{“_”：“NH三甲基锁（NH-TML）：基于艾替康的抗体-药物偶联物的稳定有效的适配器。”，“sub”：[“2”，“2”]}
{"_":"NH-trimethyl lock (NH-TML): a stable and effective adapter for exatecan-based antibody-drug conjugates.","sub":["2","2"]}
摘要(中文译文)
连接子的稳定性在抗体偶联药物（ADC）的开发中起着关键作用。稳定的连接策略可减轻脱靶毒性并提高治疗疗效。本研究基于三甲基锁（TML）系统，开发了一种NH-TML适配器，能够通过酰胺键直接连接肽链。利用该适配器，将三条肽链——Val-Ala、Gly-Gly-Phe-Gly和Gly-Phe-Leu-Gly——分别偶联，合成了连接子-载荷W1507、W2707和W2907。为进行比较，还合成了含有广泛使用的对氨基苄基氨基甲酸酯（PABC）间隔基的化合物JOEP4和JOEP8，以证明酰胺键比酯键具有更优的稳定性。研究表明，与W2707、W2907和JOEP4相比，W1507具有更好的水溶性，在ADC开发中具有更大优势。尽管化合物W1507未释放游离载荷，但在体外组织蛋白酶B介导的释放试验中检测到了Exatecan，使用NH-TML适配器设计并合成的ADC Her2-W1507在NCI-N87异种移植肿瘤模型中体内表现出与含PABC间隔基的ADC Her2-JOEP8相当的抗肿瘤活性。这表明体内还涉及其他酶促过程。这些发现凸显了NH-TML系统在ADC设计和癌症治疗中的潜力。
Abstract
The stability of the linker plays a critical role in the development of antibody-drug conjugates (ADCs). A stable linkage strategy can mitigate off-target toxicity and enhance therapeutic efficacy. In this study, an NH-TML adapter, capable of directly connecting peptide chains via an amide bond, was developed based on the trimethyl lock (TML) system. Using this adapter, three peptide chains-Val-Ala, Gly-Gly-Phe-Gly, and Gly-Phe-Leu-Gly-were conjugated to synthesize the linker-payloads W1507, W2707, and W2907, respectively. For comparison, compounds JOEP4 and JOEP8, which contain the widely used p-aminobenzyl carbamate (PABC) spacer, were also synthesized, for demonstrating that the amide linkage exhibits superior stability over ester bonds. Studies indicated that W1507 possesses better aqueous solubility compared to W2707, W2907, and JOEP4, affording it greater advantages in ADC development. Although the compound W1507 did not release free payload Exatecan was detected in in vitro cathepsin B-mediated release assay, the ADC Her2-W1507 designed and synthesized using the NH-TML adapter exhibited antitumor activity comparable to that of ADC Her2-JOEP8 with PABC spacers in vivo the NCI-N87 xenograft tumor models. This suggests the involvement of additional enzymatic processes in vivo. These findings underscore the potential of the NH-TML system in ADC design and cancer therapy.
如何引用
AMA
Xuzhuo Li, Lizhe Bai, Xiaomei Li, Xing Jiang, Jiahui Yu, Yunyun Guo, et al. {"_":"NH-trimethyl lock (NH-TML): a stable and effective adapter for exatecan-based antibody-drug conjugates.","sub":["2","2"]}. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.110038.
APA
Xuzhuo Li, Lizhe Bai, Xiaomei Li, Xing Jiang, Jiahui Yu, Yunyun Guo, et al (2026). {"_":"NH-trimethyl lock (NH-TML): a stable and effective adapter for exatecan-based antibody-drug conjugates.","sub":["2","2"]}. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.110038
GB/T 7714
Xuzhuo Li, Lizhe Bai, Xiaomei Li, Xing Jiang, Jiahui Yu, Yunyun Guo, et al. {"_":"NH-trimethyl lock (NH-TML): a stable and effective adapter for exatecan-based antibody-drug conjugates.","sub":["2","2"]}[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.110038.
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