XPro1595
Also known as: DN-TNF, dominant-negative TNF, dTNF, pegipanermin, XPro-1595, XPro1595
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Summary
XPro1595 is an investigational biologic that acts as a dominant‑negative inhibitor of tumor necrosis factor‑alpha (TNF‑α). Designed to selectively neutralise the soluble form of TNF while preserving the transmembrane form, it is being explored for neuroinflammatory conditions such as Alzheimer's disease and for vascular disorders like abdominal aortic aneurysm. The compound is administered by subcutaneous injection and remains in the research‑only category.
Mechanism of Action
XPro1595 forms inactive heterotrimers with native soluble TNF‑α, preventing the ligand from engaging TNF receptors (TNFR1 and TNFR2). By selectively blocking soluble TNF signaling, it reduces downstream pro‑inflammatory cascades while allowing transmembrane TNF to continue its immunoregulatory functions. This selective inhibition is intended to mitigate neuroinflammation and vascular inflammation without the broad immunosuppression seen with non‑selective TNF blockers.
What the Research Shows
Pre‑clinical work in the TgCRND8 mouse model of Alzheimer's disease showed that early inhibition of TNF‑α with XPro1595 normalised excitatory synaptic transmission and prevented later synaptic deficits. Reviews of astrogliosis and immunomodulation cite XPro1595 as a candidate drug targeting neuroinflammatory pathways in AD, and it appears in lists of agents under clinical investigation. In two murine models of abdominal aortic aneurysm, subcutaneous XPro1595 reduced aneurysm expansion and improved elastin integrity, with associated changes in systemic cytokine levels. Across studies, the compound consistently demonstrates selective soluble TNF blockade and modulation of inflammatory biomarkers.
Reported Benefits
Animal data suggest XPro1595 can preserve synaptic function when administered before amyloid plaque formation, indicating a potential disease‑modifying role in early Alzheimer’s disease. In vascular models, it attenuated aneurysm growth, pointing to utility in conditions driven by soluble TNF. By sparing transmembrane TNF, the drug may avoid some adverse effects linked to broader TNF inhibition, offering a more targeted anti‑inflammatory strategy.
Limitations of the Evidence
All efficacy evidence to date is limited to rodent models; no peer‑reviewed human trial results are reported. The cited reviews list XPro1595 among agents under investigation but do not provide clinical outcome data. Observed increases in systemic TNF after treatment raise questions about compensatory mechanisms. Consequently, the therapeutic relevance for humans remains unproven, and the compound has no regulatory approval.
Safety Considerations
Pre‑clinical studies reported elevated systemic TNF levels after XPro1595 administration, while non‑selective agents like etanercept increased IL‑10. No specific adverse event profile has been published, and the safety of chronic soluble‑TNF blockade in humans is unknown. Potential risks may include altered immune responses or unexpected cytokine rebound, underscoring the need for thorough safety evaluation before clinical use.
How It Is Administered
XPro1595 is formulated for subcutaneous injection. In animal studies, repeated dosing was employed to maintain soluble TNF inhibition, but dosing schedules for humans have not been established. The biologic nature of the compound requires sterile injection techniques and storage conditions typical for protein therapeutics.
Routes of Administration
Goals & Uses
- Treatment-resistant depressionPsychiatryLow
- Mild cognitive impairment (MCI) treatmentCognitive DeclineLow
- Neuroprotection in CNS diseaseNeuroprotectionLow
- ALS (amyotrophic lateral sclerosis)NeurodegenerationLow
- Alzheimer's disease neuroinflammation reductionNeurodegenerationModerate
- Multiple SclerosisAutoimmune DiseaseLow
- Traumatic brain injuryNeuroprotectionModerate
- Parkinson's diseaseNeurodegenerationModerate
- Alzheimer's diseaseNeurodegenerationModerate
Contraindications
- Demyelinating disease (e.g., multiple sclerosis)NeurologicalModerate
- Active serious infectionsInfectiousHigh
- Active tuberculosisInfectiousHigh
- Known hypersensitivity to XPro1595 or any excipientsAllergyHigh
- Active severe infectionInfectiousHigh
- Known hypersensitivity to XPro1595 or excipientsAllergy/HypersensitivityHigh
Adverse Effects
- Anti‑drug antibodiesImmunogenicityUnknown
- Injection site reactionsLocalCommon
- HeadacheNeurologicUncommonPain in the head or upper neck
- Upper respiratory tract infectionInfectiousUncommon
- FatigueGeneralUncommonLow energy or tiredness
- Injection site erythemaLocalCommonRedness at the injection site
- Anti-drug antibodiesImmunologicUnknownAntibodies formed against the therapeutic agent
- Infection susceptibilityImmunologicUncommon
Drug Interactions
- Immunosuppressants (e.g., methotrexate, azathioprine)Moderate
- Other TNF inhibitors (e.g., etanercept, adalimumab)High
- Live attenuated vaccinesHigh
- Live vaccinesHigh
- Immunosuppressive agents (e.g., azathioprine, methotrexate)Moderate
- Other biologic TNF inhibitors (e.g., etanercept, infliximab)High
Population Constraints
- PregnancyReproductive SafetyRelative
- Pediatric patientsAgeRelative
- Pediatric patients (<18 y)AgeRelative
- Pregnant womenReproductiveRelative
- Patients with History of MalignancyOncologyRelative
- Elderly patients with multiple comorbiditiesAge / ComorbidityRelative
Regulatory Status
- European UnionInvestigationalClinical trial authorization obtained in several member states
- United StatesInvestigationalIND holder: Xencor; Phase 1/2 trials ongoing
- United KingdomInvestigationalMHRA clinical trial permission; no marketing authorization
Currently under IND in the United States and similar clinical‑trial authorizations in the EU and UK; not approved for any therapeutic indication.
Evidence & Sources
- Journal ArticleModerateCavanagh C, Wong TP2018-01-01T00:00:00.000000Z
- Journal ArticleLowGriepke S, et al.2022-01-01T00:00:00.000000Z
- Journal ArticleModeratePaidlewar M, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleModerateAshvin, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleModerateUdaiyappan JP, et al.2026-01-01T00:00:00.000000Z
- Journal ArticleModerateClark IA, Vissel B2019-01-01T00:00:00.000000Z
Frequently Asked Questions
What distinguishes XPro1595 from other TNF inhibitors like etanercept?
XPro1595 selectively neutralises soluble TNF‑α by forming inactive heterotrimers, while preserving the transmembrane form of TNF. Etanercept binds both soluble and transmembrane TNF, leading to broader immunosuppression and a different safety profile.
Which diseases are currently being studied with XPro1595?
Pre‑clinical research focuses on Alzheimer’s disease, where it may protect synapses, and abdominal aortic aneurysm, where it reduces vessel expansion. Reviews also list it among agents investigated for neuroinflammatory and immunomodulatory strategies.
Has XPro1595 been tested in humans?
The literature cites XPro1595 as being in clinical investigation, but no peer‑reviewed human efficacy or safety data have been published. It remains an investigational compound without regulatory approval.
How is XPro1595 administered?
The compound is delivered by subcutaneous injection. In animal models, repeated injections were used to sustain soluble TNF blockade, but optimal dosing regimens for humans have not been defined.
What are the known safety concerns?
Animal studies observed increased systemic TNF levels after treatment, suggesting possible cytokine rebound. No detailed adverse‑event data exist for humans, so potential immune‑related risks remain speculative pending clinical trials.
What is XPro1595?
XPro1595 is an investigational biologic that acts as a dominant‑negative inhibitor of tumor necrosis factor‑alpha (TNF‑α). Designed to selectively neutralise the soluble form of TNF while preserving the transmembrane form, it is being explored for neuroinflammatory conditions such as Alzheimer's disease and for vascular disorders like abdominal aortic aneurysm. The compound is administered by subcutaneous injection and remains in the research‑only category.
What is XPro1595 used for?
XPro1595 is educationally associated with: Treatment-resistant depression, Mild cognitive impairment (MCI) treatment, Neuroprotection in CNS disease, ALS (amyotrophic lateral sclerosis), Alzheimer's disease neuroinflammation reduction, Multiple Sclerosis, Traumatic brain injury, Parkinson's disease, Alzheimer's disease. Educational only — not medical advice.
How is XPro1595 administered?
Recorded routes of administration: Intravenous, Subcutaneous.
What are the potential side effects of XPro1595?
Reported adverse effects include: Anti‑drug antibodies, Injection site reactions, Headache, Upper respiratory tract infection, Fatigue, Injection site erythema, Anti-drug antibodies, Infection susceptibility. This list is not exhaustive — consult a qualified clinician.
Who should avoid XPro1595?
Recorded contraindications: Demyelinating disease (e.g., multiple sclerosis), Active serious infections, Active tuberculosis, Known hypersensitivity to XPro1595 or any excipients, Active severe infection, Known hypersensitivity to XPro1595 or excipients. Consult a qualified clinician before use.