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

• 批准号: 10570359
• 负责人: Michael S Kuhns
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/10570359
• 关键词: Adhesions; 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 of activation protein; Molecular; Mus; Outcome; Peptides; Performance; Physiological; Population; Production; Property; Reagent; Regulation; Research; Signal Transduction; Solid Neoplasm; Sum; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Work; base; 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 binding; response; src-Family Kinases; technology development; treatment response

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 CD 4 + T细胞是免疫系统的领域将军，为先天性免疫细胞B提供指令。 细胞和其他T细胞来协调针对非自身抗原或改变的自身抗原的有效应答。的目标 这一探索性的建议是提出一种新的可溶性T细胞增殖剂，我们已经产生了 通过仿生工程，重定向CD 4 + T细胞反应用于治疗目的。通常，CD 4 + T 细胞反应来自于分子相互作用的整合，分子相互作用发生在细胞与细胞之间的界面上， CD 4 + T细胞和抗原呈递细胞（APC）。这些包括但不限于： 对MHCII分子（pMHCII）呈递的抗原肽的应答， T细胞受体（TCR）、三种信号传导模块（CD 3 δε、CD 3 γε、CD 3 γ ε）和辅助受体的作用 模块CD 4; T细胞上的LFA-1和APC上的ICAM-1之间的相互作用，提供粘附和 有助于信号传导; APC上的CD 80或CD 86的CD 28接合，其提供关键的共刺激作用。 IL-2产生和增殖的信号;以及，CTLA-4与相同共刺激配体的接合， 用于限制响应的幅度。本文提出的工作将探索仿生的效用 刺激物（BMiMS）-可溶性试剂，其在一端具有新的抗原靶向区域，并且在另一端具有CD 4 + T 另一方面是细胞刺激区。BMiMS的基本思想是，它们可以用来制造靶细胞， 看起来像APC并引发生理性CD 4 + T细胞应答。在本提案中，我们将具体致力于： 优化BMiMS的生产; 2）探索其体外功能;以及，3）探索其在体内的功能 vivo.拟议的工作将为我们提供申请更大提案所需的初步数据， 进一步测试和改进BMiMS在体内的功能，以用作治疗试剂。长期目标将是 启动临床试验，以评估BMiMS作为治疗试剂的功效。