Another Eagle has landed


Another Sphingosine -1-phosphate modulator has arrived in the USA, first we had Fingolimod, then Siponimod, the ozanimod and now ponesiod. The later three target S1P1 and S1P5 which one would you choose?

There are five main receptors S1P 1 to SP15 and the major immune effects are mediated by S1P1. This is expressed by astrocytes and lymphocytes. The mechanism linked to the action is by stoppoing white blood cells leaving lymph glands. This makes it easy to explain but it is far too simplistic. You would think that your lymph glands in groin would be swelling so you are Buster Gondad with the incredably large testicles:-). You would have a neck as thick as the rock. Some lymphocytes disappear.

S1P1 is also involved in getting white blood cells across blood vessels.

Cyster JG, Schwab SR. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol. 2012;30:69-94. doi: 10.1146/annurev-immunol-020711-075011. Epub 2011 Dec 5. PMID: 22149932.

(click above to get the full article)

Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.

We know about the effect of the SP1 on lmyph nodes, but another effect is that is is involved in shuttling B cells in the lymph glands. This shuttles B cells from places where they may contact antigens and to places where they can make antibody forming cells. This is perhaps one of the reasons why fingolimod may blunt a vaccine response.

Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone.
Cinamon G, Matloubian M, Lesneski MJ, Xu Y, Low C, Lu T, Proia RL, Cyster JG.Nat Immunol. 2004; 5:713-20.

Cinamon G, Zachariah MA, Lam OM, Foss FW Jr, Cyster JG. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008 Jan;9(1):54-62. 

The splenic marginal zone (area in the spleen) is a site of blood flow, and the specialized B cell population that inhabits this compartment has been linked to the capture and follicular delivery of blood-borne antigens. However, the mechanism of this antigen transport has remained unknown. Here we show that marginal zone B cells were not confined to the marginal zone but continuously shuttled between the marginal zone and follicular areas, such that many of the cells visited a follicle every few hours. Migration to the follicle required the chemokine receptor CXCR5, whereas return to the marginal zone was promoted by the sphingosine 1-phosphate receptors S1P1 and S1P3. Treatment with an S1P1 antagonist caused displacement of marginal zone B cells from the marginal zone. Marginal zone-follicle shuttling of marginal zone B cells provides an efficient mechanism for systemic antigen capture and delivery to follicular dendritic cells.

Fingolimod binds to S1P1, S1P3, S1P4, S1P5.

S1P3 is on the heart and one of the reason for the hear arthymia (heart issues) associated with fingolimod Therefore, the the newer mods siponimod, ozanimod and ponseimod are S1P1 and S1P5 modulators.

You can see is above it is may be involved in antibody vaccine response so what about the new mods. What happens with the other and vaccinations

“During and for up to 3 months after treatment with ozanimod, vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should, therefore, be avoided during and for up to 3 months after treatment with ozanimod”

Siponimod “Vaccinations may be less effective if administered during siponimod treatment. Discontinuation of
treatment 1 week prior to planned vaccination until 4 weeks after is recommended. When stopping
siponimod therapy for vaccination, the possible return of disease activity should be considered”.

I can’t see the ponesimod data

S1P5 is found on oligodendrocytes and was the hope that this would facilitate remyelination. It is the case that fingolimod accumulates in the brain and if it really is a remyelinating agent then it would say what remyelination can do and so we have to ask is fingolimod causing every one to recover. Why then it is fail in primary progressive MS?

CoI multiple but none relevant

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  • Definitely offerings from Norvatis for the awesome compensation to doctors! (whats happening in some markets)

  • “Which would I choose”? Depends on what other DMTs were available. For RR MS it chose none of them.

    • It will be an interesting model…4 drugs dosing the same thing and 3 very similar for the beta interferons there was the dosing schedule that was different?

    • It brings choice and competition but importantly it brings Janssen (Belgium) or should we say Johnson and Johnson (USA) into the MS space. Johnson and Johnson have a stable of treatments for example technologies to get rid of antibody forming cells in the central nervous system…..If they are in the MS space they may be more likely to do a trial and bring a new treatment.

    • this is a post in its self, have updated abit.

      To get a quick answer watch the Novartis video on you
      I think this one was originially done in 3D and with virutal reality goggles it was amazing….

      Whilst I have my B cell hat on this video shows a problem with the idea being presented it says effector memory T cells are spared…the view is given that this will allow immunity to infection to be maintained. However it is this subset of cells that accumulate in the brain during MS….Therefore fingolimod should not work. But it does so you may need another view….but when this vidoe was made, B cells were not considered to be important in MS as it was the early days for ocrelizumab

  • Having all these different pharmaceutical companies in the multiple sclerosis space most likely will help bring a cure faster since there is more competition ? ( ebv )

  • I was interested to read the recommendation for Siponimod and vaccination. My neuro had me hold Mayzent for 1 week before and after each vaccine dose in order to improve response. Aside from him, no one else had recommended this, as all general written guidance was saying not to stop for risk of rebound. I was very hesitant, but followed his recommendation. I’ll have antibody testing done end of April.

    • I understand that recommendations are being made for ongoing trials, it has a short half life about a day so will be gone soon, fingolimod half-life is 9 dyas

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