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

Bispecific T-cell Engager (BiTE) antibodies can redirect T-cells to tumor cells, and turn on the targeted lysis of tumor cells. However, BiTE has been challenging in solid tumors due to short plasma half-life, off-target effect, and immunosuppression via PD-1/PD-L1 axis. This study designed a safe, long-acting, and highly effective Protease -Activated PSTAGylated BiTE, named PAPB, which includes a shielding polypeptide domain (PSTAG), a protease-activated linker, and a BiTE core. The BiTE core consists of two scFvs targeting PD-L1 and CD3. BiTE core bound PD-L1 and CD3 in a dose-dependent manner, and PAPB can release BiTE core in response to MMP2 in the tumor microenvironment to exert antitumor activity. The plasma half-life of PAPB in mice was significantly prolonged from 2.46 h to 6.34 h of the BiTE core. In mice bearing melanoma (A375) xenografts, PAPB signifi-cantly increased infiltration of T lymphocytes in tumor tissue, and inhibited tumor proliferation without acti-vating T-cells in the peripheral blood. Overall, the engineering protein PAPB could be a promising drug candidate for solid tumor immunotherapy.

Automated summary

This study developed a Protease-Activated PSTAGylated BiTE called PAPB, which showed long-acting and highly effective anti-tumor activity in solid tumors. PAPB could release BiTE core to exert its therapeutic effect, and significantly increase T lymphocyte infiltration in tumor tissue. This engineered protein has potential as a promising drug candidate for solid tumor immunotherapy.