文章目录

免疫刺激抗体偶联物可引起强大的髓细胞激活和持久的抗肿瘤免疫

原文发布日期：2020-12-07

英文摘要：

摘要翻译：

原文链接：

文章：

免疫刺激抗体偶联物可引起强大的髓细胞激活和持久的抗肿瘤免疫

Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

原文发布日期：2020-12-07

英文摘要：

Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2− parental tumor. These results provide a strong rationale for the clinical development of ISACs.

摘要翻译：

固有模式识别受体激动剂，包括Toll样受体（TLR），改变肿瘤微环境并促进适应性抗肿瘤免疫反应。然而，系统给药的Toll样受体激动剂与广泛免疫激活相关的毒性相关。为了设计一种适合系统给药、能够安全激发肿瘤靶向应答的基于Toll样受体的治疗，我们开发了免疫刺激抗体结合物（ISACs），这些结合物由TLR 7/8 双重激动剂结合至肿瘤靶向抗体组成。经系统注射的HER2-靶向 ISACs 被广泛耐受，并在肿瘤微环境中诱发局部免疫应答，导致肿瘤清除和免疫记忆。机制上，ISACs 需要肿瘤抗原识别、Fcγ-R依赖性 phagocytosis 和TLR介导激活，从而由白细胞杀伤肿瘤细胞并随后由 T 细胞介导的抗肿瘤免疫反应。此外，ISAC-治疗的小鼠在再挑战带有HER2-背景的肿瘤时也能得到保护。这些结果为 ISAC 在临床开发中的进一步研究提供了有力支持。