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

• 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
• 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

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.

谓词SBIR I期赠款和团队的执行摘要 项目名称：靶向1型糖尿病的工程TCR-Treg细胞疗法自动抗原 组织：Gigamune Inc. PI：Matthew J Spindler博士 工程过的收养细胞疗法，包括嵌合抗原受体（CAR-T）和T细胞受体（TCR-T）细胞 疗法表现出五个FDA认可的CAR-T细胞疗法的癌症患者的强烈临床反应 用于血液学癌和许多用于治疗实体瘤的TCR-T细胞临床试验。 这些新药物都具有杠杆工程的细胞毒性T细胞，旨在直接杀死癌细胞。 与细胞毒性T细胞相反，Tregs的功能可以通过抗原特异性局部抑制免疫反应 活动。 TCR工程调节T细胞（TCR-Tregs）可用于治疗患者 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。但是，在 为了开发工程的TCR-Treg细胞疗法，识别自身抗原反应性有至关重要的需求 TCRS将Treg活动专门引入胰岛，可以在其中局部抑制自动反应性 细胞毒性T细胞引起疾病病理。 1型糖尿病（T1D）自身抗原（包括前硫蛋白，IA-2和GAD65）是理想的TCR-Treg细胞靶标 正如它们在胰岛和β（b） - 细胞中特别表达。这些自动抗原通常是 由CD4和CD8 T细胞靶向在许多HLA等位基因的T1D患者的T1D患者中。 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 I级HLA的抑制活性提出了肽。这表明针对T1D的工程TCR-Tregs 自身抗原可以抑制胰岛中的自身反应性细胞毒性T细胞。因此，一个目录 针对跨不同HLA等位基因T1D自动抗原的TCR-Treg细胞疗法将提供广泛的 T1D患者有效治疗。 R43AI170407 I期SBIR项目的具体目的是开发自然人类TCR的目录 靶标T1D自动抗原用于TCR工程Treg细胞疗法。 Gigamune的独特技术用途 微流体，基因组学和哺乳动物显示，以产生数百万的多样性，本性配对的TCRAB曲目 库。 TCRAB文库是不朽的，可以用一组抗原重复实验。这 将加快发现罕见的抗T1D TCR。该项目最近始于2022年底，我们没有技术 进度报告。完成此阶段I SBIR项目后，Gigamune将进一步发展有希望的TCRS 作为TCR-Treg细胞疗法，通过体内功效研究，体外安全研究和制造 发展。 R43AI170407 I-Corps补充剂由Gigamune联合创始人Matthew J. Spindler博士领导，专家 免疫基因组学和Gigamune技术的发明者，并由Gigamune首席执行官支持 企业家和Gigamune联合创始人David Johnson。行业专家是詹妮弗·凯勒（Jennifer Keller） 辅导员和营销经理。凯勒女士对潜在疾病的应用有广泛的了解， 以及治疗市场细分市场。这三个团队成员以前曾在NIH I-Corps上合作 Gigagen的项目，该项目最终发现了一个关键的药物开发伙伴（Grifols） 2021年以1.43亿美元的价格购买了Gigagen。这些产品在先前的NIH I-Corps过程中确定 项目目前正在Grifols的临床开发中。 所有三个I-Corps团队成员都有该计划的事先经验，都可以理解大量时间 该计划的要求并致力于成功。像所有早期生物技术公司一样 Gigamune面临着一个极具挑战性的筹款环境。因此，我们在这个I-Corps中的主要目标 补充是了解药物开发伙伴的需求，因此我们可以尽早合作， 没有进一步的股权融资。