Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.

摘要 自1978年以来，我的研究目标一直是区分癌细胞和 为了能够发现和发展健康的细胞，具有安全性和选择性，创新性 免疫疗法。在这里，我们利用我过去从原生鼠标进化而来的作品 抗体，人源化单抗，这些单抗的各种有效结合物，TCRm抗体， 并最终以咬合形式和汽车形式创造出最新一代的代理商和 现在提出了实验方案。这一科学进步已经持续了3年多 几十年。这项工作是创新的，正如我们无数次治疗的第一次和超过3次 十几项专利，包括：用于治疗急性白血病的人类抗体，靶向阿尔法- 粒子疗法，体内α粒子同位素发生器，致癌融合点疫苗， 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，现在正在进步。几种抗体和疫苗已经达到 后期的国家临床试验，如WT1疫苗、GalenPepimut和我们的阿尔法 生成器-Lintuzumab。但现在，我们如何实现真正的癌症特异性？免疫者 系统已经将T细胞和TCR进化为一种高效和真正具有选择性的系统 识别来自细胞内的病毒和突变的细胞内蛋白。因此，在 这个OIA的问题是：是否有可能制造出真正的癌症选择性单抗， 以及各种衍生的分子平台，通过模仿一种 TCR？这种方法的障碍和抗癌机制是什么？将如何 他们会被克服吗？我们如何选择正确的目标表位，同时避免不可避免的偏离- 可能导致毒性的靶标？将解决以下问题：a.目标选择：什么 从生化、生物物理或免疫学的角度来看，最好的表位是什么？是 某些种类的蛋白质或多肽结构更受欢迎？我们如何设计屏幕 TCRM？B.我们能调节表位的表达或抗原的呈递吗？ 机器？这些药物对MHC配基有什么影响？这很重要吗？ 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 帮助指导我们挑选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的治疗平台是最有意义的 表位的生物学和免疫学，以及从该工具预测的特异性 套装？

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?