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

[Jaybee00]

“Protocol ver. 1.6: Amended treatment protocol; this will apply to four additional patients included in Q1 2025, as well as retreatment of one previously included patient with partial relapse. Patients will receive the first daratumumab subcutaneous injection at week 0. For patients with signs of clinical response after the first injection, a second injection will be given at 24 weeks, and a third injection at 48 weeks.

At week 10, if there are no signs of a clinical response, a second daratumumab injection will be given, and, subject to a clinical response, the third and fourth injection will be given at week 24 and 48. If patient experiences no response after the second injection, no further daratumumab will be given.”

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@Jonathan Edwards does this amended protocol seem sensible to you?

If I recall correctly, you stated earlier (somewhere) that one initial dose of Daratumumab would be sufficient to deplete LLPCs. This protocol will only be given to several patients in the extended pilot project and it consists of only 3 injections at weeks 0, 24 and 48. For patients who don’t respond by week 10 an additional injection will be given then.

 

[someUsername]

Yes, you can improve well if you regularly work out. I was commenting on what the personal trainer said that he was surprised that you needed rest and couldn't repeat the workout without rest as a beginner and that you couldn't lift the same weight the next day.

A Personal Trainer would recognize this pretty soon and adjust intensity. But If I saw that I needed to decrease intensity for my client multiple times, and Training progress to be slow for multiple weeks/months, this would defenetly seem highly unusual.

A beginner usually makes very easy gains not only by gaining muscle mass but especially by improving brain - muscle coordination.


I tried to follow along on the discussion, but Its difficult for me to understand.
Under the hypotheses that dara workes in a subset (which is not clear yet because of N=10 and No Placebo), does this Not imply that it has to be some issues with plasma cells? And if so why does there not seem to be clear marker ? I think the responders Had somewhat normal markers right?

Sorry If this was answered before.

 

[Hutan]

We have moved and copied a number of posts about experiences of muscle fatiguability to a dedicated thread, so as to not divert the thread. Please do check the posts out here:
Muscle Fatiguability After Exertion

We have kept some of the initial posts on this topic on this thread so as to keep the point that muscle fatiguability is part of ME/CFS in this discussion.

 

[Jonathan Edwards]

@Jonathan Edwards does this amended protocol seem sensible to you?

I don't know enough about data on antibody profiles with Dara.
I am not sure what the reason for 24 and 48 weeks would be. These are relevant to rituximab because it takes approximately 24 weeks for B cell recovery but that is not relevant to plasma cell targeting where the recovery in antibody production is likely to depend purely on Dara half life, which may be about 10 days. Nobody knows why rituximab depletes B cells for 6 months as far as I know.

 

[someUsername]

@Jonathan Edwards does this amended protocol seem sensible to you?

If I recall correctly, you stated earlier (somewhere) that one initial dose of Daratumumab would be sufficient to deplete LLPCs.

In the paper they give the followung Reasoning:

"A recent review summarized experiences with daratumumab in different refractory autoimmune diseases" ...
"Among the included studies the median number of daratumumab infusions/injections used was four (range 1–24 injections). Interestingly, the authors found no significant correlation between number of daratumumab doses and either clinical response or hypogammaglobulinemia"

And (again in my limited understanding) this could be because of the negative Feedback Loop of dara needing NK cells to Work, but at the Same time killing NK cells, so that the next Dosis has less NK cells to Work with.

Does this make sense ?

 

[Kronos]

I looked at reference 46 and there is some decent information on some specific IgG4 autoimmune diseases. They are mostly neurological and the idea is that the IgG4 autoantibody blocks the self protein function without triggering inflammation - makes sense. The easy one is IgG4 myasthenia where you get neuromuscular blockade without any complement mediated damage.

So how would that fit for MECFS? Maybe it would fit rather well because in ME/CFS there is no inflammation but things aren't working! Maybe an IgG4 antibody is blocking some neural signal.

What is perhaps surprising though is that it says that autoimmunity due to IgG4 seems to respond very well to rituximab! But then there are no hard and fast rules for that sort of thing.

Would be interesting if these GPCR auto antibodies are Igg4, but either I don't remember or this info does not exist.
What you describe is what is usually called functional autoimmunity by The GPCR folks.

For what it's worth, my Igg4 has been consistently +50% above the upper limit of the normal range measured by a standard lab.

 

[someUsername]

In the Cyclo Trial they found a correlation between responding and the existence of HLA risk alleles, while they did Not find this for Ritux. Does anyone know If they looked at HLA in the dara Trial? And if Not, why?
I did Not find anything in the paper about that.

 

[ryanc97]

Hey guys, putting my thoughts here from another thread.

Dara targets CD38 expressing cells. Apparently, these are some T cells, some B cells but majority LLPCs - long lived plasma cells. These produce 90% of antibodies (ABs) in body.

Now, Fluge theorizes these cells have gone rogue and produce AABs instead of ABs. We know LLPCs hide in bone marrow and are long lived, evading immune detection.

What could have caused these cells to go rogue? There is a link to viral persistence here. We know Bhupesh Prusty and Martin Lerner like viral persistence. Now what's interesting, is that in EBV, apparently activated EBV hides in the LLPCs! And maybe this is what causes the LLPCs to produce AABs. And this causes the damage.

Moreover, we know there are paper findings of serum in CFS messing up healthy cells. So it could be the AABs doing the damage.

Lastly, the NK cells matter as the Dara will recruit NK cells to do ADCC on the CD38 expressing LLPCs. I will quote my other thread on PR:

----

I'll just say this. Look at the scatterplot of NK cells in x10^6/L vs score/treatment effect with a Spearman correlation of 0.77.

Look closely. If your NK cells are above 150, then according to the scatter you will be a responder. It's those with NK cells in the <150 range are non-responders.

It's a strong correlation. So you could go and get an NK cell test, and compare your score to the scatter, and if its high enough, then Daru could work for you in theory - according to this study.

Now the problem is small n and female only.

I don't think the IGG effect scatter is that significant there isn't any trend. But the NK cell count being predictive of response is quite strong. You can almost draw a straight line through it and get not a bad R2.

 

[ryanc97]

One thing I i’m curious about the Dara Pilot Trial :
- Dara targets LL Plasma cells which produce antibodies (immunoglobulins IgG)
- so the objective Norwegian researchers seems to be lowering of IgG

But HOW important is it to lower IgGG for response ?

I compared CycloME and Dara IgG-charts :
Pre-treatment IgG level vs Post-treatment IgG levels

1) there doesn’t seem to be a huge difference IgG depletion in the Dara Pilot :
- between responders = 56% IgG reduction
- vs NON-responders = 40% IgG reduction

2) Which is much HIGHER %-wise and in absolute terms than Cyclophosphamide IgG reduction

=> see slide 1 Dara: lowest point Dara responders around IgG=5 (+ non-responders IgG =7)
- which is still much more depletion IgG if you compare to cycloME study:
=> see slide Cyclo 2 : lowest point Cyclo responders around IgG=8

*Fluge & M emphasize the correlation with high NK-cells & responders
- But even low NK cells in Dara were more effective in bringing IgG cells down than Cyclo IgG reduction

But both trials showed >55% response.

So although IgG reduction - absolute and % level - show a correlation with response, it apparently is more complicated.
- and reduce IgG as much as possible - below a certain level is not a prerequisite for an effective treatment

Apparently more complex immune interactions at play ??

It could be the specific type of IgG being reduced that Daratumumab targets. I don't know

 

[ryanc97]

However the problem is that Dara targets NK cells which also kill the CD38 cells. So its like, each dose has a diminishing return.

In that case, it might be better to space out the Dara dose long enough so each cycle, your NK cells have time to recover to baseline and get ready for next round of LLPC killing.

So, maybe 2 month between dose might be better instead of 2W. But this is pure speculation

 

[ryanc97]

Sorry to spam to this thread, but because I am considering Dara with my immunologist, I am reading this paper EXTREMELY carefully. I know it is n=10, but nonetheless.

I believe the NK cell count over time of treatment is the most important thing in this study. Patients 07, 08, 01 are the ones who had the 'best response', defined as the most stable step count increase, NOT max SF36 difference.

So, I don't like the scatterplot that Fluge/Mella used. Using highest max SF36 difference is dodgy as patient 5 scores well but according to her step count she is a non-responder (or just doesn't like walking).

07 (4k to 11k steps), 08 (3k to 9k steps) and 01 (2k to 8.5k steps) had 300, 400 and 250 x 10^6/L respectively. Those were the 3 highest NK cell counts, and they had the 'best' step count increase.

To me, 01 had the best improvement (quadruple step count). And her NK cell pattern is interesting. Post treatment, at 2 months (4th injection), she had the highest NK cell count.

What is a normal NK cell count distribution? 60-530, so a median of ~300. So to be safe, I believe from this very small sample, you would need at least 250, not 125 as F/M suggest.

 

[forestglip]

So, I don't like the scatterplot that Fluge/Mella used. Using highest max SF36 difference is dodgy as patient 5 scores well but according to her step count she is a non-responder (or just doesn't like walking).

Good idea to look at change in steps vs baseline NK count. I made a chart with the data from the supplementary files, keeping the same clinical improvement color label they use. Diff steps is the change in daily steps from the very start of the study to the very end. (I also flipped the axes because it feels like it makes more sense to have NK cells as the x-axis.)


Not a perfect split, as for SF-36, but still looks like a strong correlation.

 

[ryanc97]

Good idea to look at change in steps vs baseline NK count. I made a chart with the data from the supplementary files, keeping the same clinical improvement color label they use. Diff steps is the change in daily steps from the very start of the study to the very end. (I also flipped the axes because it feels like it makes more sense to have NK cells as the x-axis.)
View attachment 27636

Not a perfect split, as for SF-36, but still looks like a strong correlation.

Very nice! Would it be possible to cmap the individual colors of the patients as well to the points? and also gridlines would be nice this chart is great.

It would also be interesting to see delta steps vs sum/mean of NK cell count across the trial rather than baseline NK cell count.

5 is a worry for me as 150 x 10^6/L but no change in steps, but her max SF36 delta was 50.

2 had a small step delta but a huge SF36 delta.

It's possible these two did feel better via SF36 but were cautious in their step count to avoid PEM.

You can see 1, 7 and 8 are full recoveries at least and they all had good NK cell counts. I also wonder on NK cell quality vs NK cell count, how are they correlated?

Can you have high NK cell count but poor NK cell quality? Or vice versa? I assume it is qty x qual = ADCC effect.

 

[forestglip]

Would it be possible to cmap the individual colors of the patients as well to the points? and also gridlines would be nice

Yep, here you go:

It would also be interesting to see delta steps vs sum/mean of NK cell count across the trial rather than baseline NK cell count.

I made it, but I'm not sure how useful this is because many participants are missing NK cell data at various timepoints. So some will include more later testing and some will include more testing in the middle of the trial.

 

[ryanc97]

Yep, here you go:
View attachment 27641


I made it, but I'm not sure how useful this is because many participants are missing NK cell data at various timepoints. So some will include more later testing and some will include more testing in the middle of the trial.
View attachment 27642

Hmm fair. it looks like mean NK cells doesn't mean much. Thanks alot! Baseline Nk cell vs change in steps seems the best. But I find the response of 1, 7 and 8 very encouraging - triple or quadruple step counts.

I also wonder on the dosing impact. They speculate the first dose matters most as NK cells plummet. Does the effect decay exponentially? If so, can we get away with less dosing and juicing up NK cells before hitting a heavy first dose?

 

[Utsikt]

Is it possible that NK cells are just a proxy for whatever actually responds to Dara (if it in fact is a response)?

 

[ryanc97]

Dara is an AAB to CD38 expressing LLPCs.

B cells come from stem cells, expressing CD20. Ritu targets these. A small percentage like 1% or so becomes SLPC then LLPC. These produce 90% of IGG, pumping into the bloodstream. These migrate into bone marrow and live for a long time.

F/M think somehow, the LLPCs are broken in our body. Pumping out poison in the blood basically. So, Dara attaches to the LLPC and asks the NK cell to come and induce apoptosis on the LLPC. So NK cells are needed to make Dara work.

Another problem, NK cells also have CD38 (less so than plasma cell). So if you don't have enough NK cells, they get killed off and you have none left to actually target your LLPCs.

Ritu would kill the memory B cells with CD20, but not the LLPCs.

Theory would be that: some viral infection or shock event triggers B cells to become faulty and become faulty LLPCs which stay for years pumping out AABs causing symptoms.

 

[EndME]

Is it possible that NK cells are just a proxy for whatever actually responds to Dara (if it in fact is a response)?

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).

 

[Jonathan Edwards]

Theory would be that: some viral infection or shock event triggers B cells to become faulty and become faulty LLPCs which stay for years pumping out AABs causing symptoms.

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!!

 

[Stuart79]

In a 10-patient pilot, 6 of 10 ME/CFS patients (typically moderate severity, ~2,000 steps/day) received 4-7 Daratumumab injections. Responders saw ~50% IgG drop (particularly IgG4), jumped to ~10,000 steps/day, and had higher baseline NK cell counts.

Given the association between responders and decreased IgG4 following Dara, could it be possible that depleting IgG4 is actually the key? Perhaps something along the lines of: (i) IgG4 blocking a signal necessary for resolution of immune activation; or (ii) IgG4 preventing antigen clearance by inducing some incomplete level of tolerance (e.g. one foot on the break and one foot on the gas).

Along the same lines, there are a few covid papers discussing IgG2 to IgG4 class switching following repeated vaccination. The concern seems to be that switching to IgG4 in this way might lead to unhelpful tolerance and antigen persistence. Here is one such example: https://www.journalofinfection.com/article/S0163-4453(25)00067-2/fulltext