Department of Pharmaceutics, University of Minnesota, Minneapolis, USA.
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, USA.
Sci Rep. 2021 Feb 8;11(1):3346. doi: 10.1038/s41598-021-83005-6.
There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with monoclonal antibody therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response.
人们对于设计能够增强抗体依赖的细胞介导的细胞毒性（ADCC）的治疗药物非常感兴趣，从而改善已批准抗体的临床反应。我们最近报道了将咪唑并喹啉为基础的 TLR7/8 激动剂（522）与单克隆抗体联合使用，可在体外和体内提高 ADCC。在本研究中，我们测试了几种新的小分子 TLR7/8 激动剂，与 FDA 批准的 TLR7 激动剂咪喹莫特和 522 相比，这些激动剂能诱导更高水平的细胞因子。我们评估了这些激动剂与单克隆抗体治疗的联合应用，主要目的是增强 ADCC。我们的研究表明，这些 TLR7/8 激动剂可诱导强烈的促炎细胞因子分泌并激活 NK 细胞。具体而言，我们发现激动剂 574 和 558 可显著增强体外 NK 细胞介导的 ADCC，以及在两种不同的体内小鼠模型中增强单克隆抗体的抗癌功效。此外，我们发现激动剂能够刺激 CD8 T 细胞，可能表明存在早期适应性免疫反应。
