Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens

针对 1 型糖尿病自身抗原的工程化 TCR-Treg 细胞疗法

基本信息

批准号：
10764143
负责人：
Matthew James Spindler
金额：
$ 5.5万
依托单位：
GIGAMUNE, INC.
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：
2023-05-03 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10764143
关键词：
Adoptive Cell Transfers Alleles Antigens Autoantigens Autoimmune Diseases Autoimmune Responses Beta Cell Biotechnology Blood Glucose CAR T cell therapy CD8-Positive T-Lymphocytes Cancer Patient Catalogs Cell Therapy Cell physiology Cells Chronic Clinical Clinical Trials Cytotoxic T-Lymphocytes DNA sequencing Development Disease Doctor of Philosophy Engineering Environment Epitopes Equity FDA approved Genes Genomics Goals Grant Hematologic Neoplasms Human Immune response Immunogenomics In Vitro Industry Innovation Corps Insulin Insulin deficiency Insulin-Dependent Diabetes Mellitus Islets of Langerhans Libraries Marketing Microfluidics Pathology Patients Peptides Pharmacologic Substance Phase Receptor Cell Regulatory T-Lymphocyte Replacement Therapy Reporting Small Business Innovation Research Grant Solid Neoplasm T-Cell Receptor T-Lymphocyte Technology Therapeutic Time Training United States National Institutes of Health Work autoreactivity cancer cell chimeric antigen receptor clinical development design effective therapy efficacy study experience genetic counselor glucose monitor immunoregulation in vivo manufacture member novel therapeutics preproinsulin prevent programs response safety study success targeted treatment

项目摘要

Executive Summary of Predicate SBIR Phase I Grant and Team Project Title: Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Engineered adoptive cell therapies including chimeric antigen receptor (CAR-T) and T cell receptor (TCR-T) cell therapies have shown strong clinical responses in cancer patients with five FDA approved CAR-T cell therapies for hematological cancers and numerous TCR-T cell clinical trials ongoing for the treatment of solid tumors. These new drugs have all leveraged engineered cytotoxic T cells and are designed to directly kill cancer cells. In contrast to cytotoxic T cells, Tregs function to locally suppress immune responses through antigen-specific activity. TCR engineered regulatory T cells (TCR-Tregs) could be used for the treatment of patients with autoimmune disorders, not for killing target cells but rather for preventing cells from being killed. However, in order to develop engineered TCR-Treg cell therapies, there is a critical need in identifying autoantigen reactive TCRs to specifically direct Treg activity into pancreatic islets where they can locally suppress the autoreactive cytotoxic T cells causing disease pathology. Type 1 diabetes (T1D) autoantigens, including preproinsulin, IA-2, and GAD65, are ideal TCR-Treg cell targets as they are specifically expressed in pancreatic islets and beta (b)-cells. These autoantigens are commonly targeted by CD4 and CD8 T cells in T1D patients with peptide epitopes presented across many HLA alleles. Importantly, recent studies have demonstrated that TCR clonotypes isolated from CD8+ T cells can redirect Treg suppressive activity to class I HLA presented peptides. This suggests that engineered TCR-Tregs targeting T1D autoantigens could suppress autoreactive cytotoxic T cells within the pancreatic islets. Therefore, a catalog of TCR-Treg cell therapies targeting T1D autoantigens across different HLA alleles would provide a broadly effective treatment for T1D patients. The Specific Aim of the R43AI170407 Phase I SBIR project is to develop a catalog of natural human TCRs that target T1D autoantigens for use in TCR-engineered Treg cell therapies. GigaMune's unique technology uses microfluidics, genomics, and mammalian display to generate millions-diverse, natively paired TCRab repertoire libraries. The TCRab libraries are immortal, enabling repeated experimentation with a panel of antigens. This will expedite discovery of rare anti-T1D TCRs. The project recently started in late 2022 and we have no technical progress to report. After completing this Phase I SBIR project, GigaMune will further develop promising TCRs as TCR-Treg cell therapies, through in vivo efficacy studies, in vitro safety studies, and manufacturing development. The R43AI170407 I-Corps Supplement is led by GigaMune co-founder Dr. Matthew J. Spindler, an expert in immunogenomics and inventor of the GigaMune technology and supported by GigaMune CEO, serial entrepreneur, and GigaMune co-founder David Johnson. The industry expert is Jennifer Keller, a trained genetic counselor and marketing manager. Ms. Keller has a broad understanding of potential disease applications, as well as therapeutic market segments. All three team members have previously worked together on NIH I-Corps projects at GigaGen, which culminated in discovery of a key pharmaceutical development partner (Grifols) which bought GigaGen for $143 million in 2021. The products identified during the course of the prior NIH I-Corps projects are currently under clinical development at Grifols. All three I-Corps team members, having prior experience with the program, understand the significant time requirements of the program and are committed to success. Like all early stage biotechnology companies, GigaMune is facing an extremely challenging fundraising environment. As such our primary goal in this I-Corps Supplement is to understand the needs of pharmaceutical development partners, so we can partner early, without further equity financing.

Predicate SBIR 第一阶段资助和团队的执行摘要项目名称：针对 1 型糖尿病自身抗原的工程化 TCR-Treg 细胞疗法组织：GigaMune Inc. PI：Matthew J Spindler 博士工程过继细胞疗法，包括嵌合抗原受体 (CAR-T) 和 T 细胞受体 (TCR-T) 细胞 FDA 批准的五种 CAR-T 细胞疗法在癌症患者中显示出强烈的临床反应用于血液癌症和大量 TCR-T 细胞治疗实体瘤的临床试验正在进行中。这些新药都利用了工程细胞毒性 T 细胞，旨在直接杀死癌细胞。与细胞毒性 T 细胞相比，Tregs 的功能是通过抗原特异性来局部抑制免疫反应。活动。 TCR 工程调节性 T 细胞（TCR-Tregs）可用于治疗患有以下疾病的患者自身免疫性疾病，不是为了杀死靶细胞，而是为了防止细胞被杀死。然而，在为了开发工程 TCR-Treg 细胞疗法，迫切需要识别自身抗原反应性 TCR 特异性引导 Treg 活性进入胰岛，在那里它们可以局部抑制自身反应细胞毒性 T 细胞引起疾病病理学。 1 型糖尿病 (T1D) 自身抗原，包括前胰岛素原、IA-2 和 GAD65，是理想的 TCR-Treg 细胞靶标因为它们在胰岛和 β (b) 细胞中特异性表达。这些自身抗原通常 T1D 患者的 CD4 和 CD8 T 细胞靶向这些 T1D 患者，其肽表位存在于许多 HLA 等位基因中。重要的是，最近的研究表明，从 CD8+ T 细胞中分离出的 TCR 克隆型可以重定向 Treg 对 I 类 HLA 呈递肽具有抑制活性。这表明针对 T1D 的工程 TCR-Tregs 自身抗原可以抑制胰岛内的自身反应性细胞毒性 T 细胞。因此，一个目录针对不同 HLA 等位基因的 T1D 自身抗原的 TCR-Treg 细胞疗法将提供广泛的治疗 T1D 患者的有效治疗。 R43AI170407 第一阶段 SBIR 项目的具体目标是开发一个天然人类 TCR 目录，靶向 T1D 自身抗原，用于 TCR 工程 Treg 细胞疗法。 GigaMune 独特的技术用途微流体、基因组学和哺乳动物展示可生成数百万种、本地配对的 TCRab 库图书馆。 TCRab 文库是不朽的，可以对一组抗原进行重复实验。这将加速罕见的抗 T1D TCR 的发现。该项目最近于 2022 年底启动，我们没有技术支持进展报告。完成第一期 SBIR 项目后，GigaMune 将进一步开发有前景的 TCR 作为 TCR-Treg 细胞疗法，通过体内功效研究、体外安全性研究和制造发展。 R43AI170407 I-Corps 补充品由 GigaMune 联合创始人 Matthew J. Spindler 博士领导，他是免疫基因组学和 GigaMune 技术的发明者，并得到 GigaMune 首席执行官的支持，系列企业家、GigaMune 联合创始人 David Johnson。该行业专家是詹妮弗·凯勒（Jennifer Keller），她是一位训练有素的遗传学家顾问和营销经理。 Keller 女士对潜在疾病应用有着广泛的了解，例如以及治疗细分市场。所有三名团队成员之前都曾在 NIH I-Corps 中合作过 GigaGen 的项目，最终发现了一个关键的药物开发合作伙伴 (Grifols)，该合作伙伴 2021 年以 1.43 亿美元收购了 GigaGen。在之前的 NIH I-Corps 过程中发现的产品 Grifols 项目目前正在进行临床开发。所有三名 I-Corps 团队成员都有过该计划的经验，都了解这一重要时刻计划的要求并致力于成功。与所有早期生物技术公司一样， GigaMune 面临着极具挑战性的筹款环境。因此，我们在这个 I-Corps 中的首要目标补充就是了解医药开发合作伙伴的需求，这样我们才能早点合作，无需进一步股权融资。