This work describes the enhancement of a novel antitumor therapeutic platform that combines advantages from small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine–citrulline (VCit) dipeptide linkers are commonly used cathepsin B cleavable linkers for ADCs. However, the instability of these linkers in mouse serum makes translating efficacy data from mouse to human more challenging. Replacing the VCit linker with glutamic acid–valine–citrulline (EVCit) has been reported to enhance the stability of ADCs in mouse serum. However, the effect of EVCit linker on the stability of SMDCs has not been reported. Here, we report that incorporating the EVCit linker in prostate-specific membrane antigen-targeting SMDCs, equipped with the transthyretin ligand AG10, resulted in conjugates with lower toxicity, an extended half-life, and superior therapeutic efficacy to docetaxel in a xenograft mouse model of prostate cancer. This should make SMDCs’ preclinical toxicity and efficacy data from mice more reliable for predicting human results.

中文翻译：

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通过连接基稳定和与运甲状腺素蛋白结合配体的缀合来增强基于 PSMA 的小分子药物缀合物的安全性和功效

这项工作描述了一种新型抗肿瘤治疗平台的增强，该平台结合了小分子药物偶联物（SMDC）和抗体药物偶联物（ADC）的优点。缬氨酸-瓜氨酸 (VCit) 二肽连接体是 ADC 常用的组织蛋白酶 B 可切割连接体。然而，小鼠血清中这些接头的不稳定性使得将小鼠的功效数据转化为人类更具挑战性。据报道，用谷氨酸-缬氨酸-瓜氨酸 (EVCit) 替换 VCit 连接子可增强小鼠血清中 ADC 的稳定性。然而，EVCit 连接子对 SMDC 稳定性的影响尚未见报道。在这里，我们报告称，在配备运甲状腺素蛋白配体 AG10 的前列腺特异性膜抗原靶向 SMDC 中掺入 EVCit 连接体，在异种移植小鼠模型中产生的缀合物具有较低的毒性、较长的半衰期和优于多西紫杉醇的治疗效果前列腺癌。这将使 SMDC 的临床前毒性和小鼠疗效数据更可靠地预测人类结果。