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

[ryanc97]

A few years back I tried to get an understanding years of my own blood tests that indicated NK cell count being extremely low and having some other anomalous immune results from blood tests. I ended up consulting with the head of the immunology department at a University research Hospital. he had spent his whole career in the innate immunity field. he said he only trusted trust any NK tests in the United States that came from one specific university hospital lab. He said he actually re-assayed for three times before he started to believe the numbers.

FWIW, I also remember that Dr. John Chia only would use ARUP for his NK cell testing.

i’m not claiming any expertise in this area. I’m just trying to give you some feedback… This discussion about daratumumab is certainly intriguing…

Well, I find it hard to believe that nobody can test NK cells well in the whole of USA except for one lab.

My take: for his very stringent needs maybe only that lab was good enough for him.

 

[forestglip]

If we suppose that high NK count is related to better antibody dependent cell cytotoxicity, might the fact that the correlation was with blood NK cells provide a clue about where the cells that need to be killed are?

The multiple myeloma studies found correlations with NK cells in the bone marrow, and presumably not in the blood (though maybe that study exists and I haven't seen it), so maybe that's related to needing to kill bone marrow lymphocytes. Maybe in ME/CFS, it's some type of CD38 cell accessible from the blood instead.

---

Also, if the mechanism is ADCC, might we see correlations with the other cells that do this? Wikipedia seems to say ADCC is mainly related to NK cells, but macrophages and neutrophils might also be involved:

ADCC requires an effector cell which classically is known to be natural killer (NK) cells that typically interact with immunoglobulin G (IgG) antibodies.[3] However, macrophages, neutrophils and eosinophils can also mediate ADCC, such as eosinophils killing certain parasitic worms known as helminths via IgE antibodies.[4]

 

[hotblack]

Also, if the mechanism is ADCC

That’s been a question I’ve had. Wikipedia quotes a few papers when it says:

Daratumumab binds to CD38, causing cells to apoptose via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, inhibition of mitochondrial transfer or antibody-dependent cellular phagocytosis.

Do we have a circular argument here that NK cells must be relevant because the mechanism is ADDC and the mechanism must be ADCC because NK cells are relevant? Are other mechanisms just as likely or have I missed something?

 

[forestglip]

Do we have a circular argument here that NK cells must be relevant because the mechanism is ADDC and the mechanism must be ADCC because NK cells are relevant? Are other mechanisms just as likely or have I missed something?

I don't know if it's circular. It's more like NK cells might be relevant because of the study correlation. And ADCC might be relevant if NK cells are relevant. True, there might be other possibilities for why NK cells were significant (including randomness).

 

[ryanc97]

That’s been a question I’ve had. Wikipedia quotes a few papers when it says:

Do we have a circular argument here that NK cells must be relevant because the mechanism is ADDC and the mechanism must be ADCC because NK cells are relevant? Are other mechanisms just as likely or have I missed something?

ChatGPT can give you a good overview of how Daratumumab works.


There are a few mechanisms it uses to attack the CD38 target cells, ADCC is one of them.

 

[hotblack]

Thanks @ryanc97 yeah, the papers on the Wikipedia page give a good overview of mechanisms too. And not to say NK and ADDC isn’t the mechanism that is important here, just trying to get a firmer idea of what that is grounded in and how confident we are.

And it is perhaps useful to have someone play devils advocate and encourage some discussion about other possible mechanisms.

I don’t really know anything about the details of other mechanisms mind you! I was looking at mitochondria transfer and it’s apparently linked to regulating cellular metabolism and immune processes and those obviously pop up a lot. I’ve also seen mention of mitochondria transfer being used to outsource mitophagy to tissue-resident macrophages or astrocytes, which is interesting as I think there’s potential for those cells to be involved in ME/CFS and if something there is being stopped/blocked it could be another avenue for stopping a feedback loop.

 

[hotblack]

This is a really interesting paper

The power and potential of mitochondria transfer - PMC

Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, ...

pmc.ncbi.nlm.nih.gov

Edit: thread on the paper now created here

If I’m understanding and summarising correctly, as well as mitochondria being shared from parent to daughter cells, cells can also share mitochondria through intercellular mitochondria transfer, even between different cell types.

This can happen through direct physical contact using micro tubules.

Or indirectly with mitochondria either released in extracellular vesicles (Rab7/GDP status determines if a cell exports) or as free mitochondria. With phagocytosis used by other cells to capture and import them.

So a useful process when all is going well. But this has been shown to be hijacked by some cancers, hence daratumumab being useful, it can stop this sharing.

One possibility after reading this then is, could there be a loop whereby cells under some form of load or metabolic stress will bring in mitochondria from another cell, and if that cell has malfunctioning mitochondria, it hinders rather than helps, so perpetuates the loop.

This mitochondria transfer process occurs between cells of different types and both neural and immune cells are mentioned, which is handy.

Astrocytes have been shown to release these extracellular vesicle associated mitochondria (mentioned in the paper) and also mention of macrophages transferring mitochondria to sensory neurons when there’s inflammatory signalling.

I’m not the first to think along these lines, in another thread I found when searching for mentions of RAB7

Is there then a possibility of —

Damaged mitochondria being shared around due to impaired mitophagy —> induction of more bad mitochondria (and impaired autophagy) in more cells ?

Edit: so part of a potential mechanism for daratumumab here would be to stop or at least reduce this sharing, to help break a loop there. It may well be that it’s also helping by tagging immune cells to be destroyed, but if it’s also helping stop sharing of dodgy mitochondria, perhaps even from these immune cells, that could be interesting.

Maybe something else to think about anyway. And possibly some links with other ideas floating around.

 

[arnoble]

cells can also share mitochondria through intercellular mitochondria transfer, even between different cell types.

Seems like mitochondria transfer can occur on a PEM-like timescale.

 

[hotblack]

To add some more to the above mitochondria transfer chain of thought, a couple of things from DecodeME discussions

@chillier flagged this in the candidate genes writeup

FBXL4 can cause mitochondrial DNA depletion syndrome caused by elevated mitophagy

And there’s also

DARS2 mutations cause impaired mitochondrial function,

I’m wondering if these could all be contributing factors to why a cell may look to import mitochondria or export junk mitochondria.

And possibly most relevant is this

mitophagy, and more generally the consequences for a cell should mitochondria be forming or breaking up, being cleaned up or talking to other organelles in a crappy way, is a plausible and compelling line of investigation

I’m looking forward more than ever to mitochondrial DNA results and whatever @DMissa is working on

 

[hotblack]

I’ve posted a thread on a paper which could be a good reference for helping understand mechanisms of actions and why it may not work for some people with ME/CFS here

Mechanisms of resistance to daratumumab in patients with multiple myeloma

 

[DMissa]

whatever @DMissa is working on

Regarding this line of investigation it is whatever mr dmissa can get funded, grant apps are submitted and fingers and toes are crossed

The idea is to screen primary cells from pwme for mitophagy abnormalities while measuring the activation and downstream outcomes of different signaling pathways that can respond to this (and elicit downstream effects being measured that might be relevant to symptoms)

I want to attempt versions of this for every DecodeME gene and then also various DecodeME-implicated processes in combination in relevant cells/tissue

On the B cell angle i am putting all of my spare time into a model that I think might have legs, you will hear about it when I am eventually confident that my idea isn’t nonsense

 

[hotblack]

submitted and fingers and toes are crossed

Thanks for the update, it all sounds very interesting. I’m sure we’re all joining you in crossing things regarding funding. Maybe Twoflower will turn up with some gold!

 

[DMissa]

Seems like mitochondria transfer can occur on a PEM-like timescale.

I personally would not run too far with this idea. An event that we know little about that is enabled by cells staying in contact for hours doesn't seem like fertile ground to me.

 

[hotblack]

I personally would not run too far with this idea. An event that we know little about that is enabled by cells staying in contact for hours doesn't seem like fertile ground to me.

It wasn’t the direct contact route I was most interested in but the other two routes mentioned in the paper, release and capture through EVs or even free mitochondria.

As I think I mentioned in another thread I’m very much in throwing stuff at the wall and seeing what sticks territory, with little attachment to any mechanisms or things I say though. And this doesn’t seem to be sticking

 

[oedi]

Merged
In the Fluge/Mella pilot study on Daratumumab, patients received 4 or 7 doses, with the first group receiving final injections(10wks) much earlier than the second(30wks).

I am trying to understand why NK cell recovery occurred uniformly at 9 months (39wks) in all patients. It seems that the early doses rapidly deplete NK cells as they should, and the subsequent doses don't do as much without nk cells to target cd38.

My question is: why uniformly 9 months and why suddenly as drastically? In multiple myeloma, nk cell recovery occurs within 3-6 months and shows a more gradual recovery curve.

https://www.researchgate.net/publication/320632963_Effects_of_daratumumab_on_natural_killer_cells_and_impact_on_clinical_outcomes_in_relapsed_or_refractory_multiple_myeloma#:~:text=...%20Dara%20can%20also%20mediate,(40).%20

 

[forestglip]

My question is: why uniformly 9 months and why suddenly as drastically?

At 9 months I still see 3 participants lower than the previous point.

At the next point, they all increased, but note that that point spans a very wide range spanning 6 to 12 months after the 9 month test.

Also, this shows data for only 7 out of 10 participants after 9 months.

 

[oedi]

It appears that recovery rapidly begins only after the 9 month mark in those tracked, no?

 

[forestglip]

It appears that recovery rapidly begins only after the 9 month mark in those tracked, no?

What I see is that recovery begins sometime after 9 months (in the 7 that have data past 9 months).

Maybe one participant's NK count went back up at 10 months, but they weren't tested again until 15 months, and maybe another's count didn't go back up until 20 months, and that's when they were tested. They'd both have a high point at the same location, but their NK recovery would be 10 months apart.

Basically, we don't know when exactly any of their NK cells went back up, except after 9 months and before 21 months.

 

[oedi]

What I see is that recovery begins sometime after 9 months (in the 7 that have data past 9 months).

Maybe one participant's NK count went back up at 10 months, but they weren't tested again until 15 months, and maybe another's count didn't go back up until 20 months, and that's when they were tested. They'd both have a high point at the same location, but their NK recovery would be 10 months apart.

Basically, we don't know when exactly any of their NK cells went back up, except after 9 months and before 21 months.

Ok, well that still begs my primary question. Why so much longer in me/cfs than on multiple myeloma (3/6months)?

 

[forestglip]

Ok, well that still begs my primary question. Why so much longer in me/cfs than on multiple myeloma (3/6months)?

I'm not sure. Maybe higher dose?

Here's the paper you linked to: Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma, 2017

Fig 2B

Longitudinal data representation of absolute NK-cell counts over time in peripheral blood. Peripheral blood was obtained from 21 patients during treatment with daratumumab (16 mg/kg) in GEN501 at the time of progression, and at 3 and 6 months after development of progressive disease. Data are presented as mean ± standard error of the mean.

They used 16 mg/kg in multiple myeloma for that chart. The ME/CFS study used 1800 mg. I'm not sure how many kg the participants were, but just guessing 80 kg would make it 22.5 mg/kg, so maybe that would keep the count down longer.