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

• Published in: Journal of controlled release 2023-02, Vol.354, p.606-614
• Main Authors: Liu, Dingkang, Bao, Lichen, Zhu, Haichao, Yue, Yali, Tian, Jing, Gao, Xiangdong, Yin, Jun
• Format: Article
• Language: English
• Subjects: Bispecific antibody; BiTE; Matrix metalloproteinase 2; PD-L1; PSTAG
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.01.041

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 significantly increased infiltration of T lymphocytes in tumor tissue, and inhibited tumor proliferation without activating T-cells in the peripheral blood. Overall, the engineering protein PAPB could be a promising drug candidate for solid tumor immunotherapy. [Display omitted] •Protease-activated PSTAGylation could be a universal strategy for improving the druggability of BiTE.•Anti-PD-L1 × CD3 BiTE redirect T-cell to lyse PD-L1 positive tumor cells.•PSTAGylation extends the half-life of BiTE without activity compromise.•PAPB increased infiltrating T cells in PD-L1 positive tumor.•PSTAG polypeptide serves as a shielding domain to reduce the off-target effect of BiTE.