Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens

谓词SBIR第一阶段授权和团队的执行摘要 项目名称：针对1型糖尿病自身抗原的基因工程TCR-Treg细胞疗法 组织：GigaMune Inc. 派：马修·J·斯宾德勒，博士。 包括嵌合抗原受体(CAR-T)和T细胞受体(TCR-T)细胞的工程化过继细胞疗法 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 用于血液病癌症和许多正在进行的治疗实体肿瘤的TCR-T细胞临床试验。 这些新药都利用了工程化的细胞毒性T细胞，并被设计成直接杀死癌细胞。 与细胞毒性T细胞不同，Tregs的功能是通过抗原特异性局部抑制免疫反应 活动。TCR工程调节性T细胞(TCR-Tregs)可用于治疗慢性粒细胞白血病患者 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 为了开发工程化的TCR-Treg细胞疗法，迫切需要鉴定自身抗原反应。 TCR特异性地将Treg活性引导到胰岛，在那里它们可以局部抑制自身反应 导致疾病病理的细胞毒性T细胞。 1型糖尿病(T1D)自身抗原，包括胰岛素原、IA-2和GAD65，是理想的TCR-Treg细胞靶点 因为它们在胰岛和β(B)细胞中特异表达。这些自身抗原通常是 以T1D患者的CD4和CD8T细胞为靶点，其多肽表位存在于许多HLA等位基因上。 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HLAI类分子的抑制活性呈现多肽。这表明针对T1D的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，一份 针对不同等位基因的T1D自身抗原的TCR-Treg细胞疗法将提供广泛的 对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，该目录 靶向T1D自身抗原，用于TCR工程的Treg细胞疗法。GigaMune的独特技术使用 微流体学、基因组学和哺乳动物展示产生数百万种不同的天然配对TCRab曲目 图书馆。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。该项目最近于2022年底启动，我们没有技术支持 要报告的进度。在完成第一阶段SBIR项目后，GigaMune将进一步开发有前景的TCR 作为TCR-Treg细胞疗法，通过体内疗效研究、体外安全性研究和制造 发展。 R43AI170407智能军团增刊由GigaMune联合创始人马修·J·斯平德勒博士领导，他是一名 免疫基因组学和GigaMune技术的发明者，并得到GigaMune首席执行官、系列 企业家和GigaMune联合创始人大卫·约翰逊。行业专家詹妮弗·凯勒是一位训练有素的遗传学家 顾问兼市场经理。凯勒女士对潜在的疾病应用有广泛的理解，如 以及治疗市场细分市场。这三名团队成员之前都曾在NIH I-Corps工作过 GigaGen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过程中确定的产品 Grifols的项目目前正在进行临床开发。 所有三名i-Corps团队成员都有过该项目的经验，他们都理解这段重要的时间 计划的要求，并致力于成功。像所有早期的生物技术公司一样， GigaMune正面临着一个极具挑战性的筹资环境。因此，我们在i-Corps中的主要目标是 补充是了解药物开发合作伙伴的需求，这样我们才能及早合作， 而不需要进一步的股权融资。

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.