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 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.
| 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) |
- Low-dose arm: Foralumab 50 µg
- High-dose arm: Foralumab 100 µg
- Placebo arm: Matching vehicle control
- Screening period: 4 weeks
- Treatment period: 24 weeks
- Follow-up period: 12 weeks
- Total study duration: ~40 weeks
- 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
- 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
- Safety and tolerability: Incidence of adverse events (AEs) and serious adverse events (SAEs)
- Pharmacodynamic markers: Change in CSF and plasma inflammatory biomarkers
- 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
flowchart TD
A["Foralumab IV Administration"] --> B["CD3ε Binding on T-cells"]
B --> C["T-cell Modulation"]
C --> D["Regulatory T-cell Expansion"]
C --> E["Pro-inflammatory Cytokine Reduction"]
D --> F["Peripheral Immune Normalization"]
E --> F
F --> G["Reduced CNS Immune Infiltration"]
G --> H["Microglial Activation Normalization"]
H --> I["Reduced Neuroinflammation"]
I --> J["Potential Cognitive Benefit"]
style A fill:#e1f5fe
style I fill:#c8e6c9
style J fill:#fff9c4
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