Adios to Adios….is DoDo going to be a Dodo?

Many years ago ProfG or should I say influenerG:-) as ProfG was introducted as the “Social Media influencer” at the At the Limits 2023 meeting yesterday, came up with the idea of the DoDo (Double dose) ocrelizumab trial as non-petite people did not deplete their B cells that well and showed more progression. He also came up with the Adios trial idea can’t remember what the adios was supposed to be but to me it was really a joke to say goodbye to standard 6 monthly dosing with ocrelizumab. This was based on the idea that some B cell subsets important to MS are depleted for more than 6 months and there could be similarities with cladribine and alemtuzumab. The manufacturers bit on the idea of DoDo and did the trial with a higher dose, but as Turkeys do not vote for Christmas they didn’t go for the idea of selling less product.

So the academics in the UK took up the challenge, but couldn’t get the funding and because of C0VID extended dosing was being used and had become practise in some centres. This would stop the studies having equipose as some places wouldn’t be able to recruit…so it is Adios to Adios:-(.

However COVID-19 meant the idea was sort of tested and cofirmed my hypothesis that strict 6 monthly dosing was over-dosing and that extended interval dosing (interval longer than 6 months between doses) could be done to allow for COVID-19 related vaccination whilst keeping MS in check. This supported the biology that we had suggested and it was a robust idea as others could see the same thing. The data below also supports the view that what comes back after B cell depletion is not the same as what was there before.

Rodriguez-Mogeda C, van Lierop ZYGJ, van der Pol SMA, Coenen L, Hogenboom L, Kamermans A, Rodriguez E, van Horssen J, van Kempen ZLE, Uitdehaag BMJ, Teunissen CE, Witte ME, Killestein J, de Vries HE. Extended interval dosing of ocrelizumab modifies the repopulation of B cells without altering the clinical efficacy in multiple sclerosis. J Neuroinflammation. 2023;20:215. doi: 10.1186/s12974-023-02900-z.

Background: Recent studies suggest that extended interval dosing of ocrelizumab, an anti-B cell therapy, does not affect its clinical effectiveness in most patients with multiple sclerosis (MS). However, it remains to be established whether certain B cell subsets are differentially repopulated after different dosing intervals and whether these subsets relate to clinical efficacy.

Methods: We performed high-dimensional single-cell characterization of the peripheral immune landscape of patients with MS after standard (SID; n = 43) or extended interval dosing (EID; n = 37) of ocrelizumab and in non-ocrelizumab-treated (control group, CG; n = 28) patients with MS, using mass cytometry by time of flight (CyTOF).

Results: The first B cells that repopulate after both ocrelizumab dosing schemes were immature, transitional and regulatory CD1d⁺ CD5⁺ B cells. In addition, we observed a higher percentage of transitional, naïve and regulatory B cells after EID in comparison with SID, but not of memory B cells or plasmablasts. The majority of repopulated B cell subsets showed an increased migratory phenotype, characterized by higher expression of CD49d, CD11a, CD54 and CD162. Interestingly, after EID, repopulated B cells expressed increased CD20 levels compared to B cells in CG and after SID, which was associated with a delayed repopulation of B cells after a subsequent ocrelizumab infusion. Finally, the number of changes in B cell subsets after both dosing schemes did not correlate with any relapses nor progression of the disease.

Conclusions: Taken together, our data highlight that extending the dosing interval of ocrelizumab does not lead to increased repopulation of effector B cells. We show that the increase of CD20 expression on B cell subsets in EID might lead to longer depletion or less repopulation of B cells after the next infusion of ocrelizumab. Lastly, even though extending the ocrelizumab interval dosing alters B cell repopulation, it does not affect the clinical efficacy of ocrelizumab in our cohort of patients with MS.

Anyway back to the story whilst researching my talk on “Beyond B cells” for At the limits 2023 in London, I mentioned the extended dosing, and after ingluencerGs talk I have to think would that mean an influence on progression. The same amount would get into the brain I would think so maybe no impact. However during my research for the talk ….it was evident that an Adios-like trial is being done with two doses and a watch and wait approach. (I would have done three doses to be like the phase II data and to be more like alemtzumab dose for a year…I would also monitor anti-drug antibody resposes because ocrelizumab hangs around for a long time and some may still be there when the B cells come back)Let’s see what happens. If DoDO succeeds and you get a new formulation of say 1200mg (double the current doses or may be 1800mg for big people) and extra dosing occurs this means the antibody will hang around even longer to extened dosing could be extended further.

Now influencerG was making the case that the double dose means more gets into brain (so is that 0.2% from 0.1%?) and so that is why it affects progression. Someone said intrathecal anti-CD20 delivered into the spinal cord gets it into the CNS and it didn’t do much more. The answer was the flow of the spinal fluid is down and out. However, I also remember that they drilled into peoples heads to put it in the brains and not much happened either.

Could it be there are less B cells in small people to get into the brain to do damage that is important and not what gets into the brain. However for ocrelizumab to work in the brain it needs complement and importantly natural killer cells to do the killing and there will be lower number of these cells in the MS brain than the blood.

Anyway there is a brain shuttle anti-CD20 in development which should make more get into the brain. This is based on another antibody that can cause cell suicide rather than needing complement so will it be adios to adios and dodo too? Time will tell. Anti-CD20 will probably not traget the plasma cells in the brain and maybe you need something else.

Any what was beyond B cells in my talk…Yep you guessed it “More B cell inhibitors are coming”

UPDATE I asked question of differences of atrophy of big verses little people and ofatumumab and have removed the thoughts as the data on atrophy differences accoding to BMI isnt good enough to say there is anything in the view. I am not sure there is anything to suggest that the lower dose used in ofatumumab leads to worse atrophy than ocrelizumab…suggesting to me effects may be peripherally driven and not have alot to do with CNS entry…Happy to be proved wrong

COI Multiple

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