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细胞受体模拟物（TCRm）mAb。TCRm mAb代表一类新的mAb，结构上与TCRm mAb相同。 传统mAb。然而，虽然传统的mAb识别表面蛋白的3D构象结构， TCRm mAb识别来自细胞内蛋白质的肽（9-10个氨基酸），展示在细胞表面 表面的MHC I类分子，传统上由TCR识别的复合物。这使得抗体能够 能够接触到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。的 mAb疗法的优点是众所周知的，包括它们的高靶特异性、高功效、有限的副作用、低剂量和高剂量。 效果、半衰期延长、可用性、低成本和不频繁给药。除了免疫效应子 除了mAb的功能之外，mAb还可以用作抗原特异性载体，其可以递送更有效的细胞毒性， 如毒素、药物或辐射等物质。最后，单克隆抗体可以被工程化到嵌合抗原受体中， 或双特异性抗体，以增强T细胞治疗的特异性和效力。 本项目旨在开发针对两种重要的、经验证的和肿瘤特异性的TCRm mAb， 抗原，如下所述。结合TCR识别和灵活性的最佳固有特性， 和作为药物的效力，新的TCRm mAb可以提供有效的，可控的和广泛的 适用疗法 1.在HLA-A*02：01的背景下开发针对HPV-E7衍生表位的TCRm mAb。人乳头瘤 人乳头瘤病毒（HPV）在全球范围内导致数十万种癌症。大多数宫颈癌细胞组成型 表达HPV 16型E6和E7癌蛋白，为免疫治疗提供了理想的特异性靶点。 我们选择来源于HLA-A*02：01呈递的E7蛋白（E7 p11-19）的免疫原性表位作为免疫原性表位。 TCRm mAb的靶点。在大多数宫颈癌活检中可重复检测到该表位 和细胞系中的HLA-A*02：01分子。 2.在HLA-A*02：01的背景下开发针对pIRS 2的TCRm mAb。蛋白磷酸化失调 是恶性转化的标志丝氨酸和苏氨酸残基的磷酸化保留在 在MHC I类和II类抗原加工和呈递到细胞表面的过程中，因此，我们认为， 来源于恶性细胞中各种蛋白质的不适当磷酸化的磷酸肽代表了 一类特殊的肿瘤特异性新抗原，其也广泛表达并且不是患者特异性的。 我们假设磷酸肽可以用作共享的肿瘤特异性新抗原。我们选择了一 以HLA-A*02：01为靶点的胰岛素受体底物2磷酸肽（pIRS 21097 -1105） 用于TCRm的开发。已经通过质谱法在各种癌细胞中鉴定了该表位。 我们有一套实验工具和方法来选择、表征特定的mAb并测试它们的功能。 在体外和体内的治疗效果。