Immunoengineered nanotechnology for targeted expansion of regulatory T cells

用于定向扩增调节性 T 细胞的免疫工程纳米技术

• 批准号: 10544718
• 负责人: Jamie Berta Spangler
• 金额: $ 41.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544718
• 关键词: Address; Adoption; Adoptive Transfer; Affinity; Animal Model; Animals; Antibodies; Antibody Affinity; Antigen-Presenting Cells; Antigens; Area; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Binding; Biological Models; Biomedical Engineering; Biotechnology; Cell Communication; Cell model; Cells; Chimeric Proteins; Chronic Disease; Clinical; Complex; Development; Diabetes Mellitus; Disease; Dissociation; Dose; Drug Design; Effector Cell; Encapsulated; Engineering; Goals; Graft Rejection; Health; Human; Immobilization; Immune; Immune Tolerance; Immune response; Immune system; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Incidence; Infiltration; Inflammatory Bowel Diseases; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin 2 Receptor; Interleukin-2; Islets of Langerhans; Kinetics; Lymphocyte Subset; Major Histocompatibility Complex; Medical; Medicine; Metabolic hormone; Modeling; Molecular Conformation; Monitor; Multiple Sclerosis; Mus; Nanotechnology; Outcome; Pathogenicity; Patients; Peptides; Proliferating; Protein Engineering; Protocols documentation; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Route; Safety; Scheme; Signal Transduction; Sirolimus; Specificity; Structure; Surface; System; T-Cell Activation; T-Lymphocyte; Technology; Technology Transfer; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Transgenic Organisms; Transplantation; Transplantation Tolerance; Treatment Efficacy; autoreactive T cell; autoreactivity; cell growth; chronic autoimmune disease; clinically relevant; combat; controlled release; cytokine; design; diabetogenic; effector T cell; global health; immune activation; immunoengineering; immunoregulation; in vivo; innovation; interest; islet; manufacture; mouse model; nanoparticle; new technology; novel; particle; prevent; receptor; technology platform; therapeutic development; tool; transplantation medicine; virtual

PROJECT SUMMARY/ABSTRACT Development of an immunoengineered technology to selectively stimulate and expand regulatory T (TReg) cells in vivo would be transformative for autoimmune disease treatment and transplantation medicine. Extensive evidence has established that adoptively transferred TReg cells, and in particular antigen-specific TReg cells, effectively suppress pathogenic autoimmune activity to combat disease. However, logistical and manufacturing complications as well as safety concerns associated with ex vivo expanded T cells impede clinical adoption of this approach. Thus, there is an unmet medical need for an off-the-shelf, non-cellular platform that activates antigen-specific TReg cells to manifest immunosuppression directly in patients. The interleukin-2 (IL-2) cytokine potently activates TReg cells, and has proven to be a promising alternative to adoptive TReg cell transfer. However, IL-2 concurrently stimulates activation of effector cells, resulting in harmful off-target effects and toxicities. Co- administration of IL-2 in complex with certain anti-cytokine antibodies preferentially activates and expands TReg over effector cells, but concerns about cytokine/antibody complex dissociation hinder the therapeutic development of this approach. Furthermore, IL-2 treatment induces non-specific expansion of TReg cells, with limited enrichment of therapeutically superior antigen-specific cells. This proposal aims to develop a robust and versatile platform that activates antigen-specific TReg cells and simultaneously inhibits the function of pathogenic autoreactive T cells. This technology synthesizes, for the first time, three design approaches: (1) Selective delivery of IL-2 to TReg cells; (2) Stimulation of antigen-specific TReg cells using artificial antigen-presenting cells (aAPCs); and (3) Localized release of an immunosuppressive drug to prevent effector T cell activation. The novel platform, denoted TolAPC, comprises nanoparticles coated with self peptide-loaded major histocompatibility complex (MHC) as well as a stabilized single-chain fusion format of an IL-2/antibody complex that selectively promotes TReg expansion. These particles are also engineered for controlled release of the immunosuppressive drug rapamycin. TolAPCs will be characterized in vitro and in vivo to assess selective expansion of TReg cells that can suppress pathogenic self-reactive effector T cells. They will also be therapeutically evaluated in autoimmune disease studies in mice. As a model system, TolAPC activity will be assessed in type 1 diabetes (T1D), a chronic autoimmune disease that is a growing threat to global health with incidence rising at an alarming rate of 3% annually. The modularity of the TolAPC platform will allow for ready extension to a host of applications in autoimmune disease treatment and transplant tolerance through substitution of the antigen specificity. Overall, our targeted immunomodulatory nanotechnology will serve as a powerful and general tool for biasing immune activation to effect therapeutically relevant outcomes.

项目摘要/摘要 选择性刺激和扩增调节性T(Treg)细胞的免疫工程技术研究进展 体内实验将对自身免疫性疾病的治疗和移植医学产生革命性的影响。广泛性 有证据表明，过继转移的Treg细胞，特别是抗原特异性Treg细胞， 有效抑制病原性自身免疫活动，与疾病作斗争。然而，物流和制造业 与体外扩增T细胞相关的并发症和安全问题阻碍了临床应用 这种方法。因此，存在对现成的、激活的非蜂窝平台的医疗需求未得到满足 抗原特异性Treg细胞可直接在患者体内显示免疫抑制。白介素2细胞因子 有效地激活Treg细胞，并已被证明是一种有前途的替代过继Treg细胞转移。然而， IL-2同时刺激效应细胞的激活，导致有害的非靶点效应和毒副作用。共同-- IL-2与某些抗细胞因子抗体形成的复合体优先激活和扩大Treg 超过效应细胞，但对细胞因子/抗体复合体解离的担忧阻碍了治疗 这一方法的发展。此外，IL-2治疗可诱导Treg细胞的非特异性增殖， 治疗上优越的抗原特异性细胞的有限浓缩。 这项提议旨在开发一种强大而通用的平台，激活抗原特异性Treg细胞 同时抑制致病的自身反应性T细胞的功能。这项技术综合了 第一次，有三种设计方法：(1)选择性地将IL-2输送到Treg细胞；(2)刺激抗原特异性 使用人工抗原提呈细胞(AAPC)的Treg细胞；以及(3)免疫抑制的局部释放 防止效应器T细胞激活的药物。这种名为TolAPC的新型平台包括包覆的纳米颗粒 带有自身多肽的主要组织相容性复合体(MHC)以及稳定的单链融合形式 有选择地促进Treg扩张的IL-2/抗体复合体。这些粒子还被设计用于 免疫抑制药物雷帕霉素的控释。TolAPC将在体外和体内表征 评估选择性扩增的Treg细胞能够抑制致病的自身反应性T细胞。他们会 在小鼠的自身免疫性疾病研究中也进行了治疗评估。作为一个模式系统，TolAPC活动 将被评估为1型糖尿病(T1D)，这是一种日益威胁全球健康的慢性自身免疫性疾病 发病率以每年3%的惊人速度增长。TolAPC平台的模块化将允许 通过以下方式扩展到自身免疫性疾病治疗和移植耐受方面的一系列应用 抗原特异性的替代。总体而言，我们的目标免疫调节纳米技术将作为 强大和通用的工具，偏向免疫激活，以影响治疗相关的结果。

项目成果

A Hybrid Adherent/Suspension Cell-Based Selection Strategy for Discovery of Antibodies Targeting Membrane Proteins.

• DOI: 10.1007/978-1-0716-2285-8_11
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

Redirecting the specificity of tripartite motif containing-21 scaffolds using a novel discovery and design approach.

使用新颖的发现和设计方法重定向三方基序的特异性。

• DOI: 10.1016/j.jbc.2023.105381
• 发表时间: 2023-12
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: VanDyke, Derek;Xu, Linda;Sargunas, Paul R.;Gilbreth, Ryan N.;Baca, Manuel;Gao, Changshou;Hunt, James;Spangler, Jamie B.
• 通讯作者: Spangler, Jamie B.

Biologics-based degraders - an expanding toolkit for targeted-protein degradation.

• DOI: 10.1016/j.copbio.2022.102807
• 发表时间: 2022-09
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: D. VanDyke;Jonathan D. Taylor;Kyle J Kaeo;J. Hunt;Jamie B. Spangler

A versatile design platform for glycoengineering therapeutic antibodies.

• DOI: 10.1080/19420862.2022.2095704
• 发表时间: 2022-01
• 期刊: mAbs
• 影响因子: 5.3
• 作者: Ludwig SD;Bernstein ZJ;Agatemor C;Dammen-Brower K;Ruffolo J;Rosas JM;Post JD;Cole RN;Yarema KJ;Spangler JB
• 通讯作者: Spangler JB