碳酸无水酶2-衍生药物反应域调节工程T细胞中的膜结合细胞因子表达和功能
Mara C Inniss1, Sean G Smith1, Dan Jun Li1
1Obsidian Therapeutics, Cambridge, MA, USA.
Communications biology
|January 9, 2025
概括
工程T细胞可以将细胞因子输送到固体瘤中,增强癌症治疗. 一个新的药物反应系统控制了细胞因子的输送,提高了采用细胞疗法 (ACT) 的安全性和有效性.
科学领域:
- 免疫学 免疫学 免疫学
- 生物技术是生物技术.
- 癌症研究 癌症研究
背景情况:
- 采用细胞疗法 (ACT) 在固体瘤中表现出有限的疗效,这是由于免疫抑制性瘤微环境 (TME) 的原因.
- 类细胞因子可以通过重塑TME来增强ACT,但系统性毒性需要控制的表达.
研究的目的:
- 开发一种用于调节T细胞上膜结合细胞因子的新系统,以提高ACT疗效.
- 设计具有药物反应域 (DRD) 的T细胞,以控制细胞因子的输送和增强抗瘤活性.
主要方法:
- 带有膜结合型细胞因子的工程T细胞与来自人类碳酸酶2 (CA2) 的药物反应域 (DRD) 融合.
- 利用FDA批准的抑制剂乙胺 (ACZ) 来稳定和控制CA2-DRD功能.
- 采用蛋白质工程来创建用于增强DRD价值的"调制枢纽",并通过突变选,晶体学和分子动力学 (MD) 模拟开发条件降解子.
- 通过调节膜结合IL-12并评估其在固体瘤模型中的有效性来验证该系统.
主要成果:
- 通过使用CA2-DRDs和ACZ.成功地用表面表达的,药物调节的细胞因子 (IL-2,IL-12,IL-15,IL-21,IL-23,IFNα) 设计了T细胞.
- 在体外和体内证明了细胞因子表达和功能的严格调节.
- 在固体瘤模型中展示了CA2-DRD调节的IL-12介质控制的抗瘤疗效.
结论:
- 开发的CA2-DRD系统能够精确控制工程T细胞中的膜结合细胞因子表达.
- 这种方法提供了一个潜在的策略,通过调节瘤微环境,安全地提高固体瘤采用细胞疗法的疗效.
相关概念视频
T Cell Activation and Clonal Selection
651
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
Naive T cells that have not yet encountered an antigen express two primary CD...
651
Receptor Downregulation in MVBs
2.0K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.0K
Regulation of Hematopoietic Stem Cells
3.1K
All blood and immune cells are produced from the multipotent hematopoietic stem cells (HSCs) by the process of hematopoiesis. However, they all have a limited life span. In addition, many are depleted in immune surveillance or combatting an injury or infection. This makes blood one of the most regenerative tissues. Hematopoiesis helps replenish these blood and immune cells, restoring the body's normal functioning. However, overproduction of blood and immune cells can make them cancerous or...
3.1K


