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Discovery and Evaluation of TLR-Targeted Immune Agonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-05 , DOI: 10.1021/acs.jmedchem.4c00804 Natalia Chernyak 1 , Bhagyashree Bhagwat 2 , Saraswathi Naravula 2 , Ying Chen 3 , Nicolas Solban 4 , Fan Zhang 2 , Esther Kofman 2 , Fahimeh Raoufi 2 , Xibei Dang 3 , Jianming Bao 1 , Daniela Tomazela 2 , Marc Baily 2 , Bernhard Geierstanger 2 , John A Flygare 1 , Jin-Hwan Han 5 , Aarron Willingham 2 , W Michael Seganish 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-05 , DOI: 10.1021/acs.jmedchem.4c00804 Natalia Chernyak 1 , Bhagyashree Bhagwat 2 , Saraswathi Naravula 2 , Ying Chen 3 , Nicolas Solban 4 , Fan Zhang 2 , Esther Kofman 2 , Fahimeh Raoufi 2 , Xibei Dang 3 , Jianming Bao 1 , Daniela Tomazela 2 , Marc Baily 2 , Bernhard Geierstanger 2 , John A Flygare 1 , Jin-Hwan Han 5 , Aarron Willingham 2 , W Michael Seganish 1
Affiliation
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Toll-like receptor (TLR) activation converts immunologically inactive tumors into immunologically active tumors by activating tumor residing antigen-presenting cells and recruitment of cytotoxic T lymphocytes. Targeted immune agonists (TIAs) are antibody drug conjugates with small-molecule TLR agonist payloads. The mechanism of action of TIAs involves tumor antigen recognition, Fcγ-receptor-dependent phagocytosis, and TLR-mediated activation to drive tumor killing by myeloid cells. Several new low DAR anti-HER2 TIAs conjugated with novel TLR7 or dual-TLR7/8 agonists with cleavable and noncleavable linkers were synthesized and profiled. In vitro studies demonstrated that these TIAs activate myeloid cells only in the presence of antigen-expressing cancer cells. Evaluation in ELISpot-based assays confirmed the low immunogenicity of these constructs. Systemic administration of the novel TIAs in tumor-bearing mice resulted in tumor reduction at low doses. These results provide a strong rationale for further development of the TIAs as a novel class of immunotherapeutics.
中文翻译：
TLR 靶向免疫激动剂的发现和评估
Toll 样受体 (TLR) 激活通过激活肿瘤驻留的抗原呈递细胞和招募细胞毒性 T 淋巴细胞，将免疫不活跃的肿瘤转化为免疫活跃的肿瘤。靶向免疫激动剂 (TIA) 是具有小分子 TLR 激动剂有效负载的抗体药物缀合物。 TIA 的作用机制涉及肿瘤抗原识别、Fcγ 受体依赖性吞噬作用以及 TLR 介导的激活以驱动骨髓细胞杀死肿瘤。合成并分析了几种新的低 DAR 抗 HER2 TIA，它们与具有可裂解和不可裂解接头的新型 TLR7 或双 TLR7/8 激动剂缀合。体外研究表明，这些 TIA 仅在存在表达抗原的癌细胞时才激活骨髓细胞。基于 ELISpot 的检测评估证实了这些构建体的低免疫原性。在荷瘤小鼠中全身施用新型 TIA 可以在低剂量下实现肿瘤缩小。这些结果为进一步开发 TIA 作为一类新型免疫治疗药物提供了强有力的理由。
更新日期：2024-09-05
中文翻译：
TLR 靶向免疫激动剂的发现和评估
Toll 样受体 (TLR) 激活通过激活肿瘤驻留的抗原呈递细胞和招募细胞毒性 T 淋巴细胞，将免疫不活跃的肿瘤转化为免疫活跃的肿瘤。靶向免疫激动剂 (TIA) 是具有小分子 TLR 激动剂有效负载的抗体药物缀合物。 TIA 的作用机制涉及肿瘤抗原识别、Fcγ 受体依赖性吞噬作用以及 TLR 介导的激活以驱动骨髓细胞杀死肿瘤。合成并分析了几种新的低 DAR 抗 HER2 TIA，它们与具有可裂解和不可裂解接头的新型 TLR7 或双 TLR7/8 激动剂缀合。体外研究表明，这些 TIA 仅在存在表达抗原的癌细胞时才激活骨髓细胞。基于 ELISpot 的检测评估证实了这些构建体的低免疫原性。在荷瘤小鼠中全身施用新型 TIA 可以在低剂量下实现肿瘤缩小。这些结果为进一步开发 TIA 作为一类新型免疫治疗药物提供了强有力的理由。
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