The $10 billion unicorn in INmune Bio: KOL interview with Prof. Kate Lykke Lambertsen

One motor neuron, two microglia, and two astrocytes. (c) NeuroWoodworks.com, reproduced with authorization. https://x.com/NeuroWoodworks

Introduction

Hedge fund managers often contact Key Opinion Leaders – KOLs – before investing. Of the 82 academic papers that are shown on the website of INmune Bio, many have been written by academic researchers.

I wanted to speak to a neutral voice outside of INmune Bio, who has tested XPro in several animal models of neurodegeneration, but not with a focus on Alzheimer’s disease.

One of the many academic researchers who have investigated XPro in preclinical models is Danish Prof. Dr. Kate Lykke Lambertsen. She is a prominent researcher in experimental neurobiology, an expert on TNF signaling, and perhaps thé expert on (re)myelination. She has made significant contributions to understanding neuroinflammatory responses in neurodegenerative diseases and central nervous system injuries. At the occasion of receiving the Danish Alzheimer’s research award in 2021, she gave a presentation entitled “The potential of targeting TNF in neuroinflammatory conditions.”

That interview took place on March 31, 2025. In this blog post, I include it together with some teachings of some of her work related to XPro. Prof. Lambertsen agreed to be interviewed, and agreed to publication thereof.

The blog post has been designed by first covering some of her work, with excerpts of the interview after. That makes it easier for the reader to skip to the parts that are most interesting.

1. Setting the Scene: neurological diseases and inflammation

Neurological diseases - whether sudden injuries like stroke or chronic conditions like Alzheimer’s - share a common thread: they come with either acute or chronic levels of neuroinflammation. Professor Lambertsen discusses the different types of neurological diseases - sudden (like stroke and spinal cord injury) versus chronic (like Alzheimer’s and Parkinson’s) - and emphasizes the role of inflammation across them.

2. The brain’s response to injury: glial cells

It is my understanding that any potentially disease-modifying agent should show an effect on the brain’s glial cells. They normally have a repairing function, but in the framework of neurodegenerative diseases they are seen to have a damaging pro-inflammatory phenotype. The question, however, is how to modulate them appropriately.

“So basically the research is trying to, we're trying to find out what's really going on in the brain and how can we drive that towards a situation where we can make a permissive environment in the brain for regeneration.”

3. Why TNF is a Key Therapeutic Target

I asked what makes TNF a special target. Professor Lambertsen explains that TNF acts as a "kickstarter" of inflammation after injury. By targeting it early, especially its soluble form, we might prevent the cascade of harmful inflammatory signals that worsen neurological damage.

“It's because, at least what we know from our own research, this is the first of these classical signaling molecules that is increasing in inflammatory conditions. So some of the other signaling molecules like interleukin 6 and interleukin 1 beta, which are kind of sisters to TNF, they also go up. But we see that if we keep the level of TNF down, it will also affect the level of the other side. So it's like the kickstarter of the inflammation in our heads..”

4. Connecting solTNF and tmTNF, their receptors TNFR1 and TNFR2, oligodendrocytes and myelination

Professor Lambertsen’s work has focused on TNF, particularly its two forms — soluble (solTNF) and transmembrane (tmTNF) — and how selective targeting could promote healing rather than harm.

Her findings showed that selective inhibition of sTNF clearly alters the neuroinflammatory response. In a mouse model of spinal cord injury in mice, XPro led to functional recovery (recovery of hindlimb movement), reduction of inflammatory markers such as IL-1β and IL-6, increase of anti-inflammatory levels shortly after injury, decrease of infiltration of harmful immune cells such as macrophages and neutrophils, increase of the number of microglia (the brain’s resident immune cells) near the injury site early on, and reduced microglial activation at later stages.  

XPro-treated mice also showed better preservation of myelin compared to controls. Blocking solTNF signaling did not disrupt beneficial tmTNF effects.

In a model of focal cerebral ischemia - a blood clot blocking a cerebral vessel - Prof. Lambertsen showed that genetic ablation of sTNF with preservation of mTNF is associated with neuroprotection. Mice with intact tmTNF but no sTNF display reduced infarct volumes after stroke, which were associated with improved functional outcome.

In another study, XPro reduced infarct volume and suggested a change in microglial activation, but etanercept showed no effect, suggesting “[…] that inhibitors of solTNF hold great promise for future neuroprotective treatment in ischemic stroke.”

Much of Prof. Lambertsen’s research has focused on oligodendrocytes specifically, the brain’s immune cells which are responsible for the creation of myelin.  She showed that oligodendrocytes are active modulators of inflammation in the CNS. TNFR2 expressed on oligodendrocytes plays a protective role by suppressing early inflammatory responses, maintaining blood-brain barrier integrity and limiting infiltration of immune cells into the CNS. TNFR2 signaling in oligodendrocytes is crucial to restrain early neuroinflammation, and enhancing TNFR2 activation in oligodendrocytes could be a promising therapeutic strategy for MS and other neuroinflammatory diseases. They rely on tmTNF signaling through TNFR2 to repair damaged nerves. In MS and spinal cord injury models, Prof. Lambertsen’s team found that deleting TNFR2 in oligodendrocytes worsens MS-like symptoms in mice, and that XPro promotes remyelination by silencing soluble TNF’s inflammatory signals, while allowing tmTNF to activate TNFR2.

The mechanism underlying the above findings is that blocking both solTNF (TNFR1-mediated, pro-inflammatory) and tmTNF (TNFR2-mediated, pro-repair) disrupts the process of myelination.

In a comparison in healthy mice of saline, etanercept and XPro for 2 months, treatment with etanercept led to impaired spatial learning/memory and reduced hippocampal neurogenesis. Treatment with XPro did not lead to cognitive deficits, suggesting solTNF-specific inhibition spares TNFR2-dependent neuroprotection. The conclusion of that research is that, whereas non-selective TNF inhibition may harm cognition, selective solTNF inhibition may preserve brain function.

“Inhibition of TNF is known to cause demyelination but otherwise little is known about the effects of long-term treatment in central nervous system (CNS) when CNS itself is not affected by an autoimmune disease or an insult. Since TNF signaling is associated with synaptic function and plasticity and there is evidence that it is involved in learning and memory, it is possible that long-term treatment with TNF inhibitors could alter hippocampal functions in an otherwise healthy brain.”

In a spinal cord injury model, Prof. Lambertsen showed that whereas administration of etanercept led to no effect, central administration of XPro resulted in reduced damage to the lesioned spinal cord, improved locomotor function, and decreased anxiety-related behavior. The study again concluded that, by selectively blocking solTNF, XPro is neuroprotective through alteration of the inflammatory environment without suppression of the neuroprotective effects of tmTNF signaling through TNFR2.In a model of autoimmune brain inflammation (encephalomyelitis), she showed that tmTNF-dependent repair and remyelination were mediated by the TNFR2 receptor expressed on oligodendrocytes. Mice with oligodendrocyte-specific TNFR2 ablation showed earlier disease onset, worse motor deficits, increased myelin pathology and chronic microglial activation. XPro could not reverse this, which indicated that tmTNF signaling through (the ablated) tmTNF-receptor, TNFR2, was necessary.

These findings indicate that tmTNF mediates the protective effects of TNF signaling.

“So the thing is that we actually do believe, and we have support from this also in our studies, that the membrane bound TNF is important for myelination and remyelination. And this has also been shown in animal models of multiple sclerosis; that the oligodendrocytes which are the cells that form this myelin sheath, this insulating sheet around the neurons, they need to express TNF receptor 2 for the transmembrane bound TNF to bind to this receptor and induce remyelination. […]

So it's a very important interplay between the microglia and the oligodendrocytes that drive the remyelination processes. So if you have a microglia that is more busy doing, you know, angry stuff like being inflammatory and creating a lot of inflammatory molecules, it may not be so engaged in focusing on remyelination processes. So that's why the drugs are coming into play, that we try to manipulate these responses by maybe removing the detrimental soluble and preserving the membrane bound form of the TNF.”

 XPro’s effect on remyelination, in multiple disease models, runs counter the effects seen with broad-spectrum TNF inhibitors. That fact alone already differentiates XPro from the other TNF inhibitors, and should be cause to look deeper than simply considering that TNF would just be another TNF inhibitor in trials for neurodegenerative diseases. Furthermore, remyelination is indicative of a changed activity that is taking place in all glial cells, namely a reversion to a less anti-inflammatory and more repairing profile.

5. GLP-1 agonists and neurology

GLP-1 agonists have been successful in several disease indications, indicating possible repair of metabolic dysregulation. Could they also be useful in neurodegenerative diseases. Up until now, several trials have failed to produce meaningful results.

I asked Prof. Lambertsen whether she had any thoughts on a large Phase 3 trial that is ongoing for the treatment of Alzheimer’s disease.

Professor Lambertsen shared that her lab has done early research into GLP-1 receptor agonists, originally developed for diabetes and obesity, and how they might help reduce inflammation and support brain recovery after stroke.

“So we have a strong hypothesis that probably these GLP one receptors will affect the inflammatory processes in the brain.”

6. Selective solTNF inhibition or TNFR2-agonism: XPro vs. NewSTAR2

We know that XPro targets solTNF, which primarily signals through TNFR1. We also know from Prof. Lambertsen’s research that tmTNF signaling through TNFR2 is crucial to allow repair. From that perspective, perhaps good results could come from stimulating the TNFR2 receptor, thereby promoting tmTNF signaling. NewStar2 is a selective TNF2 agonist. When tested in a model of experimental ischemic stroke, NewSTAR2 altered the central and peripheral immune responses and transiently improved neuromuscular function, but lacked long-term benefits. NewStar2 increased TNF protein levels in the brain shortly after stroke, without significant changes in TNFR1 or TNFR2 levels. The changes in chemokines and cytokines were minor. There was no effect on infarct size or neuroinflammation, and there were no significant long-term effects on astrocyte or oligodendrocyte populations. The study concluded that systemic TNFR2 activation alone was probably insufficient to significantly alter stroke progression in this disease model.

“So this would be my personal comment on this. […] I think that the TNF receptor 2 is probably not that important in this setting. In contrast, when you have these more chronic neurological diseases like Alzheimer's, where it's also beautifully been shown that TNF receptor 2 agonists are very effective, I think it's a different story. Because this is where you need to control this constant low grade systemic inflammation, whereas the stroke is this blast of acute massive inflammation. It's like this overflow of signals in the brain, so I think it's very important when you look at TNF inhibitors to differentiate between what the disease looks like. So it could be that we just timed our NewStar2 treatment wrongly, we might have given it at the wrong time point , the wrong way, with the wrong survival time. Or maybe we should have given it in in combination with soluble TNF inhibitor and we could have had a different response.”

7. Why past TNF drugs failed – the differentiated approach of XPro

I asked Prof. Lambertsen to give some background on her Alzheimer’s research award in 2021 and the presentation entitled “The potential of targeting TNF in neuroinflammatory conditions” she gave in that regard. the differentiated approach of XPro from that historical perspective.

“I think I got it, mainly because I'm focusing on the mechanisms that are driving neuro inflammation, which is very translatable to Alzheimer's disease, and also because a lot of the mechanisms that we are studying are also happening in in Alzheimer's disease.

And I think it especially relates to our finding on blocking soluble TNF in the brain of mice that had an experimental stroke, showing that this actually alleviates functional outcome, and even if you give it systemically, we didn't see any effect directly on the lesion size, but we saw that the mice were simply doing better, and we could show that this was due to changes in microglial phenotypes in the responses in the phagocytosis, and also on remyelination processes in the brains of these mice.”

Her answer further gives color to the historical failure of non-selective TNF blockers such as etanercept. Traditional TNF inhibitors come with demyelination issues. The myelin sheath is the insulating layer around axons. Even in patients without prior neurological disease, non-selective TNF inhibitors (e.g., infliximab) may trigger severe demyelination. Prof. Lambertsen has published a case-study on the damage traditional TNF inhibitors caused in a 27-year-old woman who developed irreversible demyelination after 4.5 years of infliximab, despite treatment discontinuation. That study mentioned that, as infliximab affects both the TNFR1 and TNFR2 pathways, the blocking of the protective features of TNFR2 and the remyelinating process could potentially lead to demyelinating events. This is further supported by animal studies in which a selective blocker of solTNF resulted in improved function as well as significant axonal preservation, oligodendrocyte differentiation, and remyelination. The study concluded that therefore, selective TNF inhibition or activation of TNFR2 could lead to a new treatment approach for inflammatory disease.

“But what we know now, because we've done all the research; we have had so many beautiful colleagues all over the world that helped demonstrate that, if you remove the soluble TNF, but you preserve the membrane bound TNF, targeting TNF in neurological disorders is a very strong indicator for having a good remyelination.”

Conclusion

Professor Lambertsen’s work offers a powerful roadmap. Future neurological therapies should not bluntly suppress the immune system, but selectively modulate it — blocking harmful inflammation while preserving or boosting protective signals.

With compounds like XPro advancing toward clinical readouts, and GLP-1 receptor agonists in neurology trials, we may be on the cusp of a revolution in several neurological disease indications.

Not all inflammatory signaling is bad. That is an understanding that was not existent, or at least not predominant, when traditional TNF inhibitors were approved. The future lies in precision targeting—blocking solTNF’s damage while preserving tmTNF’s healing.

Prof. Lambertsen’s work suggests that, contrary to non-selective TNF inhibitors, XPro could be transformative for both chronic and acute indications.

INmune Bio's RJ Tesi stated the following on the occassion of his closing remarks for the latest earnings call of May 10, 2025:

"We are very careful and precise with our terminology here. Stopping neuroinflammation by immunosuppression, glial suppression, is very different than stopping destructive neuroinflammation by repolarizing glial cells to support the CNS cellular unit and improving remodeling and repair. The goal of effective therapy for Alzheimer’s disease is to reestablish normal glial homeostasis.

The idea that the brains of the elderly with dementia can undergo remodeling and repair is novel. We believe data from the MINDFuL trial will change the direction of scientific research and discovery in the neurology and CNS drug development arena."

That makes sense, in light of the above.

---

INmune Bio discord investors server: https://discord.gg/JEA8r7wCGY