Foralumab (also known as TZLS-401) is a human monoclonal antibody targeting CD3 epsilon (CD3ε), a subunit of the T-cell receptor complex. This Phase 2a clinical trial (NCT06489548) evaluates the safety, tolerability, and ability of Foralumab to modulate microglial activation in patients with Alzheimer's disease (AD). The trial is conducted at Brigham and Women's Hospital in Boston, Massachusetts.
Foralumab represents a novel immunomodulatory approach to AD that targets the peripheral immune system to indirectly modulate neuroinflammation — a key pathological feature of neurodegeneration.
Background and Rationale
CD3 Targeting and Neuroinflammation
The CD3 complex is essential for T-cell receptor signaling and T-cell activation. While historically explored in autoimmune diseases and organ transplantation, CD3-targeted antibodies have emerged as potential modulators of neuroinflammation through immune tolerance mechanisms:
Peripheral immune modulation: Anti-CD3 antibodies can induce regulatory T-cell (Treg) expansion and shift cytokine profiles from pro-inflammatory to anti-inflammatory states
Indirect microglial effects: Peripheral immune modulation can reduce CNS infiltration of peripheral immune cells and decrease microglial activation
Cytokine cascade modification: Altered peripheral cytokine signaling can propagate to the brain via circumventricular organs and compromised blood-brain barrier
Foralumab Specifics
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Overview
Foralumab (also known as TZLS-401) is a human monoclonal antibody targeting CD3 epsilon (CD3ε), a subunit of the T-cell receptor complex. This Phase 2a clinical trial (NCT06489548) evaluates the safety, tolerability, and ability of Foralumab to modulate microglial activation in patients with Alzheimer's disease (AD). The trial is conducted at Brigham and Women's Hospital in Boston, Massachusetts.
Foralumab represents a novel immunomodulatory approach to AD that targets the peripheral immune system to indirectly modulate neuroinflammation — a key pathological feature of neurodegeneration.
Background and Rationale
CD3 Targeting and Neuroinflammation
The CD3 complex is essential for T-cell receptor signaling and T-cell activation. While historically explored in autoimmune diseases and organ transplantation, CD3-targeted antibodies have emerged as potential modulators of neuroinflammation through immune tolerance mechanisms:
Peripheral immune modulation: Anti-CD3 antibodies can induce regulatory T-cell (Treg) expansion and shift cytokine profiles from pro-inflammatory to anti-inflammatory states
Indirect microglial effects: Peripheral immune modulation can reduce CNS infiltration of peripheral immune cells and decrease microglial activation
Cytokine cascade modification: Altered peripheral cytokine signaling can propagate to the brain via circumventricular organs and compromised blood-brain barrier
Foralumab Specifics
Foralumab is a fully human IgG1 monoclonal antibody that binds to the CD3ε subunit. Unlike earlier mouse-derived anti-CD3 antibodies, Foralumab's fully human structure reduces immunogenicity and may enable repeated dosing.
Trial Details
| Parameter | Value | |-----------|-------| | NCT Number | NCT06489548 | | Official Title | Phase 2a Study of Foralumab (TZLS-401) in Alzheimer's Disease: Safety, Tolerability, and Microglial Modulation | | Sponsor | Brigham and Women's Hospital | | Phase | Phase 2a | | Status | Recruiting | | Study Type | Interventional | | Allocation | Randomized | | Intervention Model | Parallel Assignment | | Masking | Double Blind (Participant, Investigator) | | Enrollment | ~60 participants (planned) |
Study Design
Arms
Low-dose arm: Foralumab 50 µg
High-dose arm: Foralumab 100 µg
Placebo arm: Matching vehicle control
Duration
Screening period: 4 weeks
Treatment period: 24 weeks
Follow-up period: 12 weeks
Total study duration: ~40 weeks
Study Population
Inclusion Criteria
Age 55-85 years
Clinical diagnosis of mild-to-moderate Alzheimer's disease (MMSE 16-26)
PET or CSF evidence of amyloid pathology
Stable on baseline AD medications (if applicable) for ≥8 weeks
Able to undergo repeated IV infusions
Exclusion Criteria
History of autoimmune disease
Active infection or recent serious infection (<4 weeks)
Immunosuppressive therapy within 6 months
Significant psychiatric comorbidity
Active malignancy or history of malignancy within 5 years
Endpoints
Primary Endpoints
Safety and tolerability: Incidence of adverse events (AEs) and serious adverse events (SAEs)
Pharmacodynamic markers: Change in CSF and plasma inflammatory biomarkers
Secondary Endpoints
Microglial activation markers: Change in TSPO PET signal
Clinical outcomes: Change in CDR, ADAS-Cog, MMSE
Peripheral immune markers: Flow cytometry analysis of T-cell subsets
Pharmacokinetics: Plasma concentrations of Foralumab
Mechanism of Action
Mermaid diagram (expand to render)
Clinical Significance
This trial addresses a critical gap in AD therapeutics — the role of peripheral immune system modulation in reducing neuroinflammation. Key aspects:
Novel mechanism: First AD trial targeting peripheral T-cell CD3 to modulate CNS neuroinflammation
Microglial focus: Direct measurement of microglial activation via TSPO PET
Immunomodulatory approach: Unlike direct microglial targeting (e.g., TREM2 agonists), this approach works upstream through peripheral immune regulation
Related Mechanisms
[Neuroinflammation in AD](/mechanisms/neuroinflammation-ad)