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

zar nola said:
Autoantibodies to Arginine-rich Sequences Mimicking Epstein-Barr Virus in Post-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
They are thinking it's not just 1 target, and it's not only muscle.
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Antibodies to peptides are pretty meaningless. They seem to have found antibodies that bind to peptides from a range of proteins that share some sequence similarity to microbial proteins, which is almost certainly completely irrelevant. Peptides with similar sequences exist everywhere in everything. If they had found a qualitative difference in antibodies to one protein I would have been interested. This sort of result has been produced for all sorts of diseases for decades and tells us nothing as far as I can see.
 
Here is the revised PILOT protocol.

“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.”

Can be found here.


I think this jibes with a comment @Jonathan Edwards made earlier somewhere on this forum that one initial dose would be sufficient to deplete long-lived plasma cells.
 
I’m assuming that they didn’t go with this revised protocol for the full Phase 2 study because they didn’t want to take the risk that weren’t fully depleting LLPC’s.

With this very small sub-sample they could take the risk of doing fewer injections.

FWIW, this is very different from the multiple myeloma dosing, which I believes entails 8 initial injections.
 
Jonathan Edwards said:
Antibodies to peptides are pretty meaningless. They seem to have found antibodies that bind to peptides from a range of proteins that share some sequence similarity to microbial proteins, which is almost certainly completely irrelevant. Peptides with similar sequences exist everywhere in everything. If they had found a qualitative difference in antibodies to one protein I would have been interested. This sort of result has been produced for all sorts of diseases for decades and tells us nothing as far as I can see.
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Is this way better for finding autoantibodies? cell assay?
Autoimmune Basis for Postural Tachycardia Syndrome
We used receptor‐transfected cells to demonstrate specific autoantibody binding to the receptors. Sera from a POTS subject who demonstrated activating autoantibodies to β1AR, β2AR, and α1AR, sera from a healthy control subject and rabbit polyclonal antibodies to each receptor as positive controls were separately incubated with these cells without and with an excess of their respective ECL2 target peptide. These images are shown in Figure 6. There was significant binding to each of the receptors from the POTS sera, which was completely blocked by preabsorption with the specific ECL2 peptides. No significant binding to the cells from the control sera was observed.
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jah3-3-e000755-g6.jpg
 
Immunofluorescence assays like the pictures shown have been the gold standard for pathogenic autoantibodies. They correlate robustly if not universally with diseases we know to be antibody driven. Some would say you need to stain live cells but I don't think that is necessary. Functional assays as described here ought to be good but there are quality control and batch control problems that make it very difficult to assess their reliability in reports like this.

So, yes, the staining assay is a good one. But in Scheibenbogen's studies the rate of positives in MECFS patients is barely different from normal. Which means that the antibodies cannot possibly be directly responsible for pathology. It is said that many people with MECFS have "POTS" but if so this MECFS POTS isn't due to these GPR antibodies. Even for a non MECFS cohort of POTS like this paper it is pretty extraordinary that they were all positive and controls all negative. In other words this looks a bit too good to be true. And the trouble is that we repeatedly see invalid study designs for things like this - like only including people in your cohort you know to be positive beforehand.

I think it is quite possible that at subset of people diagnosed with POT have an autoantibody mediated problem but the evidence is that this is not generally relevant to MECFS.
 
Jonathan Edwards said:
Immunofluorescence assays like the pictures shown have been the gold standard for pathogenic autoantibodies. They correlate robustly if not universally with diseases we know to be antibody driven. Some would say you need to stain live cells but I don't think that is necessary. Functional assays as described here ought to be good but there are quality control and batch control problems that make it very difficult to assess their reliability in reports like this.

So, yes, the staining assay is a good one. But in Scheibenbogen's studies the rate of positives in MECFS patients is barely different from normal. Which means that the antibodies cannot possibly be directly responsible for pathology. It is said that many people with MECFS have "POTS" but if so this MECFS POTS isn't due to these GPR antibodies. Even for a non MECFS cohort of POTS like this paper it is pretty extraordinary that they were all positive and controls all negative. In other words this looks a bit too good to be true. And the trouble is that we repeatedly see invalid study designs for things like this - like only including people in your cohort you know to be positive beforehand.

I think it is quite possible that at subset of people diagnosed with POT have an autoantibody mediated problem but the evidence is that this is not generally relevant to MECFS.
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Nice
I didn't ask this in the context of the disease but more in the direction of focusing on the assay type.
Thanks
 
Jonathan Edwards said:
Immunofluorescence assays like the pictures shown have been the gold standard for pathogenic autoantibodies. They correlate robustly if not universally with diseases we know to be antibody driven. Some would say you need to stain live cells but I don't think that is necessary. Functional assays as described here ought to be good but there are quality control and batch control problems that make it very difficult to assess their reliability in reports like this.

So, yes, the staining assay is a good one. But in Scheibenbogen's studies the rate of positives in MECFS patients is barely different from normal. Which means that the antibodies cannot possibly be directly responsible for pathology. It is said that many people with MECFS have "POTS" but if so this MECFS POTS isn't due to these GPR antibodies. Even for a non MECFS cohort of POTS like this paper it is pretty extraordinary that they were all positive and controls all negative. In other words this looks a bit too good to be true. And the trouble is that we repeatedly see invalid study designs for things like this - like only including people in your cohort you know to be positive beforehand.

I think it is quite possible that at subset of people diagnosed with POT have an autoantibody mediated problem but the evidence is that this is not generally relevant to MECFS.
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Another question is what type of IgG is binding to the receptor?
IgG4 is not known to bind to receptors like IgG1/3 does.
 
Daratumumab and ME/CFS

Daratumumab, an anti-CD38 monoclonal antibody approved for myeloma, is being explored in ME/CFS due to CD38’s role in immune signaling and inflammation. T

Targeting CD38 may help reset immune dysregulation seen in subsets of ME/CFS patients.


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.
 
Jonathan Edwards said:
But PEM isn't about weakness or lack of available ATP. It is about feeling terrible, as I understand it.

From all the physiological studies I am not aware of any evidence for muscles not being able to generate force after a previous bout of exertion. Maybe there is, but it still isn't PEM as I have understood it.
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nor do classical genetic mitochondrial diseases seem to produce PEM (as we know it in ME/CFS), as far as I am aware. Of course this comparison is to a degree confounded by developmental issues incurred by inborn mitochondrial dysfunction but still.
 
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Jonathan Edwards said:
But PEM isn't about weakness or lack of available ATP. It is about feeling terrible, as I understand it.

From all the physiological studies I am not aware of any evidence for muscles not being able to generate force after a previous bout of exertion. Maybe there is, but it still isn't PEM as I have understood it.
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This is off-topic for the thread, but I wanted to respond about this. I know I've done too much and am probably heading into PEM when it takes more effort than normal to walk up a few steps. The power goes - it takes more directed attention and the movement is slower to get up those few steps that I would otherwise walk up without even thinking about it. It's a very weird thing.

It happens after sustained exertion - for example 30 minutes or an hour walking, or multiple flights of stairs. Of course I don't know what causes it, but it feels as though the signals to make the muscles work are getting lost - actions become clumsier. Or like when you are up at high altitude on a mountain.

I thought there were some findings of reduced power after sustained exertion. Quite a lot of us have talked about muscle fatiguability. If we don't have a thread to talk about the evidence, we should probably should have one.
 
Hutan said:
This is off-topic for the thread, but I wanted to respond about this. I know I've done too much and am probably heading into PEM when it takes more effort than normal to walk up a few steps. The power goes - it takes more directed attention and the movement is slower to get up those few steps that I would otherwise walk up without even thinking about it. It's a very weird thing.
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It might seem off topic but it follows through an argument directly relevant to the action of anti-CD38 used in the trial. I think it is a pity if these subsidiary discussions need to be in separate threads. When I had group lab meetings we might spend half an hour on discussing some background issue like this before returning to what we were trying to address. Everything is intertwined!!

I repeatedly hear that when people are in PEM they find it more and more difficult to do things. That seems clear. But PEM per se is defined as worsening of symptoms of ME/CFS. Weakness is not in that list. A sense of being unable to do things might be but that isn't the same thing. It might be due to weakness and that might be due to lack of ATP but it might not. Healthy people feel they can hardly get up stairs in various situations in which, if pressed, they would have no problem doing the next step smartish, even if they then felt even more hardly able to go on. Fatigue is like that.

So the first point is that PEM, as defined as a set of symptoms scientists want to explain, does not imply weakness or unavailability of energy. The second point is that weakness might accompany PEM but might not. When I am up a mountain in the Alps or Andes at 3-4000 metres I get short of breath and my limbs feel heavy but I can still cut a sharp unexpected turn at full speed on skis as well as people half my age. The muscles are actually fine. But if I am doing a 500 metre descent in soft snow and need maximum exertion for over a minute I get the sort of lock up I got as a runner just before the tape. The muscles are presumably short of ATP then. It is complicated.

There may be reduced power after sustained exertion in ME/CFS but it is odd that although we hear of reduced VO2 max or whatever on a second day CPET we do not regularly hear of documented fatiguability as in myasthenia. If measurable, surely it would have been pounced on as biomarker.

The key point for me is that if there is true fatiguability then that would be interesting but that is not what PEM means. I suspect that a lot of researchers have assumed that the fatigue bit of ME/CFS means lack of energy as in ATP, and both Ramsay and Behan may have encouraged that, but there was never very good reason to, I think.
 
Jonathan Edwards said:
Is it? I thought anti-CD38 was just being used as a means to deplete antibody producing cells?
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Was there even that much of a mechanistic theory? Or has that been layered on top subsequently?

Hutan said:
but it feels as though the signals to make the muscles work are getting lost - actions become clumsier.
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Your whole description is great. And that it applies to different severities too (well at least you and I where you talk of 30-1hr of walking and I may talk of 5-10 minutes cutting my hair or washing my feet with assistance) seems extremely telling.

This is the study I always go back to because it was eye opening for me when Caroline Kingdon did the repeated grip strength test on me and told me my results
Suffolkres

Thread 'Hand grip strength as a clinical biomarker for ME/CFS, 2018, Nacul et al'

Source: Frontiers in Neurology
Preprint
Date: November 5, 2018
URL:
https://www.frontiersin.org/articles/10.3389/fneur.2018.00992/abstract

Hand grip strength as a clinical biomarker for ME/CFS and disease
severity
----------------------------------------------------------
Luis C. Nacul(*), Kathleen Mudie, Caroline Kingdon(*), Taane G.
Clark, Eliana M. Lacerda
- London School of Hygiene & Tropical Medicine, United Kingdom
* Correspondence: Dr. Luis C. Nacul <luis.nacul@lshtm.ac.uk>
Mrs. Caroline Kingdon <caroline.kingdon@lshtm.ac.uk>
  • Like

But there’s a few similar ones tagged https://www.s4me.info/tags/hand-grip-strength/
 
Jonathan Edwards said:
So the first point is that PEM, as defined as a set of symptoms scientists want to explain, does not imply weakness or unavailability of energy. The second point is that weakness might accompany PEM but might not.
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This sounds right to me. Although there are definitely periods when there is what feels like weakness too. But the way PEM or that weakness both arrive and leave feels different to weakness as most healthy people understand it. I think…
Jonathan Edwards said:
When I am up a mountain in the Alps or Andes at 3-4000 metres I get short of breath and my limbs feel heavy but I can still cut a sharp unexpected turn at full speed on skis as well as people half my age. The muscles are actually fine. But if I am doing a 500 metre descent in soft snow and need maximum exertion for over a minute I get the sort of lock up I got as a runner just before the tape. The muscles are presumably short of ATP then. It is complicated.
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Comparing with my healthy activities is a good one. So after pushing myself beyond my physical limits while in the jungle in Borneo (on a hash house harrier run, which some of us actually got lost in so went way too far and up and down hills) I ached after and for days after. Walking up or down stairs was hard. My muscles, particularly in my legs, were sore and stiff and wouldn’t work properly.

But what I experience with ME/CFS and PEM is very very different. Even though in some ways we may use the same inadequate words to describe it at times. It’s not just that there are different symptoms too, it’s that the qualitative nature of similar sounding symptoms is different. But it’s really hard to describe adequately to someone who hasn’t experienced it I think, because there is little common frame of reference and what we get is so alien to normal experiences.
 
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Hutan said:
This is off-topic for the thread, but I wanted to respond about this. I know I've done too much and am probably heading into PEM when it takes more effort than normal to walk up a few steps. The power goes - it takes more directed attention and the movement is slower to get up those few steps that I would otherwise walk up without even thinking about it. It's a very weird thing.

It happens after sustained exertion - for example 30 minutes or an hour walking, or multiple flights of stairs. Of course I don't know what causes it, but it feels as though the signals to make the muscles work are getting lost - actions become clumsier. Or like when you are up at high altitude on a mountain.

I thought there were some findings of reduced power after sustained exertion. Quite a lot of us have talked about muscle fatiguability. If we don't have a thread to talk about the evidence, we should probably should have one.
Click to expand...
This is how I always feel with stairs! such a good description. For me it feels like this all the time, but is markedly worse after exertion.
 
To clarify a bit, I find it possible to get the fatigued leg muscles with sustained activity. For example, I remember one time with ME/CFS when I was more physically capable than I am now, when I was walking up 3 flights of stairs and about half way up, I could hardly make my legs move. It was weird and worrying. I had people with me and I was trying not to make a fuss, so I was trying very hard. If I could have just walked up the steps, I would have. I had to sit down for a while before making it to the top. That is one of the times I remember when I occasionally wonder if I'm just not trying hard enough.

But, the lack of power in my muscles can also happen if I have just been doing a bit more for a couple of days. Then, I feel it even when walking up a couple of steps after a short walk in the garden. But, the next day, it might be completely fine.

I'm not sure if I have that weakness during a crash. I'm generally not trying to walk up stairs then. I'll watch out next time.

You would think after all this time that I would totally understand my symptoms. But, there's quite a lot of unpredictability.
 
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