Evaluation of anticancer activity of PD-1/CTLA-4 bispecific antibody and its lgGl isotype based on target humanized mice / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：构建基于靶点人源化小鼠的程序性死亡受体-1（PD-1）/细胞毒性T淋巴细胞抗原-4（CTLA-4）双特异性抗体（BsAb）并对BsAb及其IgG1亚型进行抗癌活性评价和探讨其潜在的作用机制。方法：构建和扩增并纯化不同结构及抗体亚型的PD-1/CTLA-4抗体BsAb1、BsAb2和BsAb3，对纯化BsAb进行靶点亲和力检测，采用荧光素酶报告基因实验和FCM检测抗体的生物学活性。基于B-hPD-1-hPD-L1-hCTLA-4人源化小鼠的MC38-hPD-L1结肠癌细胞移植瘤模型对BsAb进行体内药效评估，并通过移植瘤组织中肿瘤浸润淋巴细胞（TIL）分析PD-1/CTLA-4抗体的作用机制。结果：成功制备的BsAb1、BsAb2及BsAb3对靶点PD-1和CTLA-4均有较强的特异性亲和力、对靶点通路均有不同程度的阻滞活性，均明显抑制移植瘤的生长（P<0.05或P<0.01）。IgG1亚型BsAb体内药效更优（P<0.01），TIL分析发现BsAb2-IgG1明显增加了CTL百分率（P<0.05），显著降低了肿瘤浸润Treg细胞百分率（P<0.01），使肿瘤免疫微环境更有利于杀伤肿瘤细胞；增强ADCC活性的Fc突变体亚型BsAb2-SI则不能进一步提高抗肿瘤活性。结论：具有Fc效应功能的IgG1亚型的PD-1/CTLA-4抗体体内抗癌药效更优，因其可以更好地清除TIL中的Treg细胞。

Research progress on roles of autophagy regulating T lymphocyte function in the genesis and development of diseases / 中国肿瘤生物治疗杂志

@#[Abstract] Autophagy, as an important intracellular metabolic pathway, has been proved to be ubiquitous in many kinds of cells. Its functional impairment can easily cause lots of diseases, such as cancer, leukemia, liver disease, diabetes and heart disease. In particular, autophagy is important for the development, differentiation and regulation of immune function of T lymphocytes. Abnormal autophagy of T lymphocytes can cause immune dysfunction and lead to diseases, such as inflammation, infection and autoimmunity. In view of the important role of autophagy in regulating T lymphocyte function and disease, this article illustrates the research progress on autophagy regulating the homeostasis, survival, proliferation, senescence, metabolism, immune function of T lymphocytes and many diseases, including tumors, in recent years.