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

开发一种新型双特异性抗体，模仿快速抗原特异性记忆 CD8 T 细胞介导的保护

• 批准号: 10742118
• 负责人: Jonathan R. Lai
• 金额: $ 25.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742118
• 关键词: Antibody Response; Antigens; Autophagocytosis; B-Lymphocytes; Bacteria; Binding; Biochemical; Biological Products; Biological Testing; Bispecific Antibodies; CCL3 gene; CCL4 gene; CCR; CCR1 gene; CCR5 gene; CD14 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CXCL9 gene; Cell surface; Cells; Cellular biology; Chimeric Proteins; Clonal Expansion; Communicable Diseases; Containment; Cytolysis; Cytoprotection; Development; Dose; Engineering; FCGR3B gene; Fc Receptor; Goals; Growth; Hour; Human; Human Herpesvirus 2; Immune; Immune response; Immunologics; In Vitro; Infection; Inflammatory; Interferon Type II; Ligands; Link; Listeria monocytogenes; Malaria; Mediating; Memory; Mus; Parasites; Phagocytes; Plasmodium chabaudi; Play; Production; Protein Engineering; Proteins; Public Health; Reagent; Reporting; Research; Role; Science; Series; Signal Transduction; Site; Study models; T memory cell; T-Lymphocyte; TNF gene; Testing; Therapeutic; Vaccinated; Vaccines; XCL1 gene; XCR1 gene; acute infection; antibody engineering; arm; chemokine; chemokine receptor; cytokine; design; engineering design; experimental study; gamma-Chemokines; in vivo; microbicide; monocyte; monomer; mouse model; multiphoton imaging; neoplastic cell; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic microbe; prophylactic; receptor; response; tumor

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.

摘要 虽然记忆CD8+T细胞的主要功能是识别和杀死细胞内的病原体和肿瘤， 它们还可以产生多种效应细胞因子和趋化因子，有助于保护性免疫。 回应。在接种疫苗的宿主中形成记忆CD8+T细胞保护的确切机制是 不是很清楚。过去15年来，我们一直在研究这个问题，其根本目的是 开发新的治疗策略，利用记忆CD8+T细胞的力量造福于 主持人。我们过去和最近的机制研究已经确定，一旦回忆起接种疫苗的感染 宿主、记忆性CD8+T细胞可以快速感知炎症信号和同源抗原，从而产生 干扰素γ和多组早期协调趋化因子。我们报告说这两个信号都是必需的 促进炎症性Ly6C+单核细胞高效激活杀菌效应功能并实现 对接种疫苗的宿主进行最佳保护。在这些结果的基础上，我们在这项探索性提案中建议 设计、开发和测试一种新型双特异性干扰素γ-趋化因子Fc融合“配体-陷阱”生物制品，靶向和 激活Ly6C+单核细胞杀菌功能，防止感染疾病，模拟 记忆CD8+T细胞在召回过程中介导免疫宿主有效保护的机制 感染。我们相信这种试剂有可能作为一种快速和广泛的治疗方法用于治疗 多发性急性感染。