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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.

项目总结