How does glatiramer acetate work? In the label it says “glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS”. So over its 40 years of existence it has had a lot of different mechanisms. However I have said by what ever mechanism it works by, you have to think that it may work for some and not for others, otherwise it would be high efficacy for all. So we have been spending years looking at T cell activity, but is the time changing? In this study the focus was on B cells, so how can I resist to comment on this. They took B cells from people treated with interferons and glatiramer and then stimulated them with brain tissue and measured the response. They compared responders and non responders and suggest that they have a way of predicting responders. That is eight times more likely to respond than not. This is great but the problem is the level of predictiveness as you get false positives and negatives so would you risk changing treatment or staying on treatment? It seems in this study people have been failing, but have not moved on to something effective is surprising.
The hypothesis of the study expected positive evidence of B-cell activity in GA responders and IFN-β nonresponders and no evidence of brain-related B-cell activity in GA nonresponders and IFN-β responders. However they get something different. The patients treated with GA who had positive B-cell activity and patients treated with
IFN-β who had negative B-cell activity experienced less relapse activity. So this is a difficult one to explain two drugs that have a similar level of efficacy but do the opposite in the assay. It begins to lose me, worse of all it seems when you can’t explain it, then you make stuff up. It is suggested that “RRMS develops via different auto-immunologic mechanisms, some predominantly involving T cell–mediated pathways, whereas in others, it is predominantly B-cell driven”. I have no problem with such an idea if it is supported. They say there is evidence of glatiramer having and influence on B cells and then they say numerous times that say “No direct effect of IFN-β on B cells has been reported”…They need to get out more and do some reading! Because as this is blatantly wrong e.g. Rizzo F, Giacomini E, Mechelli R, Buscarinu MC, Salvetti M, Severa M, Coccia EM.Immunol Cell Biol. 2016 Oct;94(9):886-894 and Genç K, Dona DL, Reder AT.J Clin Invest. 1997 Jun 1;99(11):2664-7
Anyway this current study was based on previously captured clinical data in association with a randomly timed blood sample so there is room for improvement. There was brain reactivity but apparently no intestinal tissue reactivity, showing the specificity for the brain tisssue. Next plan is to test ocrelizumab amd alemtuzumab. Let’s see what they find before passing any more judgement…..I can tell them now there is evidence for a B cell effect with ocrelizumab:-). If this is going to pan out start with a high efficacy treatment. It will be simpler to understand and refine, but starting with CRAB drugs to make ideas is a a hard route to take.
Looking at work by Schuberts (above) it may suggest more efficacy from the interferons than with glatiramer as the memory B cells are going down, however you need absolute numbers as percentages are decieving.
Tacke S, Braune S, Rovituso DM, Ziemssen T, Lehmann PV, Dikow H, Bergmann A, Kuerten S.Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e980.
Objective: We investigated the predictive value of the enzyme-linked immunospot technique (ELISPOT) in identifying patients with relapsing-remitting multiple sclerosis (RRMS) who will respond to treatment with glatiramer acetate (GA) or interferon-β (IFN-β), based on the brain-reactive B-cell activity of peripheral blood cells.
Methods: In this retrospective, cross-sectional, real-world multicenter study, we identified patients with RRMS in the NeuroTransData MS registry and stratified them based on their documented treatment response (relapse-free in the first 12 months of treatment) to GA or IFN-β. The GA group comprised 73 patients who responded to GA and 35 nonresponders. The IFN-β group comprised 62 responders to IFN-β and 37 nonresponders. Patients with previous or current therapy affecting B-cell activity were excluded. We polyclonally stimulated mononuclear cells from peripheral blood samples (collected after participant selection) and investigated brain-reactive B-cell activity after incubation on brain tissue lysate-coated ELISPOT plates. Validity metrics of the ELISPOT testing results were calculated (Python 3.6.8) in relation to the clinical responsiveness in the 2 treatment groups.
Results: The ELISPOT B-cell activity assay showed a sensitivity of 0.74, a specificity of 0.76, a positive predictive value of 0.78, a negative predictive value of 0.28, and a diagnostic OR of 8.99 in predicting clinical response to GA vs IFN-β therapy in patients with RRMS.
Conclusion: Measurement of brain-reactive B-cell activity by ELISPOT provides clinically meaningful predictive probabilities of individual patients’ treatment response to GA or IFN-β. The assay has the potential to improve the selection of optimal first-line treatment for individual patients with RRMS.
However other people think GA works in other ways. Now its T cells
Melnikov M, Sharanova S, Sviridova A, Rogovskii V, Murugina N, Nikolaeva A, Dagil Y, Murugin V, Ospelnikova T, Boyko A, Pashenkov M. The influence of glatiramer acetate on Th17-immune response in multiple sclerosis. PLoS One. 2020 Oct 30;15(10):e0240305.
Glatiramer acetate (GA) is approved for the treatment of multiple sclerosis (MS). However, the mechanism of action of GA in MS is still unclear. In particular, it is not known whether GA can modulate the pro-inflammatory Th17-type immune response in MS. We investigated the effects of original GA (Copaxone®, Teva, Israel) and generic GA (Timexone®, Biocad, Russia) on Th17- and Th1-type cytokine production in vitro in 25 patients with relapsing-remitting MS and 25 healthy subjects. Both original and generic GA at concentrations 50-200 μg/ml dose-dependently inhibited interleukin-17 and interferon-γ production by anti-CD3/anti-CD28-activated peripheral blood mononuclear cells from MS patients and healthy subjects. This effect of GA was reproduced using purified CD4+ T cells, suggesting that GA can directly modulate the functions of Th17 and Th1 cells. At high concentrations (100-200 μg/ml), GA also suppressed the production of Th17-differentiation cytokines (interleukin-1β and interleukin-6) by lipopolysaccharide (LPS)-activated dendritic cells (DCs). These GA/LPS-treated DCs induced lower interleukin-17 and interferon-γ production by autologous CD4+ T cells compared to LPS-treated DCs. These data suggest that GA can inhibit Th17-immune response and that this inhibitory effect is preferentially exercised by direct influence of GA on T cells. We also demonstrate a comparable ability of original and generic GA to modulate pro-inflammatory cytokine production.