Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

[forestglip]

I'm I'm not misremembering I think the NK cell findings here were somewhat related to illness duration (I'm not actually sure if anyone checked whether the correlation between response and NK count was stronger than response and illness duration), which would make that quite possible (people with long-term illnesses "responding" better for whatever reasons).

I don't see any individual level data for illness duration in the study. Just a mean and range in Table 1. And I don't see anything about NK relationship to duration. Maybe it's from a talk?

 

[EndME]

I don't see any individual level data for illness duration in the study. Just a mean and range in Table 1. And I don't see anything about NK relationship to duration. Maybe it's from a talk?

Possible, but probably more likely that I might be misremembering. I guess the table does at least suggest the possibility for a relationship.

 

[ryanc97]

Whose theory would be?
OK, it has been the received wisdom in generic immunology circles for decades, but it has nothing much to recommend it.

I think you will find forum members are up to speed on the other stuff!!

Theory from Olav Mella in his video or presentation that was recorded at Charite MECFS conference 2025.




See 14:28.

If it were a common theory, this is the first ever attempt at targeting the source of AABs, which I find odd.

 

[ryanc97]

"Furthermore, IgG4 production by antibody-secreting cells can be markedly shorter lived than for other IgG subclasses, requiring continuous input from newly differentiating B cells. Indeed, rituximab (anti-CD20) therapy for B cell depletion has been shown to be particularly beneficial in autoimmune diseases characterized by pathogenic IgG4 (auto)antibodies" The unique properties of IgG4 and its roles in health and disease.

And when rituximab was used in ME, it didn't help, even though SLPC was affected by the drug. And as you said, "Rituximab should work if the source is SLPC in theory." In reality it didn't work. Maybe the target wasn't correct, or they didn't use the drug in the optimal way in the study.

I think IgG4 makes sense because it's a blocking antibody and it's known to be noninflammatory and does not activate complement or ADCC, and there are no signs of inflammation or autoimmune tissue damage in ME. It can bind to some of the many proteins that we don't recognize yet as a target. for example, like in MuSK myastenia gravis.

The other question is why the disease hasn’t come back after stopping datratumumab if dara isn’t touching B cells?

Why new autoreactive plasma cells weren’t made

That's what Im trying to figure out. Is it a one-shot impulse style thing where during the CFS trigger, B cells went rogue?

Also, from the charts response was clearly seen at T=6 weeks. ChatGPT says IGG has a half life of 3W. Once you stop the flow of toxic antibodies, 50% gets cleared out/consumed by 3 weeks. So at 6W you might be looking at 75% of toxic antibodies cleared out and the body responds

 

[ryanc97]

Table showing B cell pipeline, CD20/CD38 expression and Ritux/Cyclo/Dara impact from ChatGPT 5.

 

[ryanc97]

Well there is another thing that complicates things, the higher IGG4 count at baseline in responders vs non responders:

NK cell counts at t=0 - higher (238 vs 97 in 10^6/L)
IGG4 counts at t=0 - higher (0.6 vs 0.21 in g/L)

I know in this thread IGG4 has been discussed already. And JE said CD20 drugs like Ritux respond better to IGG4 things according to medical theory.

We know these things:

1. The non responders were 2 severe 2 moderate, while responders were 6 moderate. So non responders were worse off at baseline.
2. Non responders had lower IGG4 levels, which would imply that IGG4 being high is less correlated to symptom severity.
3. IGG4 is produced farther back in the B cell pipeline by SLPCs and differentiating B cells, while IGG4 is less produced by LLPCs.
4. Ritux helps with IGG4 problems, obviously because the pipeline further back is more CD20 than CD38.
5. From P3 RCT we know ritux has less effect. Since if IGG4 reduction was key, Ritux would have more effect.

Why would higher IGG4 result in less severity? Makes no sense to me.

Also for the 7 dose group, 3 were responders (patients 07, 08, 10) and 1 was not (09). Annoyingly, they gave the extra 3 doses to the 3 patients with the highest NK cells....