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: 10462737
• 负责人: DAVID A SCHEINBERG
• 金额: $ 104.08万
• 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/10462737
• 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，我的研究目标就是区分癌细胞和非正常细胞的特征。 健康细胞，以便能够发现和开发安全、选择性、创新的 免疫疗法。在这里，我们利用了我过去从本地鼠标演变而来的工作成果 抗体、人源化 mAb、这些 mAb 的各种有效缀合物、TCRm 抗体、 最终以BiTE形式和CAR形式创建最新一代的代理和 现在提出了实验。这一科学进步已经持续了 3 年多 几十年。这项工作具有创新性，正如我们的众多治疗首例和超过 3 个 数十项专利，包括：用于治疗急性白血病的人类抗体、靶向α- 粒子疗法、体内α粒子同位素发生器、致癌融合点疫苗、 针对细胞内致癌蛋白的人类 TCR 模拟抗体，以及最近的各种 创新的 CAR 技术正在进行中。一些抗体和疫苗达到了 后期国家临床试验，例如 WT1 疫苗、Galenpepimut 和我们的 alpha 发生器-林妥珠单抗。但现在，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 发展为高效且真正具有选择性的系统 识别来自细胞内部的病毒和突变的细胞内蛋白质。因此，在 该 OIA 的问题是：是否有可能制造出真正的癌症选择性单克隆抗体， 以及各种衍生的分子平台，通过模仿 TCR？这种方法的障碍和抗癌机制是什么？ 他们会被克服吗？我们如何选择正确的目标表位并避免不可避免的偏离 可能引起毒性的目标？将解决以下问题： A. 目标选择：什么 从生物化学、生物物理或免疫学的角度来看，最好的表位是什么？是 某些类别的蛋白质或肽结构是首选？我们如何设计屏幕 TCRm？ B. 我们可以调节表位的表达或抗原呈递吗 机械？ MHC 配体通常如何受到这些药物的影响？这重要吗？ C. 预测工具：我们能否开发蛋白质组学和遗传工具来创建一般规则并 帮助指导我们选择表位并预测哪些表位可能是安全的？ D、什么癌症 根据我们所了解的情况，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？