从探针到前药：免疫蛋白酶体活性作为疾病选择性治疗药物的触发因素

From probe to prodrug: immunoproteasome activity as a trigger for disease-selective therapeutics.

期刊: Signal Transduction and Targeted Therapy
PMID: 42586964
原文: PubMed ↗
发布日期: 2026-08-13

作者

Cody A Loy — Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.
Yijun Gu — Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.
Samuel C Kim — Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Mariam V Mohagheghi — Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Noah B Trask — Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Marina Suarez-Pizarro — Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
Lisa E Wagar — Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Claudia A Benavente — Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.
Darci J Trader — Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA. dtrader@uci.edu.

作者单位

Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.
Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA. dtrader@uci.edu.

摘要

中文

开发能够利用细胞内源性机制在病变细胞中选择性释放毒性化合物，同时保持健康细胞不受影响的新策略是一项具有挑战性的任务。一种成熟的方法涉及肿瘤细胞上的抗原识别，通过可裂解连接子将细胞毒性化合物连接到抗体上，实现前药的靶向递送。然而，该策略依赖于高表达的表面标志物，并需开发相应抗体，从而限制了其在表达这些标志物的癌症中的适用性。一种可依赖细胞内酶疾病特异性表达的新方法，可能更广泛地靶向，从而在临床上扩展前药的治疗潜力。在此，我们证明免疫蛋白酶体（标准蛋白酶体的一种亚型，在炎症条件下上调）有潜力被用作前药释放酶。我们将高毒性且广泛使用的治疗性载荷MMAE偶联到免疫蛋白酶体选择性肽上，并证明其在癌细胞中以低nM至pM浓度选择性释放，而健康细胞保持活力。我们还建立了首次转化验证，即在体内使用免疫蛋白酶体前药可显著减小肿瘤体积，且在小细胞肺癌中无明显毒性。我们预计该方法将具有广泛适用性，因为免疫蛋白酶体在多种癌症中上调，且不需要抗体识别即可发挥作用。

English

Developing novel strategies that can exploit a cell's endogenous machinery to selectively release toxic compounds in diseased cells, while leaving healthy cells unaffected, is a challenging task to accomplish. An established approach involves antigen recognition on tumor cells, enabling targeted delivery of prodrugs in which a cytotoxic compound is appended to an antibody by a cleavable linker. However, this strategy depends on the presence of highly expressed surface markers for which antibodies can be developed, limiting its applicability to cancers that display these markers. A new approach that could rely on disease-specific expression of an intracellular enzyme, which can be more broadly targeted, could expand the therapeutic potential of prodrugs clinically. Here, we demonstrate that the immunoproteasome, an isoform of the standard proteasome that is upregulated under conditions of inflammation, has the potential to be harnessed as a prodrug release enzyme. We conjugate the highly toxic and widely used therapeutic cargo MMAE onto an immunoproteasome-selective peptide and demonstrate its selective release in cancerous cells at low nM to pM concentrations, while healthy cells remain viable. We also establish the first translational validation that using immunoproteasome prodrugs in vivo leads to a significant reduction in tumor volume without significant toxicities in small cell lung cancer. We anticipate this approach to be broadly applicable, as the immunoproteasome is upregulated in a variety of cancers and does not require antibody recognition to be effective.

分类与指标

研究类型: 基础研究
病种: 肺癌
JCR 分区: Q1
影响因子: 81.2
新锐分区: 1区