Key points

• Foralumab is a nasal anti-CD3 antibody aiming to induce Tregs via mucosal tolerance.
• Current evidence in Alzheimer's is limited to mouse data and one human case.
• The INFORM-MS trial in MS is the first controlled test but results are pending.
• TSPO-PET is a contested marker for microglial activation in AD studies.
• Foralumab's safety profile is favorable, with minor nasal side effects.
• The drug is not FDA-approved and should only be used in clinical trials.

Why it matters

Foralumab is an innovative approach in neurodegeneration, utilizing an intranasal delivery of an anti-CD3 monoclonal antibody to modulate immune responses. It aims to induce regulatory T cells (Tregs) through mucosal tolerance, potentially shifting microglia from a disease-associated to a homeostatic state. This mechanism could offer a new therapeutic avenue in conditions like Alzheimer's disease (AD) and multiple sclerosis (MS).

Key concepts

Mechanism of Action

Foralumab binds to the CD3ε chain of the T-cell receptor complex, promoting Treg induction without depleting T cells. Nasal administration targets nasal-associated lymphoid tissue, minimizing systemic exposure and cytokine release.

Current Evidence

In Alzheimer's, evidence is limited to preclinical mouse models and a single human case with TSPO-PET imaging showing reduced neuroinflammation. The INFORM-MS trial in progressive MS is the first controlled study, with results yet to be published.

TSPO-PET as a Biomarker

TSPO-PET is used to track microglial activity, but its validity as a marker is debated. It reflects myeloid cell density rather than activation state, complicating interpretations of Foralumab's effects.

Clinical application

Foralumab is not approved for clinical use outside of trials. Its role in modulating neuroinflammation through Treg induction is promising, but unproven. Clinicians should be cautious and await results from ongoing trials to assess its efficacy and safety.

Pearls & pitfalls

• Pearl: Foralumab's nasal delivery minimizes systemic side effects, making it a potentially safer option for immune modulation.
• Pitfall: The reliance on TSPO-PET as a surrogate marker may not accurately reflect clinical benefits in AD.
• Pearl: The drug's mechanism avoids T-cell depletion, reducing risks associated with immunosuppression.
• Pitfall: Current data are limited and largely uncontrolled, necessitating further research to validate findings.

Source

Fraser, Foralumab: Intranasal Anti-CD3 Immunomodulation for Neurodegeneration, 2026