Li Chen, Wenjing Qian, Fangfang Pan, Debin Li, Weiwei Yu, Li Tong, Yingying Yang, Qiming Xu, Jianfeng Ding, Ruixue Dai, Weiwei Xian, Xufeng Zhu, Pu Ren, Huaxing Zhu
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引用次数: 0
摘要
目的：开发出一种具有串联单链可变片段（scFv）结构的新型 CD19xCD3xCD28 三特异性抗体，用于治疗 B 细胞恶性肿瘤。研究方法对该三特异性抗体在体外和体内诱导肿瘤定向 T 细胞活化和细胞毒性的能力进行了评估，并将其与缺乏 CD28 靶向结构域的双特异性抗体 BiTE-CD19xCD3 进行了比较。结果显示与双特异性抗体相比，带有共刺激结构域的三特异性抗体具有更强的T细胞活化和记忆T细胞分化能力，能更快地诱导肿瘤细胞溶解。RNAseq 分析显示，三特异性抗体可调节 CD3/TCR 复合物衍生信号，并上调抗凋亡因子，从而影响 T 细胞的存活。结论通过CD3/CD28的共同参与，三特异性抗体展示了其在T细胞免疫中的优势，并有望成为一种更强大、更持久的T细胞参与因子。
A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.
Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.
期刊介绍：
Many aspects of the immune system and mechanisms of immunomodulatory therapies remain to be elucidated in order to exploit fully the emerging opportunities. Those involved in the research and clinical applications of immunotherapy are challenged by the huge and intricate volumes of knowledge arising from this fast-evolving field. The journal Immunotherapy offers the scientific community an interdisciplinary forum, providing them with information on the most recent advances of various aspects of immunotherapies, in a concise format to aid navigation of this complex field.
Immunotherapy delivers essential information in concise, at-a-glance article formats. Key advances in the field are reported and analyzed by international experts, providing an authoritative but accessible forum for this vitally important area of research. Unsolicited article proposals are welcomed and authors are required to comply fully with the journal''s Disclosure & Conflict of Interest Policy as well as major publishing guidelines, including ICMJE and GPP3.
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