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.

项目摘要 T细胞负责根除体内的感染性或癌细胞;然而，癌细胞是 能够逃避T细胞识别和激活。双特异性分子是一种新兴的治疗选择， 癌症免疫疗法，其增强T细胞识别癌细胞并执行免疫治疗的能力。 反应它们的作用机制是通过与癌细胞结合来增加T细胞对癌细胞的敏感性和功效。 T细胞和癌性pMHC。目前设计的局限性包括不能预测T细胞 结合后的活化和治疗癌症的功效。这项建议的目的是扩大我们的 理解影响双特异性分子增强T细胞性能的功效的因素。我们 假设力依赖性结合和对接取向影响双特异性抗体的总体功效， 分子。这两个具体目标是： 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亲和力和力依赖性结合寿命， vs CD 3，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 用ImmTAC分子的生化特性和生物学功能在1A中测量， 从而揭示了它们治疗效果的决定因素 目标二。评估pMHC对接方向如何影响TCR的抗肿瘤功效 目标2A。确定2D亲和力和力依赖键寿命的规范和反向取向TCR。 目标2B确定当TCR处于反向方向时，CD 8的缺乏是否是低疗效的原因。 完成这些目标将提供一个新的角度考虑时，应采取的设计 用于癌症免疫治疗的双特异性分子。