Developing a new bispecific antibody mimicking rapid antigen-specific memory CD8+ T cell-mediated protection

摘要 虽然记忆性CD 8 + T细胞的主要功能是识别和杀死细胞内病原体和肿瘤， 它们还可以产生多种效应细胞因子和趋化因子， 应答免疫宿主中记忆性CD 8 + T细胞保护作用的确切机制是： 没有很好地理解。过去15年来，我们一直在研究这个问题， 开发新的治疗策略，利用记忆性CD 8 + T细胞的力量， 主持人我们过去和最近的机制研究已经确定，在召回接种疫苗的感染后， 在宿主中，记忆性CD 8 + T细胞可以快速感知炎症信号和同源抗原， 干扰素γ（IFNγ）和早期协调趋化因子的集合。我们报告说，这两个信号都需要 促进炎性Ly 6C+单核细胞杀微生物效应子功能的有效活化， 最佳保护接种疫苗的宿主。在这些结果的基础上，我们在这一探索性建议中提出， 设计、开发和测试新型双特异性IFNγ-趋化因子Fc融合“配体捕获”生物制剂， 激活Ly 6C+单核细胞的杀微生物功能，以防止感染性疾病，模拟 记忆CD 8 + T细胞介导疫苗接种宿主在回忆期间的有效保护的机制 感染我们相信，这种试剂有潜力作为一种快速和广泛的治疗， 多重急性感染。

Abstract While the main function of memory CD8+ T cells is to recognize and kill intracellular pathogens and tumors, they can also produce multiple effector cytokines and chemokines that contribute to protective immune responses. The precise mechanism for development of memory CD8+ T cell protection in vaccinated hosts is not well understood. We have been investigating this question over the past 15 years with the underlying goal to develop novel therapeutic strategies that harness the power of memory CD8+ T cells to the benefit of the host. Our past and most recent mechanistic studies have established that, upon recall infection of vaccinated hosts, memory CD8+ T cells can rapidly sense both inflammatory signals and cognate antigen to produce interferon gamma (IFNγ) and sets of early coordinated chemokines. We reported that both signals are required to promote potent activation of inflammatory Ly6C+ monocytes microbicidal effector function and achieve optimal protection of vaccinated hosts. Building on these results, we propose in this exploratory proposal to design, develop and test a novel bispecific IFNγ-chemokine Fc-fusion “ligand-trap” biologics that target and activates Ly6C+ monocytes microbicidal functions for protection against infectious diseases, mimicking the mechanism by which memory CD8+ T cells mediate effective protection of vaccinated host during recall infection. We believe that such reagent has the potential to be used as a rapid and broad therapeutic against multiple acute infections.