ugly head… Hope you are doing well…

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