Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) research has increasingly focused on immune dysregulation and metabolic dysfunction. The interest in
daratumumab and
isatuximab represents a pivot from previous B-cell depletion strategies (like rituximab) toward targeting
CD38, a molecule expressed on long-lived plasma cells and involved in energy metabolism.
The following analysis details the mechanisms of action for these drugs and their theoretical and investigational roles in ME/CFS.
1. The Core Rationale: Why CD38?
To understand why these drugs are being explored, it is necessary to look at the failure of previous trials.[
1]
- The Rituximab Context: Large trials (RituxME) using rituximab (anti-CD20) failed to show benefit in ME/CFS.[1] Rituximab effectively depletes "upstream" B-cells but does not touch long-lived plasma cells (which reside in the bone marrow and secrete antibodies for decades) because these cells do not express CD20.
- The CD38 Shift: If ME/CFS is driven by autoantibodies produced by these long-lived plasma cells, rituximab would naturally fail to stop the production. CD38 is highly expressed on these plasma cells.[1] Therefore, daratumumab and isatuximab are used to target the specific cell population that rituximab missed.[1]
2. Mechanism of Action (MOA): Daratumumab vs. Isatuximab
While both drugs are monoclonal antibodies targeting CD38, they interact with the molecule differently.[
1][
2][
3] This distinction is critical for their potential effects in ME/CFS.
Daratumumab (Darzalex)
Daratumumab binds to a specific epitope on CD38 and recruits the immune system to kill the target cell. Its efficacy relies heavily on the patient's own immune competence.
- Antibody-Dependent Cellular Cytotoxicity (ADCC): This is the primary mechanism. The drug coats the plasma cell, acting as a "flag" for Natural Killer (NK) cells to attack and destroy it.[1]
- Relevance to ME/CFS: In the recent pilot study by Fluge et al., clinical response was correlated with baseline NK cell levels.[1] Patients with low NK cell function (a common finding in ME/CFS) responded poorly, likely because the drug couldn't work effectively without "helper" cells.[1]
- Complement-Dependent Cytotoxicity (CDC): Triggers the complement cascade to punch holes in the cell membrane.
- Antibody-Dependent Cellular Phagocytosis (ADCP): Encourages macrophages to "eat" the target cells.
- Enzymatic Effect: It is a weak inhibitor of CD38’s enzymatic activity.
Isatuximab (Sarclisa)
Isatuximab binds to a completely different epitope on CD38 and possesses unique "direct" mechanisms that daratumumab lacks.[
3]
- Direct Apoptosis: Isatuximab can force the cell to self-destruct (apoptosis) without needing cross-linking or help from effector cells like NK cells.
- Relevance to ME/CFS: This could theoretically make isatuximab effective even in ME/CFS patients with varying or poor NK cell function, overcoming the limitation seen with daratumumab.[1]
- Potent Enzymatic Inhibition: Isatuximab is a strong allosteric inhibitor of CD38's "ecto-enzymatic" function. It stops CD38 from consuming NAD+.[1]
3. Theoretical & Clinical Analysis in ME/CFS
The application of these drugs in ME/CFS relies on two major hypotheses: the
Autoimmune (Antibody) hypothesis and the
Metabolic (NAD+) hypothesis.
A. The Autoimmune Hypothesis (Targeting Plasma Cells)
- Mechanism: The drugs deplete the long-lived plasma cells in the bone marrow. This halts the production of pathogenic autoantibodies (e.g., against G-protein coupled receptors like adrenergic or muscarinic receptors).[1]
- Evidence: The recent Norwegian pilot study (Fluge et al.) using daratumumab showed that approximately 50-60% of patients responded with significant symptom improvement.
- IgG4 Connection: The study noted a reduction in IgG4 subclass antibodies.[4] IgG4 is often associated with fibrotic and inflammatory conditions; its reduction might alleviate vascular or tissue-level inflammation in ME/CFS.
B. The Metabolic Hypothesis (Restoring NAD+)
- The Problem: CD38 is not just a receptor; it is an enzyme (NADase) that consumes NAD+ (Nicotinamide Adenine Dinucleotide).[1] NAD+ is essential for mitochondrial energy production.[1] In conditions of chronic inflammation or aging, CD38 levels rise, potentially stripping cells of the NAD+ they need to make energy (ATP).[1]
- The Solution: By blocking CD38, these drugs may stop the degradation of NAD+, thereby restoring cellular energy metabolism.[1]
- Isatuximab's Advantage: Because isatuximab is a much more potent inhibitor of this enzymatic activity than daratumumab, it is theoretically the superior drug for addressing the "metabolic" aspect of ME/CFS.[1] If the disease is driven by an "NAD+ sink" caused by immune activation, isatuximab would plug that sink more effectively.[1]
4. Summary Comparison for ME/CFS
| Feature | Daratumumab | Isatuximab |
| Primary Target | CD38 (Epitope A) | CD38 (Epitope B) |
| Main Killing Mechanism | Immune-mediated (ADCC). Requires functional NK cells.[1] | Direct Apoptosis + Immune-mediated (ADCC). |
| Dependence on NK Cells | High. Low NK function predicts failure.[1] | Lower. Can kill directly without effector cells.[1] |
| Metabolic Effect | Weak inhibition of NADase. | Potent inhibition of NADase (preserves NAD+).[1] |
| Clinical Status in ME/CFS | Pilot Study: ~50% response rate.[1][5] | Theoretical: No specific ME/CFS trials yet.[4] |
| Best Theoretical Fit | Patients with "Autoimmune" phenotype (high antibodies, normal NK cells).[1] | Patients with "Metabolic" phenotype (low NAD+) or low NK function.[1] |
Conclusion
The mechanism of action for these drugs in ME/CFS is likely
bimodal:
- Immunological: Removing the "factory" (plasma cells) that produces harmful autoantibodies.[1]
- Metabolic: inhibiting the CD38 enzyme to conserve NAD+, thereby improving mitochondrial energy production.[1]
Currently,
daratumumab has clinical proof-of-concept in a subgroup of patients (likely those with sufficient NK cell function to mediate the drug's effect).
Isatuximab remains unexplored clinically in ME/CFS but offers a scientifically compelling alternative due to its ability to induce direct cell death (bypassing NK cell dysfunction) and its superior ability to protect NAD+ levels.
pmc.ncbi.nlm.nih.gov
