Bispecific molecules linking T cell receptor and tumor antigen for cancer immunotherapy

连接 T 细胞受体和肿瘤抗原的双特异性分子用于癌症免疫治疗

• 批准号: 10747580
• 负责人: Rafi Ahmed
• 金额: $ 7.99万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747580
• 关键词: Affect; Affinity; Binding; Biochemical; Biological Process; CD3 Antigens; CD8B1 gene; Cancerous; Cells; Characteristics; Data Set; Docking; Immune response; Immunotherapy; Light; Link; Malignant Neoplasms; Measures; Peptide/MHC Complex; Performance; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Treatment Efficacy; Tumor Antigens; biophysical properties; cancer cell; cancer immunotherapy; cancer therapy; design; programmed cell death protein 1; tumor

PROJECT SUMMARY T cells are responsible for the eradication infectious or cancerous cells in the body; however, cancer cells are capable of evading T cell recognition and activation. Bispecific molecules are an emerging treatment option for cancer immunotherapy that enhances the T cell’s ability to recognize cancerous cells and perform an immune response. Their mechanism of action is to increase T cell sensitivity to cancer cells and efficacy by binding to both T cells and the cancerous pMHC. Limitations in current designs include the inability to predict T cell activation after binding and in efficacy for treating cancer. The objective of this proposal is to expand our understanding of the factors that affect efficacy of bispecific molecules to enhance T cell performance. We hypothesize that force dependent binding and docking orientation impact the overall efficacy of bispecific molecules. The two specific aims are: Aim 1. Identify the determining factor(s) of the anti-tumor efficacy of bispecific molecules Aim 1A. Determine the 2D affinity and force dependent bond lifetime between several ImmTAC vs. pHLA and vs CD3, thereby providing a unique dataset only our lab is capable to obtain. Aim 1B. Examine the correlation, or the lack thereof, between the biophysical characteristics of the interactions measured in 1A with the biochemical characteristics and biological functions of the ImmTAC molecules, thereby shedding light on the determinant of their therapeutic efficacy Aim 2. Assess how the pMHC docking orientation affects anti-tumor efficacy of the TCR Aim 2A. Determine 2D affinity and force dependent bond lifetime for canonical and reversed orientation TCRs. Aim 2B. Determine if the absence of CD8 is responsible for low efficacy when TCR is in reversed orientation. Completing these aims will provide a new perspective on the considerations to be taken when designing bispecific molecules for cancer immunotherapy.

项目概要 T 细胞负责消灭体内的感染细胞或癌细胞，但癌细胞则不然。 能够逃避 T 细胞识别和激活的双特异性分子是一种新兴的治疗选择。 癌症免疫疗法可增强 T 细胞识别癌细胞并执行免疫的能力 它们的作用机制是通过结合来提高 T 细胞对癌细胞的敏感性和功效。 当前设计中 T 细胞和癌性 pMHC 的局限性包括无法预测 T 细胞。 结合后激活并有效治疗癌症 该提案的目的是扩大我们的研究范围。 了解影响双特异性分子增强 T 细胞性能功效的因素。 研究发现力依赖性结合和对接方向影响双特异性的整体功效 两个具体目标是： 目标1.确定双特异性分子抗肿瘤功效的决定因素 目标 1A。确定几种 ImmTAC 与 pHLA 之间的 2D 亲和力和力依赖性键合寿命 与 CD3 相比，从而提供了只有我们实验室才能获得的独特数据集。 目标 1B。检查相互作用的生物物理特征之间的相关性或缺乏相关性。 在1A中测量ImmTAC分子的生化特征和生物功能， 从而揭示其治疗效果的决定因素 目标 2. 评估 pMHC 对接方向如何影响 TCR 的抗肿瘤功效 目标 2A。确定规范和反向 TCR 的 2D 亲和力和力依赖性键寿命。 目标 2B。确定 CD8 的缺失是否会导致 TCR 方向相反时的低功效。 完成这些目标将为设计时的考虑提供新的视角 用于癌症免疫治疗的双特异性分子。