化学
TLR7型
药理学
体内
连接器
体外
Toll样受体
生物化学
受体
先天免疫系统
生物
计算机科学
操作系统
生物技术
作者
Michael G. Brant,Graham A. E. Garnett,Joy Guedia,Manuel Lasalle,Samuel Lawn,Matthew J. Petersen,Renee Duan,José Méndez-Campos,Truman Hirkala-Schaefer,Geoffrey C. Winters,Stuart D. Barnscher
标识
DOI:10.1016/j.bmcl.2023.129348
摘要
Pairing immunostimulatory small molecules with the targeting capability of an antibody has emerged as a novel therapeutic modality with the potential to treat a variety of solid tumors. A series of compounds based on an imidazo-thienopyridine scaffold were synthesized and tested for their ability to agonize the innate immune sensors toll-like receptor 7 and 8 (TLR7/8). Structure-activity relationship (SAR) studies revealed that certain simple amino-substituents could enable TLR7 agonism at low nanomolar concentrations. Drug-linkers containing either payload 1 or 20h were conjugated to the HER2-targeting antibody trastuzumab at the interchain disulfide cysteine residues using a cleavable valine-citrulline dipeptide linker and stochastic thiol-maleimide chemistry. In vitro, these immune-stimulating antibody drug-conjugates (ADCs) were found to induce cytokine release in a murine splenocyte assay when co-cultured with the HER2-high NCI-N87 cancer cell line. In vivo, tumor regression was observed with a single dose in an NCI-N87 gastric carcinoma xenograft model in BALB/c nude mice.
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