Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.

使用治疗性单克隆抗体理解和模拟 TCR 识别。

• 批准号: 10238855
• 负责人: DAVID A SCHEINBERG
• 金额: $ 106.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-14 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238855
• 关键词: Acute leukemia; Address; Affect; Alpha Particles; Antibodies; Antibody Therapy; Antigen Presentation; Antigen Targeting; Biochemical; Biology; Biophysics; Bite; Cell Therapy; Cells; Clinical Trials; Epitopes; Generations; Genetic; Goals; Human; Immune system; Immunologics; Immunology; Immunotherapy; Isotopes; Legal patent; Light; Malignant Neoplasms; Molecular; Monoclonal Antibodies; Mus; Mutate; Oncogenic; Pharmaceutical Preparations; Proteins; Proteomics; Research; Specificity; System; T-Lymphocyte; Technology; Therapeutic; Therapeutic Monoclonal Antibodies; Toxic effect; Vaccines; Viral; WT1 gene; Work; base; cancer cell; cancer therapy; design; effective therapy; experimental study; in vivo; innovation; particle therapy; peptide structure; predictive tools; resistance mechanism; therapeutically effective; tool; tumor

Abstract The goals of my research since 1978 have been to distinguish the features of cancer cells from healthy cells in order to be able to discover and develop safe and selective, innovative immunotherapies. Here, we leverage my past body of work that has evolved from native mouse antibodies, to humanized mAb, to various potent conjugates of these mAb, to TCRm antibodies, and ultimately to BiTE forms and CAR forms to create the latest generation of agents and experiments now proposed. This scientific progression has been sustained for more than 3 decades. This work is innovative, as noted by our numerous therapeutic firsts and more than 3 dozen patents, including: human antibodies for the treatment of acute leukemia, targeted alpha- particle therapies, in vivo alpha-particle isotope generators, oncogenic fusion point vaccines, human TCR mimic antibodies to intracellular oncogenic proteins, and most recently, various innovative CAR technologies, now in progress. Several of the antibodies and vaccines reached late stage, national clinical trials such as a WT1 vaccine, Galenpepimut, and our alpha generator-Lintuzumab. But now, how do we achieve true cancer specificity? The immune system has evolved the T cell and TCR as a highly efficient and truly selective system capable of recognizing viral and mutated intracellular proteins derived from inside the cell. Therefore, in this OIA the questions are: Is it possible to make truly cancer selective monoclonal antibodies, and various derived molecular platforms, that will be effective therapeutically by mimicking a TCR? What are the obstacles and cancer resistance mechanisms to this approach and how will they be overcome? How do we select the right target epitopes and also avoid inevitable off- targets that may cause toxicity? The following issues will be addressed: A. Target choices: What are the best epitopes from a biochemical, biophysical, or immunological point of view? Are certain classes of proteins or structures of peptides preferred? How do we design screens for TCRm? B. Can we modulate the expression of the epitopes or the antigen presentation machinery? How is the MHC ligandome generally affected by these drugs and is this important? C. Predictive tools: Can we develop proteomic and genetic tools to create general rules and to help guide us to picking epitopes and predicting which may be safe? D. What cancer therapeutic platform for the TCRm makes the most sense in light of what we have learned about the biology and immunology of the epitope, as well as the predictions of specificity from the tool sets?

抽象的 自1978年以来我研究的目标是将癌细胞的特征与 健康的细胞，以便能够发现并发展安全，有选择性，创新性 免疫疗法。在这里，我们利用我过去从本地鼠标演变的工作 对这些mAb的各种有效偶联物的人性化mAb的抗体，抗体抗体，抗体抗体，TCRM抗体， 并最终咬一口形式和汽车形式，以创建最新一代的代理商和 现在提出的实验。这种科学进步已经维持了3个以上 几十年。这项工作具有创新性，正如我们众多的治疗性的第一件事所指出的那样，超过3个 十二种专利，包括：用于治疗急性白血病的人类抗体，针对α- 粒子疗法，体内α-粒子同位素发生器，致癌点疫苗， 人类TCR模拟细胞内致癌蛋白的抗体，最近，各种 创新的汽车技术正在进行中。到达了几种抗体和疫苗 晚期，国家临床试验，例如WT1疫苗，Galenpepimut和我们的Alpha 发电机林图珠单抗。但是现在，我们如何实现真正的癌症特异性？免疫 系统已将T细胞和TCR演变为高效且真正选择性的系统 识别从细胞内部衍生的病毒和突变的细胞内蛋白。因此，在 这个问题是：是否有可能使真正的癌症选择性单克隆抗体， 以及各种派生的分子平台，这将通过模仿A来有效治疗 tcr？这种方法的障碍和抗癌机制是什么？ 他们被克服了吗？我们如何选择合适的目标表位，也避免不可避免的偏离 - 可能导致毒性的目标？将解决以下问题：A。目标选择：什么 是从生化，生物物理或免疫学角度出发的最好的表位吗？是 某些类别的蛋白质或肽的结构首选？我们如何设计屏幕 tcrm？ B.我们可以调节表位或抗原表现的表达 机械？ MHC长甘血通常如何受这些药物影响，这很重要？ C.预测工具：我们可以开发蛋白质组学和遗传工具来创建一般规则和 帮助我们指导我们选择表位并预测哪些安全？ D.什么癌 鉴于我们学到的知识，TCRM的治疗平台最有意义 表位的生物学和免疫学以及工具的特异性预测 套？