Mechanism of Action of HLX3901

In recent years, cancer immunotherapy has evolved from the single-target era to a multi-dimensional synergy era.

HLX3901, a next-generation tetraspecific antibody developed by Henlius, represents a major innovation in antibody engineering. It simultaneously targets:

• Two epitopes of DLL3
• CD3 (T cell activation)
• CD28 (co-stimulation)

👉 This enables precise tumor targeting + full T cell activation

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Tetraspecific Antibodies: Beyond Bispecific Design

Traditional approaches:

• Monoclonal antibodies → single target
• Bispecific antibodies → tumor + T cell bridging

HLX3901 goes further:

• Dual DLL3 binding → stronger tumor recognition
• CD3 + CD28 → complete immune activation

👉 It acts as an immune system orchestrator, not just a connector.

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Mechanism of Action: Triple-Synergy Model

1️⃣ Dual-Epitope DLL3 Targeting

DLL3 is highly expressed in small cell lung cancer (SCLC).

Advantages:

• Higher binding affinity
• Stronger tumor localization
• Reduced antigen escape

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2️⃣ CD3 Activation Signal (Signal 1)

• Activates T cells
• Initiates cytotoxic response
• Triggers tumor cell killing

👉 Equivalent to “turning on the engine”

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3️⃣ CD28 Co-Stimulation (Signal 2)

• Enhances T cell proliferation
• Improves survival
• Promotes cytokine release (IL-2, IFN-γ)

👉 Converts T cells into sustained high-efficiency killers

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Why HLX3901 Is a Breakthrough

🔬 Full Simulation of T Cell Activation

• Signal 1 (CD3)
• Signal 2 (CD28)

👉 Mimics physiological immune activation

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🧬 Enhanced Anti-Tumor Activity

• Stronger tumor killing
• Better immune infiltration
• Reduced immune escape

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💊 Resistance Prevention Potential

• Multi-pathway activation
• Harder for tumors to bypass

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Key Indication: Small Cell Lung Cancer (SCLC)

SCLC characteristics:

• Highly aggressive
• High relapse rate
• Limited treatment options
• Poor prognosis

👉 DLL3 is one of the most promising targets in this field.

HLX3901 may represent a new therapeutic paradigm.

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Challenges and Risks

⚠️ Safety

• Cytokine Release Syndrome (CRS)
• Overactivation of immune system

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⚠️ Manufacturing Complexity

• Multi-specific structure
• Stability challenges
• Higher production cost

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⚠️ Clinical Validation

• More complex trials required
• Long validation timeline

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Conclusion

HLX3901 represents a major step forward in immunotherapy:

👉 From single-target inhibition
👉 To multi-mechanism immune orchestration

By integrating:

• Dual-epitope DLL3 targeting
• CD3 activation
• CD28 co-stimulation

it opens a new era of network-level immune activation.

As clinical data mature, HLX3901 may become a key therapy for SCLC and other solid tumors.