新闻发布
礼进生物将在2023年ASCO上报告4-1BB激动剂临床成药性突破
图1. 生理性TNFRSF家族4-1BB激活机制。 4-1BB受体激活机制是通过细胞之间配体(4-1BBL)和受体(4-1BB)相结合时诱导形成多聚体,受体-配体三聚体的交联和寡聚是受体下游信号激活的前提条件。这个天然调节机制保证精细的时间和空间激活信号。
图3. 4-1BB和PD-1信号通路的交叉及4-1BB激动剂和PD-1抑制剂的协同效应。 4-1BB激活促进免疫细胞因子释放,诱导PD-L1升高和PD-1活化,而阻断PD-1活性可引起4-1BB升高。4-1BB和PD-1胞内信号通路的交叉,共同协调T细胞的抑瘤免疫功能。因此, 4-1BB激动抗体LVGN6051和PD-1抑制抗体Pembrolizumab能产生协同效应,增强免疫细胞功能。
参考文献
1.Chester, C., et al., Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood, The Journal of the American Society of Hematology, 2018. 131(1): p. 49-57.
2.Shuford, W.W., et al., 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. The Journal of experimental medicine, 1997. 186(1): p. 47-55.
3.Pollok, K.E., et al., Inducible T cell antigen 4-1BB. Analysis of expression and function. Journal of Immunology (Baltimore, Md.: 1950), 1993. 150(3): p. 771-781.
4.Horton, B.L., et al., Intratumoral CD8+ T-cell Apoptosis Is a Major Component of T-cell Dysfunction and Impedes Antitumor ImmunityApoptosis of CD8+ TILs Limits Antitumor Immunity. Cancer immunology research, 2018. 6(1): p. 14-24.
5.Melero, I., et al., Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nature medicine, 1997. 3(6): p. 682-685.
6.Liu, L., et al., Antibody-targeted TNFRSF activation for cancer immunotherapy: the role of FcγRIIB cross-linking. Frontiers in Pharmacology, 2022: p. 2317.
7.Qi, X., et al., Optimizationof 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with
FcγR affinity. Nature Communications, 2019. 10(1): p. 2141.