INmune Bio, Inc. (NASDAQ: INMB) is a clinical-stage immunotherapy company developing products that modulate the human innate immune system to treat cancer and chronic inflammation. The company's neurodegeneration program centers on XPro1595, a novel dominant-negative TNF-alpha (dnTNF) inhibitor designed to selectively neutralize the neurotoxic soluble form of TNF-alpha while preserving the beneficial membrane-bound form. This approach targets the JAK-STAT and NF-kappaB signaling pathways implicated in Parkinson's disease neuroinflammation, offering a differentiated mechanism from broad immunosuppressants.
Company Profile
| Attribute | Details | |-----------|--------| | Headquarters | Boca Raton, Florida, USA | | Founded | 2015 | | CEO | Dr. Raymond J. Kelleher Jr., MD, PhD | | Ticker | NASDAQ: INMB | | Employees | ~20 | | Market Cap | ~$50 million (2024) |
Technology Platform
XPro1595: Dominant-Negative TNF Inhibitor
XPro1595 is a next-generation TNF inhibitor that represents a significant advance over first-generation anti-TNF therapies like etanercept and infliximab:
Key Differentiation:
First-generation anti-TNF drugs block both soluble and membrane-bound TNF, disrupting beneficial immune signaling
XPro1595 selectively neutralizes only the soluble trimeric form of TNF-alpha
Preserves membrane-bound TNF signaling, maintaining normal immune surveillance
Does not cross the blood-brain barrier significantly — acts peripherally to modulate neuroinflammation via reduced peripheral cytokine signaling
Mechanism of Action:
Soluble TNF-alpha drives microglial activation and conversion of astrocytes to the toxic A1 phenotype[@a1astro]
A1 astrocytes lose supportive functions (metabolic coupling, neurotrophic factor release) and gain neurotoxic properties
A Phase 1 dose-escalation study evaluated the safety, tolerability, and pharmacodynamics of XPro1595 in patients with mild-to-moderate Parkinson's disease[@pd2022]:
Key Findings:
XPro1595 was well-tolerated at all dose levels
No serious adverse events related to study drug
Dose-dependent reduction in soluble TNF-alpha levels in CSF
Evidence of target engagement in the CNS
Trends toward improved motor and non-motor outcomes at higher doses
Phase 2 Trial (Ongoing)
The Phase 2 trial (NCT04472052) is a randomized, double-blind, placebo-controlled study in patients with early-stage Parkinson's disease:
Primary endpoint: Safety and tolerability at 12 weeks
Secondary endpoints: Change in MDS-UPDRS Part III (motor), non-motor symptoms, CSF biomarkers
Enrollment: Ongoing at multiple US sites
Rationale: Early intervention in PD when neuroinflammatory processes are active but neuronal loss is not yet advanced
AD represents a parallel indication where neuroinflammation driven by TNF-alpha and JAK-STAT signaling contributes to disease progression. The Phase 2 AD trial follows the same mechanistic rationale as the PD program.
Scientific Rationale
TNF-alpha in Neurodegeneration
TNF-alpha is elevated in the brains and CSF of patients with Parkinson's disease and Alzheimer's disease[@pd2024]:
A1 astrocyte conversion: TNF, along with IL-1α and C1q, triggers the conversion of astrocytes to a neurotoxic A1 phenotype
Synaptic dysfunction: TNF-alpha at synapses promotes excitotoxicity and impairs neurotransmission
Blood-brain barrier permeability: Elevated TNF compromises BBB integrity, allowing peripheral immune cells to infiltrate the CNS
Why Selective TNF Inhibition Matters
First-generation TNF inhibitors (used in autoimmune disease) block both soluble and membrane-bound TNF. This broad blockade:
Increases infection risk (membrane TNF is needed for immune defense)
May interfere with CNS repair (membrane TNF has neurotrophic functions)
Does not penetrate BBB (limiting direct CNS effects)
XPro1595's selective approach may offer a superior safety and efficacy profile for chronic neurodegeneration indications[@tnfreview].
Intersection with JAK-STAT Pathway
The JAK-STAT pathway in PD is activated by multiple cytokines including TNF-alpha, IL-6, IL-1β, and IFN-γ. XPro1595 modulates this network by:
Reducing the primary activator: TNF-alpha is one of the earliest and most potent pro-inflammatory cytokines in the cascade
Downstream effects: Less TNF → less IL-6 → less STAT3 phosphorylation → reduced neuroinflammation
Astrocyte preservation: By preventing TNF-driven A1 conversion, XPro1595 maintains the neuroprotective astrocyte state that supports dopaminergic neurons
Competitive Landscape
| Company | Drug | Target | Stage | Mechanism | |---------|------|--------|-------|-----------| | INmune Bio | XPro1595 | Soluble TNF | Phase 2 (PD/AD) | dnTNF inhibitor; upstream of JAK-STAT | | Eli Lilly | Baricitinib | JAK1/JAK2 | Phase 2 (PD) | Direct JAK inhibitor | | Neuraly | NLY01 | GLP-1R | Phase 2 (PD) | Astrocyte modulation (indirect anti-inflammatory) |
Related Pages
[JAK-STAT Signaling in Parkinson's Disease](/mechanisms/jak-stat-parkinsons)
[Neuroinflammation in Parkinson's Disease](/mechanisms/neuroinflammation-parkinsons)
[TNF-alpha Signaling in Neurodegeneration](/mechanisms/tnf-alpha-signaling-neurodegeneration)