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: 10684310
• 负责人: Jason Jakob Lohmueller
• 金额: $ 44.24万
• 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/10684310
• 关键词: Acidosis; Address; Adoptive Cell Transfers; Adoptive Transfer; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Area; Autoimmune Diseases; Biological; Biological Process; Biology; Cell Therapy; Cells; Characteristics; Chemicals; Chronic; Clinical; Collaborations; Development; Disease; Engineering; Enzymes; 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; Receptor Activation; Receptor Signaling; Response to stimulus physiology; SNAP receptor; Safety; Signal Transduction; Site; Solid Neoplasm; Specificity; Stimulus; Synthetic immunology; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Therapeutic Effect; Therapeutic antibodies; Toxic effect; Validation; Virus Diseases; Xenograft procedure; antigen binding; 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; pharmacologic; 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 使用抗原受体工程化的T细胞的免疫细胞疗法是一种非常有前途的治疗方法， 所述细胞经遗传修饰以表达抗原受体蛋白， 植入病人体内然后，这些细胞作为一种“活药物”，可以引起有效的治疗效果， 在身体任何地方的细胞上感应目标抗原。这种方法正在彻底改变血液的治疗方法 在治疗实体瘤、自身免疫性疾病和慢性病毒性肝炎的细胞疗法中显示出前景。 感染我们正在开发高度模块化的通用适配器版本的受体，我们称之为SNAP-CAR 和SNAP-synNotch。这些受体是“通用的”，因为它们可以通过化学编程靶向任何一种- 通过共同施用的衔接子分子，所述衔接子分子由缀合至抗原结合区的抗原结合区组成， 苄基鸟嘌呤基序通用受体系统可用于靶向单个患者中的多种抗原，或 通过简单地改变靶向抗原的衔接子分子， 尽管抗原受体技术具有巨大的前景，但它们的实施受到以下因素的限制： 通过单一抗原靶向获得病变细胞特异性的困难，以及不需要的靶向， 获得/脱离疾病毒性和过度活跃细胞的毒性。我们正在解决这些技术差距， 抗原受体信号传导特异性，通过采取化学生物学方法并结合化学控制， 生物系统通过刺激反应基团与受体工程。 本提案的目的是开发条件激活的通用抗原受体系统 或通过包括小分子暴露在内的控制器刺激以及化学变化特征而失活 病变细胞微环境和抗原组合的影响。这将通过完成 以下目的：（1）用OFF开关衔接子有条件地控制通用抗原受体信号传导。（二） 使用开启开关衔接子的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CAR T细胞。 我们的方法的基本原理是在适配器和自标记之间形成共价键 SNAPtag酶与受体融合。除了细胞信号传导的强烈激活外， 抗体和受体之间的联系使我们能够在广泛的刺激反应中拨号，包括化学反应。 和生物触发剂，基于连接分子的不同化学设计。我们的特征包括 在体外使用原代人T细胞和在体内在人细胞异种移植物小鼠模型中进行证明。 使用抗原受体工程化细胞的免疫细胞疗法是开发和临床应用的活跃领域， 并且，作为一个长期目标， 通过改进靶向和治疗新疾病适应症的能力，改善患者预后。