Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
J Med Chem. 2024 Aug 22;67(16):13959-13974. doi: 10.1021/acs.jmedchem.4c00753. Epub 2024 Jul 23.
Traditional antibody-drug conjugates (ADCs) mainly suppress tumor growth through either chemotherapy with cytotoxic payloads or immunotherapy with immuno-modulators. However, a single therapeutic modality may limit their exploration. Herein, we developed a new type of drug conjugate termed CAR-EDC (CAR-M-derived exosome-drug conjugate) by using CAR-exosomes from CAR-M cells as the targeting drug carrier that contains a high level of CXCL10. CAR-exosomes could significantly enhance the immunological activation and migratory capacity of T lymphocytes and promote their differentiation into CD8+ T cells. It also increased the proportion of M1 macrophages. The CAR-EDC, covalently loaded with SN-38, was internalized into Raji cells through endocytosis mediated by the CAR molecules. It exerted excellent antitumor activity in vivo by virtue of not only chemotherapy by SN38 but also immunotherapy by CXCL10-mediated antitumor immunity. Generally, this study provides an exosome-drug conjugate system with enhanced antitumor effects over traditional ADCs through the synergism of chemotherapy and immunotherapy.
传统抗体药物偶联物（ADCs）主要通过细胞毒药物有效载荷的化疗或免疫调节剂的免疫疗法来抑制肿瘤生长。然而，单一的治疗方式可能限制了它们的探索。在此，我们通过使用源自 CAR-M 细胞的 CAR-外泌体作为靶向药物载体，开发了一种新型药物偶联物，称为 CAR-EDC（CAR-M 衍生的外泌体-药物偶联物），其中包含高水平的 CXCL10。CAR-外泌体可以显著增强 T 淋巴细胞的免疫激活和迁移能力，并促进其分化为 CD8+T 细胞。它还增加了 M1 巨噬细胞的比例。CAR-EDC 通过 CAR 分子介导的内吞作用将 SN-38 共价加载到 Raji 细胞中。它通过 SN-38 的化疗和 CXCL10 介导的抗肿瘤免疫的免疫疗法，在体内发挥了优异的抗肿瘤活性。总的来说，这项研究通过化疗和免疫疗法的协同作用，提供了一种具有增强抗肿瘤效果的外泌体药物偶联物系统，优于传统 ADC。
