PO.CL07.05 · 临床研究
靶向肿瘤内皮细胞和癌细胞的抗PRND抗体药物偶联物用于治疗胶质母细胞瘤和肉瘤等富血管肿瘤
Tumor endothelial cell and cancer cell targeting anti-PRND antibody-drug conjugate to treat hypervascular tumors such as glioblastoma and sarcomas
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
抗体药物偶联物（ADCs）已成为靶向治疗药物的一大类别，但仍受限于肿瘤穿透性差、抗原异质性以及治疗窗口狭窄。为克服这些局限，我们开发了一种靶向PRND（Doppel）的抗PRND ADC，PRND是一种朊病毒样糖蛋白，选择性地表达于肿瘤内皮细胞（TECs）和癌细胞，但除睾丸外在正常组织中不存在。这种定位使得无需扩散屏障即可实现直接的血管靶向，并为向肿瘤血管系统精确递送药物提供了独特的机会。所得抗体药物偶联物3H9-KGDEVD-MMAE是一种均质ADC（DAR = 8），不含可溶性聚集体。它将高亲和力抗PRND抗体（3H9）与一种caspase/组织蛋白酶B可切割的KGDEVD连接子偶联，该连接子可被组织蛋白酶B和caspase-3/7特异性切割。这种双重激活使MMAE通过溶酶体组织蛋白酶B释放并诱导PRND阳性细胞凋亡，而靶细胞凋亡产生的caspase-3/7诱导邻近肿瘤组织凋亡。caspase介导的切割建立了一个原位反馈放大环路，维持持续的局部药物释放、持久的细胞毒性，并产生强大的旁观者效应以克服抗原异质性。通过将TEC和癌细胞特异性靶向与caspase/组织蛋白酶响应性连接子相结合，3H9-KGDEVD-MMAE（抗PRND ADC）实现了深度瘤内穿透、强大的血管破坏和持久的抗肿瘤疗效。在胶质母细胞瘤、肉瘤和肾细胞癌（RCC）等ADC选择有限的富血管恶性肿瘤临床前模型中，抗PRND ADC诱导了广泛而持久的肿瘤消退，且无全身毒性。总的来说，这些发现确立了抗PRND ADC作为一种新一代血管破坏性ADC，将内皮对接与凋亡触发的药物放大整合起来，以强效且选择性地控制高度血管化的肿瘤。
致谢：本研究由韩国科学技术信息通信部资助的韩国药物开发基金（HN21C0264）以及韩国政府（MSIT）资助的韩国研究基金会（NRF）拨款（2020R1A2C2015026）支持。
查看英文原文 English abstract
Antibody-drug conjugates (ADCs) have emerged as a major class of targeted therapeutics but remain limited by poor tumor penetration, antigen heterogeneity, and a narrow therapeutic window. To overcome these limitations, we developed an anti-PRND ADC targeting PRND (Doppel), a prion-like glycoprotein selectively expressed in tumor endothelial cells (TECs) and cancer cells but absent in normal tissues except in the testis. This localization enables direct vascular targeting without diffusion barriers and provides a unique opportunity for precise drug delivery to the tumor vasculature. The resulting antibody-drug conjugate, 3H9-KGDEVD-MMAE, is a homogeneous ADC (DAR = 8) free of soluble aggregates. It couples a high-affinity anti-PRND antibody (3H9) with a caspase/cathepsin B-cleavable KGDEVD linker that can be specifically cleaved by both cathepsin B and caspase-3/7. This dual activation allows MMAE release through lysosomal cathepsin B and induces apoptosis of PRND positive cells, and caspase-3/7 from the apoptosis of target cells induces the apoptosis of adjacent tumor tissues. The caspase-mediated cleavage establishes an in-situ feedback amplification loop that maintains continuous local drug release, sustained cytotoxicity, and producing a potent bystander effect that overcomes antigen heterogeneity. By combining TEC and cancer cell-specific targeting with a caspase/cathepsin-responsive linker, 3H9-KGDEVD-MMAE (anti-PRND ADC), achieves deep intratumoral penetration, robust vascular disruption, and durable antitumor efficacy. In preclinical models of glioblastoma, sarcoma, and renal cell carcinoma (RCC) - hypervascular malignancies with limited ADC options, anti-PRND ADC induced extensive and durable tumor regressions without systemic toxicity. Collectively, these findings establish anti-PRND ADC as a next-generation vascular-disrupting ADC, integrating endothelial docking with apoptosis-triggered drug amplification for potent and selective control of highly vascularized tumors.
Acknowledgments: This research was supported by the Korea Drug Development Fund (HN21C0264) funded by the Ministry of Science and ICT and the National Research Foundation of Korea (NRF) grant (2020R1A2C2015026) funded by the Korea government (MSIT).
利益披露 Disclosure
B. Kim, None..
H. Lee, None..
S. Choi, None..
S. Lee, None..
S. Kim, None..
Y. Byun, None.