The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28...

Area of Science:

• Immunology
• Oncology
• Drug Development

Background:

• Current T cell checkpoint inhibitors (CTLA-4, PD-1) show limited efficacy in many cancer patients.
• Suboptimal CD28 costimulation and impaired adaptive anti-tumor immunity contribute to poor responses.
• Resistance to checkpoint blockade necessitates novel therapeutic strategies.

Purpose of the Study:

• To engineer a novel therapeutic agent, davoceticept (ALPN-202), that enhances T cell activation and anti-tumor immunity.
• To combine CD28 costimulation with dual PD-1/CTLA-4 pathway inhibition.
• To overcome resistance to existing cancer immunotherapies.

Main Methods:

• Directed evolution was used to engineer a CD80 IgV domain with enhanced PD-L1 affinity.
• The engineered CD80 domain was fused to an immunoglobulin Fc domain to create davoceticept (ALPN-202).
• In vitro cell-based assays and in vivo mouse tumor models were employed to evaluate efficacy.

Main Results:

• Davoceticept (ALPN-202) provides PD-L1-dependent CD28 costimulation.
• The therapy antagonizes PD-1/PD-L1 and CTLA-4/CD80/CD86 interactions.
• ALPN-202 demonstrated enhanced T cell activation and superior anti-tumor efficacy compared to checkpoint blockade alone in preclinical models.

Conclusions:

• Combining CD28 costimulation with dual checkpoint inhibition represents a promising strategy for cancer immunotherapy.
• Davoceticept (ALPN-202) has the potential to generate potent and clinically meaningful anti-tumor immunity.
• This novel therapeutic approach may overcome resistance and improve outcomes for patients unresponsive to current therapies.