Microenvironment-responsive anti-PD-L1 × CD3 bispecific T-cell engager for solid tumor immunotherapy

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Bispecific T-cell engager (BiTE) antibodies redirect T-cells for targeted tumor cell lysis.
• BiTEs face challenges in solid tumors, including short plasma half-life, off-target effects, and PD-1/PD-L1 mediated immunosuppression.

Purpose of the Study:

• To design and evaluate a safe, long-acting, and effective protease-activated PSTAGylated BiTE (PAPB) for solid tumor immunotherapy.
• To engineer a BiTE with a shielding domain and protease-activated linker for tumor-specific activation.

Main Methods:

• Developed PAPB comprising a PSTAG shielding domain, protease-activated linker, and a BiTE core targeting PD-L1 and CD3.
• Assessed BiTE core binding to PD-L1 and CD3 in a dose-dependent manner.
• Evaluated PAPB's plasma half-life, tumor infiltration, and anti-tumor activity in a melanoma xenograft mouse model.

Main Results:

• PAPB significantly prolonged the plasma half-life of the BiTE core from 2.46 h to 6.34 h in mice.
• PAPB treatment increased T lymphocyte infiltration in tumor tissue and inhibited tumor proliferation.
• PAPB demonstrated tumor-specific activity without activating T-cells in peripheral blood.

Conclusions:

• The engineered protein PAPB shows potential as a therapeutic candidate for solid tumor immunotherapy.
• PAPB effectively overcomes key limitations of traditional BiTEs, offering a promising approach for cancer treatment.