Toll 样受体 7 和 8 参与调节适应性和先天免疫反应，它们的激活已显示出作为免疫肿瘤学领域的治疗策略的前景。虽然全身暴露于 TLR7/8 激动剂可能会导致耐受性差，但联合疗法和通过抗体药物偶联物 (ADC) 进行靶向递送可以帮助减轻不良反应。本文描述了一系列新型有效的基于吡唑并嘧啶的 TLR7/8 激动剂的鉴定，该激动剂具有可调节的受体选择性。该系列的代表性激动剂能够成功诱导人外周血单核细胞产生各种促炎细胞因子和趋化因子。由此类有效负载制成的抗 HER2-25 和抗 HER2-26 ADC 在 THP1/N87 共培养系统中证明了 TLR7/8 的基于机制的激活。

Toll-like receptors 7 and 8 are involved in modulating the adaptive and innate immune responses, and their activation has shown promise as a therapeutic strategy in the field of immuno-oncology. While systemic exposure to TLR7/8 agonists can result in poor tolerance, combination therapies and targeted delivery through antibody-drug conjugates (ADCs) can help mitigate adverse effects. Described herein is the identification of a novel and potent series of pyrazolopyrimidine-based TLR7/8 agonists with tunable receptor selectivity. Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.