PO.ET02.03 · 实验与分子治疗
靶向人乳腺癌和胃癌的C2LP-ADC与CLP2-ADC的体外和体内研究
In vitro and in vivo study of C 2 LP-ADC & CLP 2 -ADC targeting human breast and gastric cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
抗体药物偶联物是一类靶向抗癌治疗药物，将单克隆抗体的特异性与细胞毒性药物的效力相结合。这种设计能够将药物选择性地递送至癌细胞，同时避免损伤健康组织。这些疗法开发中仍存在的一些挑战包括治疗窗口狭窄以及由于载荷非特异性释放导致的显著脱靶毒性。另一个主要挑战是肿瘤耐药。凭借我们在连接子合成方面的经验，我们着手设计新一代连接子，以解决ADC开发中的持续挑战。我们的策略核心是创建一个包含两个不同切割事件的切割级联系统，增强连接子的稳健性并降低非特异性载荷释放的风险（C2LP-ADC）。作为耐药问题的潜在解决方案，我们设计了能够定制药物-抗体比（DAR）的连接子，从而实现多种载荷的整合（CLP2-ADC）。我们使用C2LP和CLP2连接子合成并偶联了已知抗HER癌症ADC的类似物。在体外和体内将C2LP与参比ADC进行比较，显示出改善的治疗指数和降低的脱靶毒性，受试对象维持体重的时间长于接受参比ADC治疗者。此外，连接子-载荷复合物在血浆中的稳定性证明远长于参比ADC。用CLP2-ADC体外处理耐药细胞系显示出相对于参比ADC增强的治疗疗效。这些发现凸显了连接子技术在优化ADC性能中的关键作用。整合C2LP和CLP2连接子可显著改善靶向HER阳性乳腺癌和胃癌的ADC的安全性、稳定性和治疗疗效，为克服耐药和最小化全身毒性提供了一种有前景的策略。
查看英文原文 English abstract
Antibody-Drug Conjugates are a class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic agents. This design enables selective delivery of the agents to cancer cells, while avoiding healthy tissue. Some of the challenges that remain with the development of these treatments is the narrowness of the therapeutic window and significant off target toxicity due to non-specific release of the payload. One of the other major challenges is tumor resistance. Leveraging our experience in linker synthesis, we set out to design next-generation linkers that address the persistent challenges of ADC development. Our strategy centered on creating a cleavage cascade system incorporating two distinct cleavage events, enhancing linker robustness and reducing the risk of non-specific payload release (C 2 LP-ADC). As a potential solution to drug resistance, we engineered linkers with the ability to tailor the Drug-to-Antibody Ratio (DAR), enabling incorporation of multiple payloads (CLP 2 -ADC). We synthesized and conjugated analogues of known ADCs for Anti-HER cancers using both C 2 LP and CLP 2 linkers. The C 2 LP was compared in vitro and in vivo to a reference ADC, demonstrating improved therapeutic index and decreased off-target toxicity, with the test subjects maintaining body mass for longer than those treated with the reference-ADC. In addition, the linker-payload complex was demonstrated to be stable in plasma for much longer than the reference-ADC. In vitro treatment of resistant cell lines with CLP 2 -ADC demonstrated enhanced therapeutic efficacy with respect to the reference-ADC.These findings highlight the critical role of linker technology in optimizing ADC performance. Incorporation of C 2 LP and CLP 2 linkers can substantially improve safety, stability, and therapeutic efficacy in ADCs targeting HER-positive breast and gastric cancers, offering a promising strategy for overcoming resistance and minimizing systemic toxicity.
利益披露 Disclosure
X. Ma, None..
G. Liang, None..
W. Shi, None..
B. Li, None..
S. Lu, None..
X. Yang, None..
Q. Chen, None..
G. Wang, None..
Y. Ma, None.