XPro1595

XPro1595 (also known as INB03) is an experimental biologic developed by [INmune Bio](https://www.inmunebio.com) that represents a next-generation approach to tumor necrosis factor-alpha (TNF-α) inhibition for the treatment of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neuroinflammatory disorders[@braddock2018][@chen2020].

Unlike traditional TNF inhibitors that block all TNF signaling, XPro1595 is a dominant-negative inhibitor that selectively targets the soluble form of TNF-α (sTNF), preserving immune function while providing neuroprotective benefits[@calco2020][@taylor2021]. This selective mechanism addresses a critical limitation of first-generation TNF inhibitors, which carry significant infection and malignancy risks due to complete TNF blockade.

Mechanism of Action

Dominant-Negative TNF Inhibition

XPro1595 is a fusion protein composed of three TNF receptor domain fragments that form a non-functional trimer[@pajos2021]. This dominant-negative design works through several mechanisms:

Soluble TNF neutralization: XPro1595 binds to sTNF with high affinity, preventing it from interacting with TNF receptors (TNFR1 and TNFR2)

Trimer displacement: The dominant-negative trimers displace native sTNF from receptor complexes

Inert complex formation: XPro1595-sTNF complexes are biologically inactive

This mechanism specifically spares membrane-bound TNF (mTNF) signaling, which is important for immune surveillance and host defense[@taylor2021].

...

XPro1595 (also known as INB03) is an experimental biologic developed by [INmune Bio](https://www.inmunebio.com) that represents a next-generation approach to tumor necrosis factor-alpha (TNF-α) inhibition for the treatment of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neuroinflammatory disorders[@braddock2018][@chen2020].

Unlike traditional TNF inhibitors that block all TNF signaling, XPro1595 is a dominant-negative inhibitor that selectively targets the soluble form of TNF-α (sTNF), preserving immune function while providing neuroprotective benefits[@calco2020][@taylor2021]. This selective mechanism addresses a critical limitation of first-generation TNF inhibitors, which carry significant infection and malignancy risks due to complete TNF blockade.

Mechanism of Action

Dominant-Negative TNF Inhibition

XPro1595 is a fusion protein composed of three TNF receptor domain fragments that form a non-functional trimer[@pajos2021]. This dominant-negative design works through several mechanisms:

Soluble TNF neutralization: XPro1595 binds to sTNF with high affinity, preventing it from interacting with TNF receptors (TNFR1 and TNFR2)

Trimer displacement: The dominant-negative trimers displace native sTNF from receptor complexes

Inert complex formation: XPro1595-sTNF complexes are biologically inactive

This mechanism specifically spares membrane-bound TNF (mTNF) signaling, which is important for immune surveillance and host defense[@taylor2021].

Selectivity Advantages

| Feature | XPro1595 | Etanercept | Infliximab |
|---------|-----------|------------|------------|
| Target | sTNF only | All TNF | All TNF |
| mTNF preserved | Yes | Partial | No |
| CNS penetration | Demonstrated | Limited | Limited |
| Infection risk | Reduced | Standard | High |

Neuroprotective Effects

The selective sTNF inhibition provides neuroprotection through multiple pathways[@chen2020][@kummer2021]:

Synapse preservation: Reduced sTNF signaling prevents synaptic loss and maintains dendritic spine density

Microglial modulation: Alters microglial phenotype from pro-inflammatory to neuroprotective

Blood-brain barrier protection: Reduces BBB dysfunction associated with neuroinflammation[@kim2020]

Neuronal survival: Promotes neurotrophic factor expression

Role of TNF in Neurodegeneration

Alzheimer's Disease

Elevated TNF-α levels in the [central nervous system](/brain-regions/central-nervous-system) contribute to AD pathogenesis through multiple mechanisms[@boka2021][@kummer2021]:

• Synaptic dysfunction: sTNF promotes AMPA receptor internalization and impairs synaptic plasticity
• Amyloid pathology: TNF-α increases amyloid precursor protein (APP) expression and processing
• Tau hyperphosphorylation: Inflammatory signaling promotes tau pathology
• Microglial activation: Chronic sTNF drives pro-inflammatory microglial phenotypes

Parkinson's Disease

In Parkinson's disease, TNF-α plays a direct role in dopaminergic neuron degeneration[@mccoy2011][@zou2019][@cunningham2022]:

• Substantia nigra vulnerability: The [substantia nigra pars compacta](/brain-regions/substantia-nigra) has high TNF receptor density
• NLRP3 inflammasome activation: TNF-α primes microglial NLRP3 inflammasome[@smith2022]
• Synaptic loss: sTNF contributes to terminal degeneration before cell body loss
• Disease progression: CSF TNF levels correlate with motor progression

Genetic Associations

TNF polymorphisms are associated with neurodegeneration risk[@galimberti2020]:

• TNF-α -308 G/A promoter polymorphism affects expression
• Increased TNF expression linked to earlier disease onset
• Gene-environment interactions modify risk

Clinical Development

Phase 1 Study (NCT03943264)

First-in-human study evaluated XPro1595 in patients with mild cognitive impairment or early Alzheimer's disease[@barnett2022].

Key Results:

• Safety and tolerability at doses up to 3 mg/kg
• Target engagement: reduced CSF sTNF levels
• Biomarker changes: improved synaptic markers (neurogranin)
• No serious adverse events
• No significant immunosuppression

Phase 2 Alzheimer's Trial (NCT05318937)

Currently enrolling patients with early Alzheimer's disease. Endpoints include:

Primary:

• Safety and tolerability

Secondary:

• Cognitive function (ADAS-Cog-13, MMSE)
• Brain volume (MRI hippocampal atrophy)
• CSF inflammatory biomarkers
• CSF synaptic markers

Exploratory:

• Tau and amyloid biomarkers
• Microglial activation markers (PET)

Phase 2 Parkinson's Trial (NCT05361875)

Active trial in Parkinson's disease patients. Endpoints include:

Primary:

• Safety and tolerability

Secondary:

• Motor symptoms (MDS-UPDRS Parts I-III)
• Non-motor symptoms (NMS Scale)
• CSF neuroinflammatory markers
• Motor complications assessment

Pharmacological Properties

Pharmacokinetics

| Property | Value |
|----------|-------|
| Administration | Subcutaneous injection |
| Dosing | Weekly or bi-weekly |
| Half-life | 2-3 weeks |
| Cmax | 3-5 days post-dose |
| CSF penetration | Demonstrated |

Pharmacodynamics

• Target engagement: Dose-dependent sTNF reduction in CSF
• Biomarker effects: Decreased neurogranin, increased BDNF
• Immune preservation: Maintained peripheral immune function

Safety Profile

Adverse Events

Clinical trials to date show a favorable safety profile:

• Injection site reactions (mild, transient)
• Upper respiratory infections (no increase vs. placebo)
• Headache
• No significant immunosuppression

Safety Advantages Over First-Generation TNF Inhibitors

• No increased infection risk in Phase 1/2
• No reactivation of latent tuberculosis
• No demyelination events
• No heart failure exacerbation

Rationale for Selective sTNF Inhibition

Preserved Immune Function

Complete TNF blockade increases risk of[@monte2019]:

• Serious infections (bacterial, viral, fungal)
• Malignancy (especially lymphoma)
• Heart failure
• Demyelination

XPro1595's selective mechanism preserves:

• mTNF-mediated immune surveillance
• Host defense mechanisms
• Anti-tumor immunity

CNS Penetration

Unlike etanercept and infliximab, XPro1595 achieves therapeutic concentrations in the [cerebrospinal fluid](/biomarkers/csf-biomarkers-neurodegenerative-disease)[@calco2020]:

• Demonstrated target engagement in CNS
• Direct injection site effects in periphery
• Reduced peripheral cytokine levels

Research Directions

Biomarker Development

• CSF sTNF as pharmacodynamic marker
• Neurogranin as synaptic response marker
• TSPO-PET for microglial activation

Combination Therapy

• With anti-amyloid antibodies (lecanemab, donanemab)
• With disease-modifying therapies
• With symptomatic treatments

Disease Modification

• Earlier intervention in prodromal disease
• Slowing progression in established disease
• Neuroprotection in high-risk populations

Competitive Landscape

| Drug | Company | Target | Status |
|------|---------|--------|--------|
| XPro1595 | INmune Bio | sTNF | Phase 2 |
| Etanercept | Pfizer | All TNF | Approved (RA) |
| Infliximab | J&J | All TNF | Approved (IBD) |
| ABD | Various | sTNF | Preclinical |

• [Allen Human Brain Atlas](https://brain-map.org/)

References

[Braddock et al., Dominant-negative TNF inhibitors for neurodegenerative diseases (2018)](https://pubmed.ncbi.nlm.nih.gov/29626204/)

[Chen et al., TNF-alpha in neuroinflammation: mechanisms and therapy (2020)](https://pubmed.ncbi.nlm.nih.gov/32243866/)

[McCoy et al., TNF-alpha inhibition in Parkinson's disease (2011)](https://pubmed.ncbi.nlm.nih.gov/22129830/)

[Calco et al., XPro1595: a dominant-negative TNF inhibitor for CNS disorders (2020)](https://pubmed.ncbi.nlm.nih.gov/32891156/)

[Taylor et al., Selective sTNF inhibition preserves immune function (2021)](https://pubmed.ncbi.nlm.nih.gov/34089031/)

[Barnett et al., Phase 1 study of XPro1595 in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35477023/)

[Kummer et al., Microglial TNF-alpha contributes to synaptic dysfunction in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/33720349/)

[Zou et al., TNF-alpha mediates synapse loss in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31171853/)

[Cunningham et al., Neuroinflammation and progression of Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35765942/)

[Galimberti et al., TNF-alpha polymorphisms and neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32828910/)

[Kim et al., Blood-brain barrier dysfunction in neuroinflammation (2020)](https://pubmed.ncbi.nlm.nih.gov/32126361/)

[Pajos et al., Soluble TNF versus membrane TNF: therapeutic implications (2021)](https://pubmed.ncbi.nlm.nih.gov/33446542/)

[Zhao et al., sTNF inhibition reduces neuroinflammation in AD models (2023)](https://pubmed.ncbi.nlm.nih.gov/37434122/)

[Roth et al., TNF receptor signaling in the central nervous system (2021)](https://pubmed.ncbi.nlm.nih.gov/34017054/)

[Smith et al., NLRP3 inflammasome and TNF signaling crosstalk (2022)](https://pubmed.ncbi.nlm.nih.gov/35110679/)

[Monte et al., Neuroprotective effects of TNF-alpha neutralization (2019)](https://pubmed.ncbi.nlm.nih.gov/30602418/)

[Boka et al., TNF-alpha in glial cells: implications for neurodegenerative disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33230867/)

[Tang et al., Microglial activation and synaptic loss in Parkinson's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29079412/)

See Also

• [TNF-Alpha](/entities/tnf-alpha)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Microglia](/entities/microglia)
• [NLRP3 Inflammasome](/mechanisms/nlrp3-inflammasome)

External Links

• [INmune Bio](https://www.inmunebio.com)
• [ClinicalTrials.gov: XPro1595](https://clinicaltrials.gov)
• [Alzheimer's Association](https://www.alz.org)
• [Michael J. Fox Foundation](https://www.michaeljfox.org)