Developing therapeutic TCR mimic monoclonal antibodies for cancer

开发治疗癌症的 TCR 模拟单克隆抗体

• 批准号: 10515878
• 负责人: Tao Dao
• 金额: $ 13.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515878
• 关键词: 3-Dimensional; Amino Acids; Antibodies; Antigen Presentation Pathway; Antigens; Biopsy; Bispecific Antibodies; Cell Line; Cell surface; Cervix carcinoma; Complex; Cytotoxic agent; Development; Dose; Engineering; Epitopes; HLA-A gene; HPV E7; Half-Life; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Human Papillomavirus; Human papillomavirus 16; Immune; Immunotherapy; In Vitro; Insulin Receptor; MHC Class I Genes; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mass Spectrum Analysis; Membrane Proteins; Methods; Molecular Conformation; Monoclonal Antibodies; Monoclonal Antibody Therapy; Oncoproteins; Peptides; Pharmaceutical Preparations; Phosphopeptides; Phosphorylation; Proteins; Radiation; Serine; Specificity; Structure; T cell therapy; T-Cell Receptor; Testing; Therapeutic; Threonine; Toxin; Treatment Efficacy; Tumor Antigens; cancer cell; chimeric antigen receptor; cost; flexibility; immunogenic; in vivo; neoantigens; novel; side effect; tool; tumor

T cell receptor mimic (TCRm) mAbs. TCRm mAbs represent a new class of mAbs, structurally identical to traditional mAbs. However, while traditional mAbs recognize 3D conformational structure of a surface protein, TCRm mAbs recognize peptides (9-10 amino acids) derived from intracellular proteins, displayed on cell surface by MHC class I molecules, the complexes traditionally recognized by TCR. This allows an antibody to have access to vast majority, truly tumor-specific antigens, most of them are intracellular proteins. The advantages of mAb therapy are well known that include their high target specificity, high efficacy, limited side effects, prolonged half-life, availability, low cost, and infrequent dosing. In addition to the immune effector functions of a mAb, mAb can also serve as antigen-specific vehicles that can deliver more potent cytotoxic agents such as toxins, drugs, or radiation. Finally, mAbs can be engineered into chimeric antigen receptors or bi-specific antibodies in order to enhance the specificity and the potency of T cell therapy. This project aimed at developing novel TCRm mAbs specific for two important, validated and tumor-specific antigens, as described below. Combining the best inherent features of both TCR recognition and the flexibility and potency of the mAbs as drugs, the new TCRm mAbs could offer a potent, controllable and widely applicable therapy. 1. Developing TCRm mAb to HPV-E7-derived epitope in the context of HLA-A*02:01. Human papilloma virus (HPV) causes hundreds of thousands of cancers worldwide. Most cervical carcinoma cells constitutively express HPV type 16 E6 and E7 oncoproteins, which provide an ideal and specific target for immunotherapies. We selected an immunogenic epitope derived from E7 protein (E7 p11-19) presented by HLA-A*02:01 as the target for the TCRm mAb. This epitope has been reproducibly detected in a majority of cervical cancer biopsies and cell lines in the context of HLA-A*02:01 molecule by mass spectrometry. 2. Developing TCRm mAb to pIRS2 in the context of HLA-A*02:01. Dysregulated protein phosphorylation is a hallmark of malignant transformation. Phosphorylation of serine and threonine residues is retained on peptides during MHC class I and class II antigen processing and presentation on the cell surface. Therefore, phosphopeptides derived from inappropriate phosphorylation of various proteins in malignant cells represent an extraordinary class of tumor specific neoantigens, that are also widely expressed and not patient-specific. We hypothesize that phosphopeptides could be used as shared tumor specific neoantigens. We selected a phosphopeptide of insulin receptor substrate2 (pIRS21097-1105) in the context of HLA-A*02:01 as the target for the TCRm development. This epitope has been identified in various cancer cells by mass spectrometry. We have a set of experimental tools and methods to select, characterize specific mAbs and to test their therapeutic efficacy both in vitro and in vivo.

T细胞受体模拟（TCRM）mAb。 TCRM mabs代表了新的单元格，在结构上与 传统的mab。但是，尽管传统mAb识别表面蛋白的3D构象结构，但 TCRM mAb识别源自细胞内蛋白的肽（9-10个氨基酸），显示在细胞上 MHC I类分子的表面，传统上由TCR识别的复合物。这允许抗体 可以使用绝大多数，真正的肿瘤特异性抗原，其中大多数是细胞内蛋白质。这 MAB治疗的优势是众所周知的，包括其高目标特异性，高疗效，有限的一面 效果，长时间寿命，可用性，低成本和不经常给药。除了免疫效应子 mAb的功能，mAb也可以用作抗原特异性车辆，可以提供更有效的细胞毒性 毒素，药物或辐射等药物。最后，可以将mAb设计成嵌合抗原受体 或生物特异性抗体，以增强T细胞疗法的特异性和效力。 该项目旨在开发针对两个重要，经过验证和肿瘤特异性的新型TCRM mABS 抗原，如下所述。结合TCR识别和灵活性的最佳固有特征 MABS作为药物的效力，新的TCRM mAB可以提供有效，可控制的且广泛的 适用的疗法。 1。在HLA-A*02：01的背景下，将TCRM mAb开发到HPV-E7衍生的表位。人乳头瘤 病毒（HPV）在全球范围内引起数十万种癌症。大多数宫颈癌细胞组成性细胞 Express HPV 16 E6和E7癌蛋白，为免疫疗法提供了理想和特定的靶标。 我们选择了由HLA-A*02：01提出的源自E7蛋白（E7 P11-19）的免疫原性表位为 TCRM mAb的目标。在大多数宫颈癌活检中都检测到该表位 在HLA-A*02：01分子的质谱法中，细胞系和细胞系。 2。在HLA-A*02：01的上下文中开发TCRM mAb至PIRS2。蛋白质磷酸化失调 是恶性转变的标志。丝氨酸和苏氨酸残基的磷酸化保留在 MHC I类和II类抗原加工和细胞表面上的表现过程中的肽。所以， 来自恶性细胞中各种蛋白质不适当磷酸化的磷酸肽代表 一种非凡的肿瘤特异性新抗原，也广泛表达且不表达患者。 我们假设磷酸肽可以用作共享肿瘤特异性新抗原。我们选择了一个 HLA-A*02：01的胰岛素受体底物2（PIRS21097-1105）的磷酸肽 用于TCRM开发。该表位已通过质谱法在各种癌细胞中鉴定出来。 我们有一组实验工具和方法可以选择，表征特定的mab并测试其 体外和体内的治疗功效。