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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的记忆CD8+ T细胞的主要功能是识别和杀死细胞内病原体和肿瘤，但它们还可以产生多种效应子细胞因子和趋化因子，从而有助于保护免疫回答。在接种宿主中开发记忆CD8+ T细胞保护的精确机制是不太了解。在过去的15年中，我们一直在调查这个问题的基本目标制定利用记忆CD8+ T细胞的力量的新颖理论策略使主持人。我们的过去和最新的机械研究已经确定，在召回接种疫苗后的感染后宿主，记忆CD8+ T细胞可以迅速感知炎症信号和同源抗原以产生干扰素伽玛（IFNγ）和早期协调趋化因子集。我们报告说两个信号都是必需的促进炎性LY6C+单核细胞杀菌效应子功能的潜在激活并实现对接种宿主的最佳保护。在这些结果的基础上，我们在此探索性建议中提出了设计，开发和测试一种新型的双特异性IFNγ-脱脂素FC融合“配体陷阱”生物制剂，其靶向和靶向激活LY6C+单核细胞杀菌功能，以防止感染性疾病，模仿记忆CD8+ T细胞介导召回期间接种宿主的有效保护的机制感染。我们认为，这种试剂有可能被用作反对的快速而广泛的治疗多种急性感染。