PO.CL05.04 · 临床研究
一种双特异性TROP2/PDL1抗体药物偶联物展现出增强的抗肿瘤活性和良好的安全性特征
A bispecific TROP2/PDL1 antibody-drug conjugate demonstrates enhanced antitumor activity and favorable safety profile
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的
本研究旨在开发并表征一种同时靶向TROP2和PDL1的双特异性抗体药物偶联物（ADC），以解决当前单靶点疗法在晚期癌症中的局限性。
方法
我们构建了一种针对TROP2和PDL1的人源化双特异性抗体（bsAb）（α TROP2/PDL1），随后使用优化的亲水连接子和TOP1抑制剂载荷制备了双特异性ADC。全面的体外表征包括结合亲和力、内化效率和PDL1降解检测。在多个异种移植模型中评估了体内疗效，同时在转基因小鼠和非人灵长类动物中进行了安全性评估。
结果
α TROP2/PDL1展现出强效的双特异性活性，具有高效的细胞结合和快速内化。该bsAb诱导了显著的PDL1内化和降解，并在MC-38-huTrop2/PDL1模型中显示出明显的肿瘤生长抑制。偶联TOP1i的bsAb ADC（α TROP2/PDL1-TOP1i）表现出增强的效力，特征为对多种表达Trop2/PDL1的细胞系具有强效细胞毒性、强效旁观者杀伤效应，以及在多个CDX模型中的肿瘤消退。值得注意的是，该ADC在食蟹猴中表现出优异的稳定性和耐受性，安全性研究中未观察到显著不良反应。
结论
α TROP2/PDL1-TOP1i代表了一种针对治疗耐药性癌症的有前景的治疗策略，有效地将PD1/PDL1免疫检查点阻断与TROP2靶向细胞毒性载荷递送相结合，同时保持良好的安全性特征，支持其推进至临床开发。
查看英文原文 English abstract
Purpose
This study aimed to develop and characterize a bispecific antibody-drug conjugate (ADC) targeting both TROP2 and PDL1, to address the limitations of current single-target therapies in advanced cancers.
Methods
We engineered a humanized bispecific antibody (bsAb) against TROP2 and PDL1 (alpha TROP2/PDL1), and subsequently produced the bispecific ADC using an optimized hydrophilic linker and TOP1 inhibitor payload. Comprehensive in vitro characterization encompassed binding affinity, internalization efficiency, and PDL1 degradation assays. In vivo efficacy was assessed across multiple xenograft models, while safety assessment was conducted in transgenic mice and non-human primates.
Results
alpha TROP2/PDL1 demonstrated potent bispecific activity, featuring efficient cellular binding and rapid internalization. The bsAb induced significant PDL1 internalization and degradation, and showed marked tumor growth inhibition in MC-38-huTrop2/PDL1 model. The bsAb TOP1i conjugated ADC (alpha TROP2/PDL1-TOP1i) exhibited enhanced potency, characterized by robust cytotoxicity against multiple Trop2/PDL1-expressing cell lines, potent bystander killing effects, and tumor regression in multiple CDX models. Notably, the ADC showed excellent stability and tolerability in cynomolgus monkeys, with no significant adverse effects observed in safety studies.
Conclusion
alpha TROP2/PDL1-TOP1i represents a promising therapeutic strategy for treatment-resistant cancers, effectively combining PD1/PDL1 immune checkpoint blockade with TROP2-targeted cytotoxic payload delivery while maintaining a favorable safety profile, supporting its advancement to clinical development.
利益披露 Disclosure
C. Chen, None..
Y. Wu, None..
C. Su, None..
D. Liu, None..
J. Tian, None..
Y. Li, None..
Y. Shang, None..
X. Chen, None..
R. Yan, None..
L. Tian, None..
J. Peng, None..
Z. Zhu, None.