Engineering and Testing of Biomimetic Stimulators for Therapeutic Applications

用于治疗应用的仿生刺激器的工程和测试

基本信息

批准号：
10705808
负责人：
Michael S Kuhns
金额：
$ 23.03万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705808
关键词：
Adhesions Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Autoantigens B-Lymphocytes Baculoviruses Binding Biomedical Engineering Biomimetics Bypass CD19 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene CD86 gene CTLA4 gene Cell Adhesion Molecules Cell surface Cells Clinical Trials Data Engineering Event Future Generations Glycocalyx Goals ITAM Immune Immune response Immune system Immunization Immunotherapy In Vitro Infection Instruction Intercellular adhesion molecule 1 Interleukin-2 Label Learning Ligands Lymphoma Mammalian Cell Mediator Molecular Mus Outcome Peptides Performance Phosphorylation Physiological Population Production Proliferating Property Reagent Regulation Research Signal Transduction Solid Neoplasm Sum Surface T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Work bi-specific T cell engager cell type chimeric antigen receptor chimeric antigen receptor T cells cost effective cytokine efficacy evaluation experience immune checkpoint blockade immunological synapse formation in vivo innovation microbial neoantigens neoplastic cell novel protein expression protein purification receptor receptor binding response src-Family Kinases technology development treatment response

项目摘要

PROJECT SUMMARY CD4+ T cells are the field generals of the immune system, providing instructions to innate immune cells, B cells, and other T cells to coordinate effective responses against non-self or altered-self antigens. The goal of this exploratory proposal is to advance a new class of soluble T cell engagers, which we have generated through biomimetic engineering, to redirect CD4+ T cell responses for therapeutic purposes. Normally, CD4+ T cell responses emerge from the integration of molecular interactions that occur at the interface between a CD4+ T cell and an antigen presenting cell (APC). These include but are not limited to: signals generated in response to antigenic peptides presented by MHCII molecules (pMHCII) that result from the coordinated actions of the T cell receptor (TCR), three signaling modules (CD3δε, CD3γε, CD3ζζ), and the coreceptor module CD4; interactions between LFA-1 on the T cell and ICAM-1 on the APC that provide adhesion and contribute to signaling; CD28 engagement of CD80 or CD86 on the APC that provides a critical costimulatory signal for IL-2 production and proliferation; and, CTLA-4 engagement of the same costimulatory ligands that serve to limit the magnitude of the response. The work proposed herein will explore the utility of biomimetic stimulators (BMiMS) – soluble reagents that have a novel antigen targeting region on one end and a CD4+ T cell stimulatory region on the other. The idea underlying BMiMS is that they can be used to make a target cell look like an APC and elicit physiological CD4+ T cell responses. In this proposal we will specifically work to: 1) optimize the production of BMiMS; 2) explore their functionality in vitro; and, 3) explore their functionality in vivo. The proposed work will provide us with the preliminary data needed to apply for larger proposals to further test and refine BMiMS function in vivo for use as therapeutic reagents. The long-term goal will be to initiate clinical trials to evaluate the efficacy of BMiMS as therapeutic reagents.

项目摘要 CD4+ T细胞是免疫系统的场将军，为先天免疫细胞提供指示，B 细胞和其他T细胞以协调针对非自身或改变自身抗原的有效反应。目标该探索性建议是推进一类新的实心T细胞参与者，我们已经生成了通过仿生工程，用于治疗目的的CD4+ T细胞反应。通常，CD4+ t 细胞反应来自于分子相互作用的整合，该分子相互作用发生在A之间的界面 CD4+ T细胞和抗原呈现细胞（APC）。这些包括但不限于：在 MHCII分子（PMHCII）提出的对抗原的PETIDE的反应 T细胞受体（TCR），三个信号模块（CD3δε，CD3γε，CD3ζζ）的作用模块CD4; T细胞上LFA-1与APC上ICAM-1之间的相互作用，可提供粘合剂和有助于信号； CD28 CD80或CD86在APC上的参与度提供了关键的共刺激 IL-2产生和增殖的信号；并且，CTLA-4参与相同的共刺激配体服务限制响应的大小。本文提出的工作将探索仿生的实用性刺激剂（BMIMS） - 可溶性试剂一端具有新型抗原靶向区域，CD4+ T 另一个细胞刺激区域。 BMIMS的基础想法是它们可用于制造目标单元看起来像APC，并引起物理CD4+ T细胞反应。在此提案中，我们将专门针对：1）优化BMIM的生产； 2）在体外探索它们的功能； 3）探索它们的功能体内。拟议的工作将为我们提供申请更大建议所需的初步数据进一步的测试和完善BMIMS在体内功能作为治疗试剂。长期目标将是启动临床试验，以评估BMIMS作为治疗试剂的有效性。