Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

• Published in: Acta pharmaceutica Sinica. B 2024-03, Vol.14 (3), p.1428-1440
• Main Authors: Lee, Youngjoo, Song, Sukyung, Yang, Suah, Kim, Jinseong, Moon, Yujeong, Shim, Nayeon, Yoon, Hong Yeol, Kim, Sehoon, Shim, Man Kyu, Kim, Kwangmeyung
• Format: Article
• Language: English
• Subjects: Anti-PD-L1 peptide; Cancer immunotherapy; Crosslinked lipid nanoparticles; Immune checkpoint blockade; Lysosomal PD-L1 degradation; Original; PD-L1 multivalent binding; PEGylated liposome; Tumor-targeting
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.09.007

Immune checkpoint blockade (ICB) therapy targeting PD-L1 via monoclonal antibody (mAb) has shown extensive clinical benefits in the diverse types of advanced malignancies. However, most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism. Herein, we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes (immune checkpoint blockade liposomes; ICB-LPs) to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells. The ICB-LPs are prepared by formulation of DC8,9PC with photo-polymerized diacetylenic moiety, 1,2-dipalmitoylphosphatidylcholine (DPPC) and anti-PD-L1 peptide (D-form NYSKPTDRQYHF)-conjugated DSPE-PEG2k (anti-PD-L1-DSPE-PEG2k) in a molar ratio of 45:45:10, followed by cross-linking of liposomal bilayer upon UV irradiation. The 10 mol% anti-PD-L1-DSPE-PEG2k incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7 ± 1.04 nm, showing a high stability in serum condition. Importantly, the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane, which are endocytosed with aim to deliver PD-L1 to the lysosomes, wherein the durable PD-L1 degradation is observed for 72 h, in contrast to anti PD-L1 mAbs showing the rapid PD-L1 recycling within 9 h. The in vitro co-culture experiments with CD8+ T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis. When ICB-LPs are intravenously injected into colon tumor-bearing mice, they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting, inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation. Collectively, this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosomes. Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes promote multivalent binding with PD-L1 on the tumor cell surface, thereby promoting lysosomal PD-L1 degradation and enhancing T cell-mediated antitumor immunity. [Display omitted]