SHR-1707 for Alzheimer's Disease (NCT06199037)

Overview

NCT06199037 is a Phase 2 clinical trial investigating SHR-1707, a novel bispecific antibody targeting both IL-17 and PD-1, in patients with Alzheimer's disease. The trial is sponsored by Shanghai Hengrui Pharmaceutical and is currently recruiting participants.

SHR-1707 represents an innovative approach to treating Alzheimer's disease by simultaneously modulating two key immune checkpoint pathways—IL-17 signaling and PD-1 signaling—potentially addressing the neuroinflammation that contributes to disease progression.

Trial Details

Overview

NCT06199037 is a Phase 2 clinical trial investigating SHR-1707, a novel bispecific antibody targeting both IL-17 and PD-1, in patients with Alzheimer's disease. The trial is sponsored by Shanghai Hengrui Pharmaceutical and is currently recruiting participants.

SHR-1707 represents an innovative approach to treating Alzheimer's disease by simultaneously modulating two key immune checkpoint pathways—IL-17 signaling and PD-1 signaling—potentially addressing the neuroinflammation that contributes to disease progression.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06199037 |
| Phase | Phase 2 |
| Status | Recruiting |
| Enrollment | 45 participants |
| Sponsor | Shanghai Hengrui Pharmaceutical |
| Intervention | SHR-1707 (bispecific antibody) |
| Study Type | Interventional |

Background

Bispecific Antibody Mechanism

SHR-1707 is a bispecific antibody engineered to bind to two distinct targets:

• IL-17 is produced by Th17 cells and contributes to inflammatory responses
• Elevated IL-17 levels have been associated with neurodegenerative processes
• Blocking IL-17 signaling reduces neuroinflammation in preclinical models

• PD-1 negatively regulates T-cell activity and immune responses
• PD-1 signaling can suppress anti-inflammatory responses
• Modulating PD-1 can enhance immune surveillance and clearance

Rationale for AD

The dual-targeting approach of SHR-1707 addresses multiple aspects of neuroinflammation in Alzheimer's disease:

• Chronic neuroinflammation: IL-17 promotes pro-inflammatory cytokine release from microglia
• Immune checkpoint modulation: PD-1 modulation may enhance neuroprotective immune responses
• Synergistic effect: Simultaneous IL-17 and PD-1 modulation may provide greater anti-inflammatory effect than single-target approaches
• Complementary pathways: Targeting both pathways addresses multiple inflammatory cascades

Preclinical Evidence

Research on IL-17 and PD-1 pathways in AD models has shown:

• IL-17 receptor signaling contributes to microglial activation
• PD-1 blockade can enhance amyloid clearance
• Combined immune modulation shows promise in preclinical neurodegeneration models
• Bispecific antibodies offer advantages over combination therapy with single-target agents

Study Design

The trial will evaluate the safety and efficacy of SHR-1707 in patients with mild-to-moderate Alzheimer's disease. Key endpoints likely include:

• Cognitive function measures (ADAS-Cog, MMSE)
• Biomarker assessments (amyloid PET, tau PET, CSF markers)
• Safety and tolerability
• Immunological markers
• Brain volume changes (MRI)

Cross-Links

• [Neuroinflammation in AD](/mechanisms/neuroinflammation-alzheimers)
• [TREM2 Signaling](/mechanisms/trem2-signaling)
• [TREM2 Cytokine Regulation](/mechanisms/trem2-cytokine-regulation)
• [IL-17 in Neuroinflammation](/mechanisms/il-17-neuroinflammation)
• [PD-1 Immune Checkpoint](/mechanisms/pd-1-checkpoint-neurodegeneration)

IL-17 and PD-1 Biology in AD

IL-17 Pathway

Interleukin-17 (IL-17) is a pro-inflammatory cytokine produced primarily by Th17 cells[@il17ad2023]. In Alzheimer's disease:

• [Microglial activation**: IL-17 stimulates pro-inflammatory cytokine production (IL-1β, TNF-α)](/cell-types/microglia)
• [Blood-brain barrier**: IL-17 can disrupt BBB integrity](/mechanisms/blood-brain-barrier)
• [Neuronal damage**: Chronic IL-17 signaling contributes to synaptic dysfunction](/mechanisms/synaptic-dysfunction)
• [Amyloid interaction**: IL-17 may enhance amyloidogenic APP processing](/proteins/app)

PD-1 Pathway

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activity[@pd1neuro2024]:

• [Immune](/companies/ad-neuroimmune-checkpoint-trem2-pathway-companies)suppression**: PD-1 limits excessive immune responses
• Microglial function: PD-1 expression on microglia affects their phagocytic capacity
• Therapeutic potential: PD-1 modulation may enhance immune clearance of pathological proteins

Bispecific Antibody Technology

Advantages over Monotherapy

Bispecific antibodies represent a significant advancement in immunotherapy[@bispecific2024]:

| Feature | Single-target | Bispecific |
|---------|---------------|------------|
| Pathway coverage | Single pathway | Multiple pathways |
| Dosing burden | Multiple drugs | Single molecule |
| Pharmacokinetics | Variable | Optimized |
| Cost | Higher | Lower potential |

SHR-1707 Design

SHR-1707 employs a novel bispecific format:

• Simultaneous binding: Engages both IL-17 and PD-1
• Balanced modulation: Appropriate dosing for both targets
• Convenience: Single IV infusion regimen

Clinical Development Considerations

Biomarker Strategy

The trial likely incorporates:

• Neuroinflammatory markers: CSF IL-17, cytokines
• Amyloid/tau PET: Track pathological burden
• Neurodegeneration markers: NfL, t-tau
• Cognitive measures: ADAS-Cog13, CDR-SB

Safety Profile

Key safety considerations:

• Immune-related adverse events: Monitor for cytokine-related effects
• Infections: Checkpoint modulation may increase infection risk
• Autoimmunity: Long-term effects on autoimmunity

Comparison with Other Neuroinflammation Approaches

| Agent | Target | Company | Phase |
|-------|--------|---------|-------|
| SHR-1707 | IL-17/PD-1 | Hengrui | Phase 2 |
| AL002 | TREM2 | Alector | Phase 2 |
| Xpro1595 | TNF-α | INmune Bio | Phase 2 |
| Tilavonemab | Tau | AbbVie | Phase 2 |

Shanghai Hengrui Pharmaceutical

Company Profile

Hengrui is a leading Chinese pharmaceutical company:

• Headquarters: Lianyungang, China
• R&D focus: Oncology, immunology, CNS
• Pipeline: Multiple bispecific antibodies in development

Previous Experience

• Developed several approved oncology bispecifics
• Strong immunology franchise
• Established clinical trial infrastructure

References