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

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.

I don't think that difference is likely to be relevant. Most of these doses are just guessed at because for monoclonals of this sort dose does not seem to be that critical within a factor of at least two. Longer term effects on populations are mysterious because they last a lot longer than several drug half-lives.

I think a significantly different impact on the profile of NK cell numbers in ME/CFS with Dara could be worth taking seriously as a clue to what is going on.
 
CD38 only popped up as significantly different between ME and controls when we stimulated the B cells in vitro.
Could this potentially have something to do with the fact that CD38 was associated with deterioration in this long covid study?

Immunological and non-immunological features specific to Long-COVID: multiple overlapping aetiologies and potential biomarkers

Frederique C Ponchel

[Line breaks added]


Abstract
Long-COVID (LC) is a serious clinical condition characterised by debilitating fatigue together with a wide array of symptoms that significantly reduce the quality of life of patients. Currently no holistic or even symptom specific treatment options are available, likely due to both a lack of insight into the disease processes that drive LC symptoms and an extreme heterogeneity in patients’ profiles.

We characterised patients and post infection controls, with respect to their immunological profiles with a non-exhaustive panel of biomarkers rationalised based on their potential role in driving symptoms.

We observed that the patients’ symptoms could be grouped into 4 clusters suggesting possible stratification. Systemic inflammation persisted and did not normalize over time in LC. This was not related to persistent SARS-CoV-2 infection, as the presence of circulating N-protein was detected similarly in both patients and controls.

No obvious deviation in B-cells and monocytes profiles were observed with minor changes for NK-cells (CD62L+/CD16+/HLA-DR+). Major changes affected CD4+T-cells (and to a lesser extent CD8+T-cells) with respect to exhaustion (PD1+/LAG3+/CD44+), regulation (Treg) and differentiation (naïve/memory-CD62L+).

Several candidate biomarkers (cytokines, microRNAs, phosphate metabolism) were present more frequently in LC at high levels and provided information on underlying disease processes. While frequencies of candidate autoantibody+ participants were not different, levels of some antibodies were higher in LC. Yet none of these candidates stood out as a universal biomarker for LC, with the exception of CRP (73% cases), and loss of Treg (50%). However, we confirmed that several overlapping underlying aetiologies may be involved in this complex disease.

Specific groups of biomarkers also associated with the 4 cluster of patients. Although to be taken with caution due to small numbers, 3 biomarkers discriminated controls from patients (Treg/CD4+PD1+/CD4+CD161+), others were associated with symptoms recovery (low IL10/IL12/IL4 and high miR766) or deterioration (high CD4+CD38+/ CD8+naiveCD62L+/low IL2) over 12 months.

This study provides rational for developing targeted therapeutic strategies as well as biomarkers to stratify LC patients most likely to respond.

Web | PDF | Preprint: MedRxiv | Open Access
 
I don't think that difference is likely to be relevant. Most of these doses are just guessed at because for monoclonals of this sort dose does not seem to be that critical within a factor of at least two. Longer term effects on populations are mysterious because they last a lot longer than several drug half-lives.

I think a significantly different impact on the profile of NK cell numbers in ME/CFS with Dara could be worth taking seriously as a clue to what is going on.

Half-life of Dara is around 3 weeks. You think it might actually be a lot longer (e.g. plasma half life vs. biological half life)?

By the NK cell dynamics, do you mean the interesting thing is the difference among patients (responders vs. non) or the general pattern of depletion/repletion or the difference between multiple myeloma and ME/CFS?
 
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I don't think that difference is likely to be relevant. Most of these doses are just guessed at because for monoclonals of this sort dose does not seem to be that critical within a factor of at least two. Longer term effects on populations are mysterious because they last a lot longer than several drug half-lives.

I think a significantly different impact on the profile of NK cell numbers in ME/CFS with Dara could be worth taking seriously as a clue to what is going on.
Can you explain what you mean in the last sentence in more detail?
 
Half-life of Dara is around 3 weeks. You think it might actually be a lot longer (e.g. plasma half life vs. biological half life)?

Rituximab half life was something similar but its effect lasts 6 months to 5 years. I don't think that is a 'biological half life' (not sure what that would mean). We don't understand a lot about these drugs. I think there was a study showing that you could get depletion with muh lower dosages of ritux. We found no great difference with a halving of dose.
 

NK cell count as predictor of clinical response in patients with rheumatoid arthritis treated with rituximab​



Same in RA @Jonathan Edwards
 
IMG_0387.jpeg
Figure S6. Proportions and counts of (…) natural killer (NK) cells (…) in relation to treatment with daratumumab. For whole blood flow cytometric analysis, standardized preformulated dry antibody panels were applied as described in the methods section. Results are provided as percentages of parent cell populations (pseudocolor plots) as well as absolute counts calculated in relation to white blood cell counts. Plots show the proportions of (…) (B) CD3-CD56+ NK cells (after gating for CD19- lymphocytes).
From:
CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection



It looks like there is a shift in the type of NK cells. Do we have any data on that in the Dara pilot?

Edit: and the NK cell count did not bounce back in 9 months.
 
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An IgG degrader called efgartigimod (vvygart) was trialed in long covid a couple of years back. It was trialled for POTS, and the primary outcome was a questionaire called COMPASS or something similar.

Many people in the trial reported significant improvement in PEM and POTS/OI, including improved readings on tilt table tests. The drug company ignored all of this, and because it wasnt picked up on their questionnaire, declared the trial failed.

The patients say the questionnaire was a terrible measure of improvement, and last I heard were campaigning for the release of the raw data. I don't think the study tracked PEM at all.

As we have discussed elsewhere in regard to other drugs we can't say for sure why these people improved but a mechanism like you propose here could probably explain it.

Article about these trial participants.
 
It looks like there is a shift in the type of NK cells. Do we have any data on that in the Dara pilot?
I don’t think so and this was the question I had in the other thread about mechanisms of resistance to daratumumab in multiple myeloma

This seems to indicate the characteristics or quality of the NK cells as much as the quantity is important, especially for primary rather than acquired resistance?
There seems to be a lot of focus on NK cell quantity but less on other details which could be important here. I’d like to understand more or find out if studies are going to try to do so. I agree it could be really important.
 
Not sure if this is right thread to add this but I found this paper


Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma​


Which says that vitamin A and interferon alfa increase CD38 expression on MM cells?

"
However, CD38 expression on effector cells must be taken into account, because primary NK-cells and NK-92 CD16a also express CD38 resulting in a fratricide phenomenon following addition of daratumumab [14,15]. Percentages of fratricide when NK-92 CD16a cells were co-cultured with different MM cell lines also varied according to levels of CD38 expression. Indeed, if CD38-expression is higher on target cells compared to effector cells, the balance between ADCC and fratricide leans towards lysis of target cells. In contrast, the balance between ADCC and fratricide leans towards effector cell lysis when the latter express more CD38 than target cells.
"

"In our study, we were able to demonstrate that IFNα increases CD38 expression on the surface of MM cells, but to a lesser extent compared to ATRA (Figure 6A"

"
Increasing the CD38 expression on target cells is another way to modify the ADCC/fratricide balance in favor of the ADCC. Studies have already tried to improve responses mediated by daratumumab by increasing CD38 expression thanks to all-trans retinoic acid (ATRA) since the latter directly controls the CD38 transcription [24,28,29]. ATRA upregulated CD38 expression in cell lines tested and in primary MM cells, and increased daratumumab-mediated lysis in ADCC assays [24]. This strategy is currently being investigated in a clinical trial combining daratumumab with ATRA in patients with MM (ClinicalTrials.gov Identifier: NCT02751255).
"

Basically, they administered these on MM cells and measured the CD38 compared to baseline. Vitamin A was found to be more effective.

The problem is, as above, if this also increases CD38 on the effector NK cells, then that is back to square one.,.,.
 
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Vitamin A

" Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients."



----

@Jonathan Edwards if vit A increases CD38 expression levels on MM, could this potentially backfire if it is a CD38 problem and not an antibody problem? Im thinking of adding this in to the protocol to do when ON dara if I ever do it. Can you extrapolate this to all plasma cells or would it be too much of a stretch?
 
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From AI

Oral all-trans retinoic acid (ATRA), also known as tretinoin, is
a potent chemotherapy agent used primarily to treat acute promyelocytic leukemia (APL). Unlike topical tretinoin, which treats acne, the oral form causes cancerous white blood cells to mature and die naturally. Oral ATRA requires strict medical supervision due to significant side effects and safety precautions.
 
From AI

Oral all-trans retinoic acid (ATRA), also known as tretinoin, is
a potent chemotherapy agent used primarily to treat acute promyelocytic leukemia (APL). Unlike topical tretinoin, which treats acne, the oral form causes cancerous white blood cells to mature and die naturally. Oral ATRA requires strict medical supervision due to significant side effects and safety precautions.
If I’m not wrong that’s just vitamin A which you can buy from iherb
 
No, oral all-trans retinoic acid (ATRA) is not the same as vitamin A, but it is a derivative of vitamin A and belongs to the same class of compounds called retinoids. While vitamin A has many functions, ATRA is a more specific, active metabolite that is used as a medication to force immature cancer cells to mature and become functional, particularly in treating acute promyelocytic leukemia (APL).

  • Vitamin A:
    A fat-soluble vitamin that is essential for many bodily functions, including vision, immune function, and cell growth. It is consumed as a nutrient.

  • All-trans retinoic acid (ATRA):
    An active metabolite of vitamin A that is derived from it and circulates in the body. It is used as a prescription medication to treat specific conditions like APL, where it works by causing the cancerous cells to differentiate into mature, functional white blood cells.
 
No, oral all-trans retinoic acid (ATRA) is not the same as vitamin A, but it is a derivative of vitamin A and belongs to the same class of compounds called retinoids. While vitamin A has many functions, ATRA is a more specific, active metabolite that is used as a medication to force immature cancer cells to mature and become functional, particularly in treating acute promyelocytic leukemia (APL).

  • Vitamin A:
    A fat-soluble vitamin that is essential for many bodily functions, including vision, immune function, and cell growth. It is consumed as a nutrient.

  • All-trans retinoic acid (ATRA):
    An active metabolite of vitamin A that is derived from it and circulates in the body. It is used as a prescription medication to treat specific conditions like APL, where it works by causing the cancerous cells to differentiate into mature, functional white blood cells.
Alright so on Dara, I’m going to be loading up on Vitamin A to boost CD38 on those plasma cells.

Along with black pepper and cardamom to increase the NK cell killing power.
 
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