Conditional control of universal antigen receptor signaling

通用抗原受体信号传导的条件控制

• 批准号: 10367215
• 负责人: Jason Jakob Lohmueller
• 金额: $ 43.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367215
• 关键词: Acidosis; Address; Adoptive Cell Transfers; Adoptive Transfer; Ally; Antigen Receptors; Antigen Targeting; Antigens; Area; Autoimmune Diseases; Biological; Biological Process; Biology; CAR receptor; Cell Therapy; Cells; Characteristics; Chemicals; Chronic; Clinical; Development; Disease; Engineering; Enzymes; Fc Receptor; Foundations; Genes; Goals; Hematopoietic Neoplasms; Human; In Vitro; Label; Lead; Logic; Malignant Neoplasms; Manuscripts; Medical; Methods; Modality; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Receptor Activation; Receptor Signaling; Response to stimulus physiology; S-nitro-N-acetylpenicillamine; SNAP receptor; Safety; Signal Transduction; Site; Solid Neoplasm; Specificity; Stimulus; Synthetic immunology; System; T-Cell Receptor; T-Lymphocyte; Tars; Technology; Therapeutic; Therapeutic Effect; Therapeutic antibodies; Toxic effect; Validation; Virus Diseases; Xenograft procedure; antigen binding; base; biological systems; blood treatment; cellular engineering; chemical group; chimeric antigen receptor; chimeric antigen receptor T cells; combinatorial; covalent bond; design; engineered T cells; experience; genetically modified cells; improved; in vivo; interest; mouse model; notch protein; novel; programs; receptor; receptor binding; response; small molecule; spatiotemporal; tumor xenograft

PROJECT SUMMARY Adoptive cell therapy using antigen receptor engineered T cells is a highly promising therapeutic approach, in which cells are genetically modified to express an antigen receptor protein and are then adoptively transferred into the patient. These cells then act as a “living drug” that can elicit potent therapeutic effects in response to sensing a target antigen on a cell anywhere in the body. This approach is revolutionizing the treatment of blood cancers and shows promise in cell therapies for treating solid tumors, auto-immune disease, and chronic viral infection. We are developing highly modular universal adaptor versions of receptors, that we termed SNAP-CAR and SNAP-synNotch. These receptors are “universal” as they can be chemically programmed to target any an- tigen of interest by a co-administered adaptor molecule consisting of an antigen binding region conjugated to a benzylguanine motif. Universal receptor systems can be used to target multiple antigens in a single patient or across several disease indications by simply changing the antigen-targeting adaptor molecules. Despite the tremendous promise of antigen receptor technologies, their implementation has been limited by difficulties in attaining diseased cell-specificity through single antigen targeting, as well as unwanted on-tar- get/off-disease toxicities and toxicities from overactive cells. We are addressing these technological gaps in antigen receptor signaling-specificity by taking a chemical biology approach and combining chemical control of biological systems through stimulus-reactive groups with receptor engineering. The objective of this proposal is to develop universal antigen receptor systems that are conditionally activated or deactivated by controller stimuli including small molecule exposure, as well as chemical changes characteristic of diseased cellular microenvironments and antigen combinations. This will be achieved through completion of the following aims: (1) Conditional control of universal antigen receptor signaling with OFF-switch adaptors. (2) Conditional control of universal antigen receptor signaling using ON-switch adaptors. (3) Combinatorial control of universal adaptor CAR T cells. The underlying principle of our approach is a covalent bond formation between the adaptor and a self-labeling SNAPtag enzyme fused to the receptor. Besides robust activation of cell signaling, the synthetic chemical linker between the antibody and the receptor allows us to dial in a wide range of stimuli responses, including chemical and biological triggers, based on distinct chemical designs of the linker molecules. Our characterization includes demonstration in vitro using primary human T cells and in vivo in human cell xenograft mouse models. Adoptive cell therapy with antigen receptor engineered cells is an active area of development and clinical use, and the unprecedented level of conditional control enabled by the proposed systems will, as a long-term goal, lead to improved patient outcomes through improved targeting and the ability to treat new disease indications.

项目摘要 使用抗原受体工程T细胞使用的收养细胞疗法是一种高度有前途的治疗方法， 哪些细胞在遗传上修饰以表达抗原受体蛋白，然后适当转移 进入病人。然后，这些细胞充当一种“活着的药物”，可以对 在体内任何地方感测靶抗原。这种方法正在彻底改变血液的治疗 癌症和表现出的细胞疗法有望治疗实体瘤，自身免疫性疾病和慢性病毒 感染。我们正在开发高度模块化的通用适配器版本的接收器，我们称之为snap-car 和snap synnotch。这些受体是“通用的” 由共同辅助辅助分子组成的抗原结合区域的共同辅助衔接子分子相结合 苄鸟氨酸基序。通用接收器系统可用于靶向单个患者或 在几种疾病的指示中，简单地改变了抗原靶向衔接子分子。 尽管抗原受体技术具有巨大的希望，但它们的实施受到了限制 难以通过单个抗原靶向获得患病的细胞特异性，以及不必要的tar- 从过度活跃的细胞中获取/脱份毒性和毒性。我们正在解决这些技术差距 通过采用化学生物学方法并结合化学控制，抗原受体信号传导特异性 通过受体工程刺激反应组的生物系统。 该建议的目的是开发有条件激活的通用抗原受体系统 或通过控制器刺激（包括小分子暴露）以及化学变化的特征而停用 疾病的细胞微环境和抗原组合。这将通过完成 以下目的：（1）用外切换适配器对通用抗原受体信号传导的条件控制。 （2） 使用开关适配器对通用抗原受体信号传导的条件控制。 （3）组合控制 通用适配器T细胞。 我们方法的基本原理是适配器与自标记之间的共价形成 Snaptag酶融合到接收器上。除了强大的细胞信号激活外，合成化学连接器 在抗体和受体之间使我们可以拨打广泛的刺激反应，包括化学 基于接头分子的不同化学设计。我们的特征包括 使用原代人T细胞和人体异种移植小鼠模型中的体内进行体外演示。 抗原受体工程细胞的收养细胞疗法是发育和临床使用的活跃领域， 作为长期目标，提议的系统实现了前所未有的条件控制水平 通过改善靶向和治疗新疾病适应症的能力，导致患者的预后改善。