PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way

• DOI: 10.1136/jitc-2022-004590
• Publication Date: 2022-10-17T15:11:20Z
• Authors: Xiaolu Yu; Yiru Long; Binfan Chen; Yongliang Tong; Mengwen Shan; Xiaomin Jia; Chao Hu; Meng Liu; Ji Zhou; Feng Tang; Henglei Lu; Runqiu Chen; Pan Xu; Wei Huang; Jin Ren; Yakun Wan; Jianhua Sun; Jia Li; Guangyi Jin; Likun Gong
• Keywords: TLR7

Background Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation serve as promising targets for combination enhance ICB Here, we aimed improve efficacy anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on PD-L1 nanobodies TLR7 agonist developed. Methods were obtained phage display screening identified through bioassay, in vivo imaging quantitative biodistribution study. Immune PD-L1-inducing of agonists evaluated diverse cell models. We constructed NDCs chemically coupling agonists. The antitumor effect was via several murine or humanized solid tumor Immunophenotyping, depletion, rechallenge, RNA sequencing PD-L1-deficient models combined determine mechanism function. dynamics behaviors assessed multiorgan changes levels. Results screened characterized tumor-targeting alleviated immunosuppression. induced broad responses intratumoral expression antigen-presenting cells (APCs), its dependent delivery. activated both immunity upregulated PD-L1-related signaling pathways. After form NDCs, exerted synergistic effects safety either ‘hot’ ‘cold’ early advanced models, reshaped microenvironment memory. CD8 + T natural killer main effector promote APCs cells, subsequently achieve targeted enrichment tumors. Moreover, is biased toward dependence host PD-L1. Conclusions novel NDC exhibited potent against heterogeneous orchestrating could act strategy shows prospects clinical development.