XPro1595 (also known as INB03) is an experimental biologic developed by INmune Bio that represents a next-generation approach to tumor necrosis factor-alpha (TNF-α) inhibition for the treatment of Alzheimer's disease, Parkinson's disease, and other neuroinflammatory disorders[1][2].
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[3][4]. This selective mechanism addresses a critical limitation of first-generation TNF inhibitors, which carry significant infection and malignancy risks due to complete TNF blockade.
XPro1595 is a fusion protein composed of three TNF receptor domain fragments that form a non-functional trimer[5]. This dominant-negative design works through several mechanisms:
This mechanism specifically spares membrane-bound TNF (mTNF) signaling, which is important for immune surveillance and host defense[4:1].
| 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 |
The selective sTNF inhibition provides neuroprotection through multiple pathways[2:1][6]:
Elevated TNF-α levels in the central nervous system contribute to AD pathogenesis through multiple mechanisms[8][6:1]:
In Parkinson's disease, TNF-α plays a direct role in dopaminergic neuron degeneration[9][10][11]:
TNF polymorphisms are associated with neurodegeneration risk[13]:
First-in-human study evaluated XPro1595 in patients with mild cognitive impairment or early Alzheimer's disease[14].
Key Results:
Currently enrolling patients with early Alzheimer's disease. Endpoints include:
Primary:
Secondary:
Exploratory:
Active trial in Parkinson's disease patients. Endpoints include:
Primary:
Secondary:
| Property | Value |
|---|---|
| Administration | Subcutaneous injection |
| Dosing | Weekly or bi-weekly |
| Half-life | 2-3 weeks |
| Cmax | 3-5 days post-dose |
| CSF penetration | Demonstrated |
Clinical trials to date show a favorable safety profile:
Complete TNF blockade increases risk of[15]:
XPro1595's selective mechanism preserves:
Unlike etanercept and infliximab, XPro1595 achieves therapeutic concentrations in the cerebrospinal fluid[3:1]:
| 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 |
Braddock M, et al. Dominant-negative TNF inhibitors for neurodegenerative diseases. Nat Rev Drug Discov. 2018. ↩︎
Chen X, et al. TNF-alpha in neuroinflammation: mechanisms and therapy. Neuron. 2020. ↩︎ ↩︎
Calco GN, et al. XPro1595: a dominant-negative TNF inhibitor for CNS disorders. J Neuroinflammation. 2020. ↩︎ ↩︎
Taylor A, et al. Selective sTNF inhibition preserves immune function in neurodegenerative disease. Sci Transl Med. 2021. ↩︎ ↩︎
Pajos A, et al. Soluble TNF versus membrane TNF: therapeutic implications. Pharmacol Rev. 2021. ↩︎
Kummer MP, et al. Microglial TNF-alpha contributes to synaptic dysfunction in Alzheimer's disease. Brain. 2021. ↩︎ ↩︎
Kim J, et al. Blood-brain barrier dysfunction in neuroinflammation. Nat Rev Neurosci. 2020. ↩︎
Boka G, et al. TNF-alpha in glial cells: implications for neurodegenerative disease. Glia. 2021. ↩︎
McCoy MK, et al. TNF-alpha inhibition in Parkinson's disease: a new therapeutic approach. Nat Rev Neurol. 2011. ↩︎
Zou W, et al. TNF-alpha mediates synapse loss in Parkinson's disease models. Nat Neurosci. 2019. ↩︎
Cunningham C, et al. Neuroinflammation and progression of Parkinson's disease. Mov Disord. 2022. ↩︎
Smith JA, et al. NLRP3 inflammasome and TNF signaling crosstalk in neurodegeneration. Cell Death Differ. 2022. ↩︎
Galimberti D, et al. TNF-alpha polymorphisms and neurodegeneration. J Neurol Sci. 2020. ↩︎
Barnett J, et al. Phase 1 study of XPro1595 in Alzheimer's disease: safety and biomarkers. Alzheimers Dement. 2022. ↩︎
Monte M, et al. Neuroprotective effects of TNF-alpha neutralization in vivo. J Neurosci. 2019. ↩︎