Bispecific Aptamer-Based Recognition-then-Conjugation Strategy for PD1/PDL1 Axis Blockade and Enhanced Immunotherapy
Yang Sun, Liuting Mo, Xiaoxiao Hu, Die Yu, Sitao Xie, Jianglin Li, Zilong Zhao, Xiaohong Fang, Mao Ye, Liping Qiu, Weihong Tan, Yu Yang
Abstract
Cytotoxic T cells initiate antitumor effects mainly through direct interactions with tumor cells. As a counter to this, tumor cells can put the brakes on such T-cell activity via specific linkage between programmed death ligand 1 (PDL1) and its receptor programmed cell death protein 1 (PD1). Bispecific inhibitors that enabled synchronous blockade of PD1 and PDL1, thereby releasing the brakes on T-cell antitumor activity, should significantly improve the efficacy of immune checkpoint blockade (ICB) therapy. In this work, we identified a DNA aptamer, Ap3, that could specifically recognize PDL1 on tumor cells and competed with the binding of PD1. By integrating Ap3 with an anti-PD1 aptamer, the bispecific aptamer Ap3–7c was constructed, and it showed promise for improving the T-cell immune response. We further designed a dibenzocyclooctyne (DBCO)-labeled bispecific aptamer, D-Ap3–7c, allowing covalent conjugation of aptamers onto PD1 and PDL1 after specific cell recognition. Our in vivo studies showed that this recognition-then-conjugation strategy could induce a potent immunological effect against tumors. This work is expected to provide clues for antitumor immunotherapy.