Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biology, School of Science, King Mongkut's Institute of Technology Ladkrabang, Bangkok 10520, Thailand.
Cell Chem Biol. 2024 May 16;31(5):904-919.e11. doi: 10.1016/j.chembiol.2024.02.014. Epub 2024 Mar 27.
Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engagement of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessitating novel approaches to enhance performance. Here, we report the development of antibody fusion proteins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The complementary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell activation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic antibodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes.
程序性死亡配体 1（PD-L1）通过与其受体程序性死亡-1（PD-1）在激活的 T 细胞上的结合，驱动抗原特异性 T 细胞反应的抑制。这些免疫检查点蛋白在肿瘤微环境中的过度表达促使设计了靶向抗体来破坏这种相互作用。尽管这些抗体具有临床成功，但反应率仍然很低，因此需要新的方法来提高疗效。在这里，我们报告了抗体融合蛋白的开发，这些融合蛋白通过靶向分子运输的独特机制阻断免疫检查点途径。通过与 PD-L1 上的多个受体表位结合，我们设计的多价抗体以表位和拓扑结构依赖性的方式快速诱导聚类、内化和降解。配体阻断和受体下调的互补机制导致更持久的免疫细胞激活，并显著降低了小鼠肿瘤中的 PD-L1 可及性。总的来说，这些多价抗体为免疫检查点蛋白运输及其如何被操纵以重新编程免疫结果提供了机制上的见解。
