Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
Biomaterials. 2021 Mar;270:120685. doi: 10.1016/j.biomaterials.2021.120685. Epub 2021 Jan 22.
The interaction of programmed cell death 1 ligand 1 (PD-L1) with its receptor, programmed cell death 1 (PD-1), inhibits T cell responses. Monoclonal antibodies that block this interaction have been shown effective as immunotherapy. However, only a subset of cancers exhibits a durable response to PD-1/PD-L1 blockade. Moreover, antibody-based immune checkpoint blockade is costly and is occasionally accompanied by systemic side effects. To overcome these limitations of antibody-based immune checkpoint blockade, an immune checkpoint-blocking ferritin nanocage displaying 24 PD-L1 binding peptides (PD-L1pep1) on its surface was designed and constructed. These ferritin nanocages displaying PD-L1pep1 (PpNF) specifically bind to PD-L1 expressed on cancer cells or to purified PD-L1 with a ~30 nM binding affinity. The addition of PpNF to co-cultures of T cells and cancer cells inhibited PD-1/PD-L1 interactions and restored T cell activities. In a mouse model of syngeneic colon cancer, PpNF specifically targeted tumors and showed antitumor activity. Moreover, PpNF nanocages encapsulating the chemotherapeutic drug doxorubicin had more potent antitumor activity than a monoclonal antibody against PD-L1. These results demonstrate that ferritin nanocages displaying surface PD-L1pep1 can be efficiently applied for immunotherapy, especially when encapsulating small chemotherapeutic drugs. These nanocages may have promise as an immunotherapeutic nanomedicine against various solid tumors.
程序性细胞死亡蛋白 1 配体 1（PD-L1）与其受体程序性细胞死亡蛋白 1（PD-1）的相互作用抑制了 T 细胞的反应。已证明阻断这种相互作用的单克隆抗体作为免疫疗法是有效的。然而，只有一部分癌症对 PD-1/PD-L1 阻断有持久的反应。此外，基于抗体的免疫检查点阻断费用高昂，偶尔伴有全身副作用。为了克服基于抗体的免疫检查点阻断的这些限制，设计并构建了一种表面展示 24 个 PD-L1 结合肽（PD-L1pep1）的免疫检查点阻断铁蛋白纳米笼。这些展示 PD-L1pep1 的铁蛋白纳米笼（PpNF）特异性结合癌细胞表面表达的 PD-L1 或与纯化的 PD-L1 以约 30 nM 的结合亲和力结合。将 PpNF 添加到 T 细胞和癌细胞的共培养物中，抑制了 PD-1/PD-L1 相互作用并恢复了 T 细胞的活性。在同源结肠癌的小鼠模型中，PpNF 特异性靶向肿瘤并表现出抗肿瘤活性。此外，封装化疗药物阿霉素的 PpNF 纳米笼比针对 PD-L1 的单克隆抗体具有更强的抗肿瘤活性。这些结果表明，表面展示 PD-L1pep1 的铁蛋白纳米笼可以有效地应用于免疫治疗，特别是在封装小化疗药物时。这些纳米笼可能有望成为针对各种实体瘤的免疫治疗纳米医学。
