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Semaphorin 4D (SEMA4D) blocking antibody pepinemab shows promise in treating neurodegenerative diseases like Alzheimer's by reducing neuroinflammation and improving cognitive function. Clinical trials indicate significant cognitive benefits and biomarker improvements in early Alzheimer's patients.

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Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Semaphorin 4D (SEMA4D) and its receptors are implicated in reactive gliosis and neurodegenerative diseases like Alzheimer's Disease (AD) and Huntington's Disease (HD).
  • SEMA4D protein upregulation in diseased neurons activates astrocytes, leading to metabolic transporter downregulation and inflammatory cytokine release.
  • Previous studies show SEMA4D blockade with pepinemab reduced astrogliosis biomarkers and slowed cognitive decline in HD patients.

Purpose of the Study:

  • To investigate the effects of SEMA4D blockade with pepinemab on neuropathology, behavior, and vascular integrity in preclinical models.
  • To evaluate the safety, efficacy, and biomarker changes associated with pepinemab treatment in individuals with mild AD dementia.

Main Methods:

  • Preclinical studies utilized a mouse model of HD and an in vitro brain chip model to assess SEMA4D blockade effects.
  • The Phase 1b/2 SIGNAL-AD trial (NCT04381468) involved 50 individuals with mild AD dementia treated with pepinemab or placebo for 12 months.
  • Key objectives included safety assessments, cognitive evaluations using standard scales, and biomarker analysis via CSF O-link proteomic analysis.

Main Results:

  • In preclinical models, SEMA4D blockade reduced glial activation, increased synaptic markers, and improved cognitive deficits.
  • Pepinemab treatment in the SIGNAL-AD trial demonstrated tolerability and meaningful cognitive improvements in the mild cognitive impairment-early AD subgroup, with over 70% slowing of cognitive decline.
  • CSF analysis revealed pepinemab-related reductions in biomarkers for reactive astrocytes, microglia clearance, and tau pathology.

Conclusions:

  • SEMA4D blockade with pepinemab effectively reduces neuroinflammation and associated vascular disruption.
  • Pepinemab demonstrates potential as a treatment for cognitive dysfunction and neurodegenerative diseases by targeting glial activation.
  • These findings support the broad application of glial regulators for treating neurodegenerative conditions, offering an alternative or complement to anti-amyloid therapies.