PO.ET02.04 · 实验与分子治疗
采用TMEAlinker和eribulin载荷的新型ALDC和ADC在临床前评估中展现出优异的安全性和疗效
Novel ALDC and ADC with TMEAlinker and eribulin payload demonstrate excellent safety and efficacy in preclinical evaluation
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肿瘤微环境（TME）中细胞外legumain的过表达在肿瘤侵袭和转移中发挥关键作用。TMEAlinker（TME激活型连接子）是legumain激活型连接子，已在legubicin（一种白蛋白药物偶联物，ALDC）的3期研究中获得临床概念验证（POC）。利用这一TMEAlinker平台，eribulin可通过TMEAlinker偶联至白蛋白或抗体，以生成新型ALDC和ADC。
QHL-1848是一种基于TMEAlinker、携带eribulin为载荷的ALDC。在体外和体内研究中，QHL-1848相较于游离载荷均表现出显著改善的安全性数据。在37℃的人血浆中，孵育7天后仅约0.5%的游离eribulin被释放，表明血浆稳定性高。QHL-1848在犬中的最大耐受剂量（MTD）为0.491 μmol/kg（QWx4），显示出相对于eribulin（MTD = 0.054 μmol/kg，犬QWx3）显著优越的安全性特征。在小鼠HT1080异种移植模型中，QHL-1848以1 μmol/kg给药3次的方案实现了大体积（750 mm³）肿瘤的完全消退。
IMD2128是一种靶向EGFR/c-Met的双特异性ADC，以药物抗体比（DAR）为2通过TMEAlinker偶联eribulin。IMD2128在多个异种移植模型中表现出强效的治愈性抗肿瘤活性，包括肺癌和胰腺癌，以单次3.75 mg/kg的剂量实现肿瘤完全清除。值得注意的是，IMD2128在对基于DXd的ADC耐药的模型中仍保持疗效。在食蟹猴中，IMD2128耐受性良好，最高非严重毒性剂量（HNSTD）超过16 mg/kg，相较于基于VC连接子-eribulin的ADC（例如MORAb-202，HNSTD = 1.95 mg/kg）显示出优越的安全性特征。猴体内药代动力学研究显示，IMD2128 ADC的Cmax为291.07 μmol/mL，而游离eribulin的Cmax为0.0000823 μmol/mL（Cmax比值≈3.54 × 10⁶ : 1），证实了在循环中强的连接子稳定性。总之，这些发现凸显了TMEAlinker平台在开发携带eribulin载荷的ALDC和ADC方面的多功能性，在临床前评估中展现出优异的安全性和疗效。
查看英文原文 English abstract
Overexpression of extracellular legumain in the tumor microenvironment (TME) plays a critical role in tumor invasion and metastasis. TMEAlinkers (TME-activated linkers) are legumain-activated linkers with clinical proof-of-concept (POC) from the phase 3 study of legubicin (an albumin drug conjugate, ALDC). Leveraging this TMEAlinker platform, eribulin can be conjugated to albumin or antibodies via TMEAlinker to generate novel ALDCs and ADCs.
QHL-1848 is a TMEAlinker-based ALDC carrying eribulin as payload. In both in vitro and in vivo studies, QHL-1848 exhibited markedly improved safety data compared with the free payload. In human plasma at 37 °C, only ~0.5% of free eribulin was released after 7 days of incubation, indicating high plasma stability. The maximum tolerated dose (MTD) of QHL-1848 was 0.491 µmol/kg (QWx4) in dogs, displaying a significantly superior safety profile relative to eribulin (MTD = 0.054 µmol/kg, QWx3 in dogs). In murine HT1080 xenograft models, QHL-1848 achieved complete tumor regression of large (750 mm³) tumors with a dosing regimen of 1 µmol/kg given 3 times.
IMD2128, a bispecific ADC targeting EGFR/c-Met, is conjugated with eribulin via TMEAlinker at a drug-to-antibody ratio (DAR) of 2. IMD2128 demonstrated potent curative antitumor activities across multiple xenograft models, including lung and pancreatic carcinomas, achieving complete tumor elimination with a single dose of 3.75 mg/kg. Remarkably, IMD2128 retained efficacy in models resistant to DXd-based ADCs. In cynomolgus monkeys, IMD2128 was well tolerated with a highest nonseverely toxic dose (HNSTD) over 16 mg/kg, showing a superior safety profile compared to VC linker-eribulin based ADCs (e.g., MORAb-202, HNSTD = 1.95 mg/kg). Pharmacokinetic studies in monkeys revealed a Cmax of 291.07 µmol/mL for IMD2128 ADC versus a Cmax of 0.0000823 µmol/mL for free eribulin (Cmax ratio ≈ 3.54 × 10⁶ : 1), confirming strong linker stability in circulation. Together, these findings highlight the versatility of the TMEAlinker platform for developing both ALDCs and ADCs with eribulin payloads, demonstrating excellent safety and efficacy in preclinical evaluations.
利益披露 Disclosure
T. Chen,
Affinity Biopharmaceutical Co., Ltd. Employment, Stock.
C. Liu,
Affinity Biopharmaceutical Co., Ltd. Employment, Stock.
Y. Liu,
Affinity Biopharmaceutical Co., Ltd. Employment, Stock.