PO.ET02.11 · 实验与分子治疗
针对pan-mKRAS或PTEN缺失肿瘤的靶向肽药物偶联物（Maleimide-KGDEVD-Doxorubicin/Exatecan）的1期临床试验中期结果
Interim results of clinical trial phase 1 of pan-mKARS or PTEN loss tumor targeting peptide drug conjugates (Maleimide-KGDEVD-Doxorubicin/Exatecan)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
mKRAS和PTEN改变在多种癌症类型中高度普遍——约45%的结直肠癌（CRC）和高达30-50%的非小细胞肺癌（NSCLC）中发生——但它们在很大程度上仍不可成药。这些恶性肿瘤表现出增强的白蛋白代谢和巨胞饮作用，以维持其升高的代谢需求，为选择性的、代谢导向的药物递送提供了独特的机会。我们开发了下一代白蛋白结合型肽药物偶联物（PDC）平台，以靶向mKRAS和/或PTEN缺失肿瘤。先导候选物MPD-1（Maleimide-KGDEVD-Doxorubicin）代表了该系列中首个临床阶段原型。MPD-1将用于共价白蛋白偶联的马来酰亚胺锚定物与一个双可切割的KGDEVD连接子偶联，后者对cathepsin B和caspase-3/7均有响应，能够在肿瘤微环境内实现高度选择性、凋亡响应性的载荷释放。这种双触发机制通过溶酶体cathepsin B活性确保doxorubicin在细胞内的释放，并通过邻近凋亡细胞中的caspase-3/7切割进行二次放大——通过原位反馈放大和强效旁观者效应维持细胞毒活性。临床前研究表明，MPD-1在mKRAS突变型结直肠癌和PTEN缺失型NSCLC模型中表现出强大的抗肿瘤疗效，全身毒性约比游离doxorubicin低十倍。与放疗、PARP抑制、DNA-PK阻断或免疫治疗的联合方案产生了进一步的协同效应。正在进行的I期临床试验[NCT06944457]是一项开放标签、单中心、剂量递增和剂量探索试验，旨在评估MPD-1在晚期mKRAS和/或PTEN缺失实体瘤患者中的MTD、RP2D和药代动力学。我们将报告MPD-1作为一种首创的、caspase/cathepsin响应性、白蛋白结合型肽药物偶联物的临床研究中期结果。我们接下来将MPD-5（Maleimide-KGDEVD-Exatecan）工程改造为经优化以获得更高效力的第二代偶联物。MPD-5将该平台扩展至拓扑异构酶I抑制，并在多种mKRAS癌症和PTEN缺失癌症中显示出更优的疗效。
致谢：本研究由韩国药物开发基金（HN21C0264）支持。
查看英文原文 English abstract
mKRAS and PTEN alterations are highly prevalent across multiple cancer types - occurring in approximately 45% of colorectal cancers (CRC) and up to 30-50% of non-small cell lung cancers (NSCLC) - yet they remain largely undruggable. These malignancies exhibit enhanced albumin metabolism and macropinocytosis to sustain their elevated metabolic demands, presenting a unique opportunity for selective, metabolism-guided drug delivery. We developed a next-generation platform of albumin-binding peptide drug conjugates (PDCs) to target mKRAS and/or PTEN loss tumors. The lead candidate, MPD-1 (Maleimide-KGDEVD-Doxorubicin), represents the first clinical-stage prototype in this series. MPD-1 couples a maleimide anchor for covalent albumin conjugation with a dual-cleavable KGDEVD linker that responds to both cathepsin B and caspase-3/7, enabling highly selective, apoptosis-responsive payload release within the tumor microenvironment. This dual-trigger mechanism ensures intracellular liberation of doxorubicin through lysosomal cathepsin B activity and secondary amplification via caspase-3/7 cleavage in neighboring apoptotic cells - sustaining cytotoxic activity through in-situ feedback amplification and a potent bystander effect. Preclinical studies demonstrated that MPD-1 exhibits strong antitumor efficacy in mKRAS -mutant colorectal and PTEN -loss NSCLC models, with approximately ten-fold lower systemic toxicity than free doxorubicin. Combination regimens with radiation, PARP inhibition, DNA-PK blockade, or immunotherapy yielded further synergistic effects. The ongoing Phase I clinical trial [NCT06944457] is open-label, single-center, dose-escalation and dose-finding trial to evaluate the MTD, RP2D and pharmacokinetics of MPD-1 in patients with advanced mKRAS and/or PTEN loss solid tumors. We are going to report the interim results of clinical study of MPD-1 as a first-in-class, caspase/cathepsin-responsive, albumin-binding peptide drug conjugate. We next engineered MPD-5 (Maleimide-KGDEVD-Exatecan) as a second-generation conjugate optimized for higher potency. MPD-5 extends the platform to topoisomerase I inhibition, and it showed superior efficacy in various mKRAS cancers and PTEN loss cancers.
Acknowledgments: This research was supported by the Korea Drug Development Fund (HN21C0264).
利益披露 Disclosure
B. Kim, None..
H. Lee, None..
Y. Ko, None..
K. Kim, None..
Y. Byun, None.