PO.IM01.09 · 免疫学
携带第二信号的三特异性TCE可提升实体瘤应答的疗效、持久性与安全性
Trispecific TCE with second signal boosts solid tumor response efficacy, durability and safety
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
T细胞衔接器(TCE)药物在血液系统恶性肿瘤中已展现出显著的临床获益,但其在实体瘤治疗中的应用仍面临挑战。主要障碍包括靶向非肿瘤(on-target off-tumor)毒性、免疫细胞向肿瘤微环境浸润不足以及T细胞耗竭。此外,持续刺激第一信号可诱导T细胞失能或凋亡,这凸显了对更安全、更有效的下一代TCE的迫切需求。
本研究中,我们开发了FPE021,一种靶向CD3、CD28和CDH17的三特异性TCE。通过对第一信号和第二信号亲和力的优化以及合理的结构筛选,FPE021不会诱导T细胞自相残杀(fratricide)或非特异性激活,提示其具有良好的安全性。值得注意的是,与双特异性TCE相比,FPE021在体外表现出更强的细胞毒性,在体内表现出更强效的肿瘤抑制作用。此外,第二信号的整合可有效增强T细胞增殖并减轻T细胞凋亡。总之,FPE021代表了一种有前景的治疗策略,有望克服当前限制TCE在实体瘤治疗中疗效的障碍。
查看英文原文 English abstract
T-cell engager(TCE) drugs have demonstrated substantial clinical benefits in hematological malignancies, yet their application to solid tumor therapy remains challenging. Key hurdles include on-target off-tumor toxicity, inadequate immune cell infiltration into the tumor microenvironment, and T-cell exhaustion. Moreover, sustained stimulation of the first signal can induce T-cell anergy or apoptosis, underscoring an urgent need for safer and more effective next-generation TCEs.
Herein, we have developed FPE021, a triple-specific TCE targeting CD3, CD28, and CDH17. Through optimized affinities for the first and second signals combined with rational structural screening, FPE021 does not induce T-cell fratricide or non-specific activation, indicating a favorable safety profile. Notably, compared with bispecific TCEs, FPE021 exhibits stronger cytotoxicity in vitro and more potent tumor suppression in vivo. Furthermore, the integration of the second signal effectively enhances T-cell proliferation and mitigates T-cell apoptosis. Collectively, FPE021 represents a promising therapeutic strategy to overcome the current barriers limiting TCE efficacy in solid tumor treatment.
利益披露 Disclosure
Y. Wang, None..
C. Liu, None.