Targeting aberrant glycopeptide tumor antigens for generation of novel cancer therapeutics with enhanced selectivity and utility

靶向异常糖肽肿瘤抗原以产生具有增强选择性和实用性的新型癌症疗法

• 批准号: 9551654
• 负责人: Alex Jordan Harvey
• 金额: $ 21.29万
• 依托单位: VIAMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9551654
• 关键词: Address; Adverse drug effect; Adverse effects; Affect; Affinity; Animals; Antibodies; Antibody Therapy; Antigen Targeting; Antigens; Biliary; Binding; Breast; Carbohydrates; Cardiac Myocytes; Cell Line; Cell Separation; Cell Surface Proteins; Cell surface; Cellular Structures; Characteristics; Collaborations; Colon; Colon Carcinoma; Complex; Congestive Heart Failure; Data; Development; Dimerization; ERBB2 gene; Epitopes; Esophageal; Exhibits; Generations; Glycopeptides; Goals; Growth; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Human; Immunoglobulin G; Immunologic Adjuvants; Lead; Legal patent; Lung; Malignant Neoplasms; Maps; Methodology; Methods; Monoclonal Antibodies; Mus; Normal Cell; Normal tissue morphology; Oryctolagus cuniculus; Ovarian; Pancreas; Patients; Peptides; Pertuzumab; Phase; Polysaccharides; Protein Glycosylation; Proteins; Research; Resistance; Signal Transduction; Site; Solid Neoplasm; Specificity; Structure; Surface; System; Therapeutic; Therapeutic Agents; Therapeutic Monoclonal Antibodies; Tissues; Tn antigen; Toxic effect; Trastuzumab; Tumor Antigens; Work; base; cancer cell; cancer therapy; cancer type; clinical development; glycosylation; improved; interest; malignant breast neoplasm; malignant stomach neoplasm; neoplastic cell; novel; overexpression; polyclonal antibody; pre-clinical; protein aminoacid sequence; success; therapeutic development; tumor; tumor specificity

Project Summary The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success, leading to breakthroughs in the treatment of many types of cancer. In most cases cancer mAbs act by distinguishing normal and tumor cells by the extent of elevated expression of the target protein on the tumor cell. As there is no structural difference in the binding epitopes seen on normal and tumor cells, mAbs are still able to bind and effect normal cells, even if the target protein is expressed at low levels. As a result existing mAbs on the market can have significant side effects which disallows use for many patients. Development of numerous mAbs against novel tumor targets have incurred insurmountable hurdles due to off-target effects. The goal of this project is develop mAb-based therapeutics that exhibit superior selectivities and efficacies by combined targeting of proteins that are overexpressed by cancer cells and the presence of tumor- associated aberrant glycosylation. To achieve the goal of tumor specific targeting, we are focused on exploiting a specific glycan structure that is found on the cell surface of most solid tumors including those of the breast, lung and colon. This aberrant glycan exposes protein epitopes on cancer cells that are normally shielded on healthy tissues. There are numerous cell surface proteins that have a high potential of displaying these aberrant glycans and are known to be over-expressed on major cancers. For this proposal we are focusing on a target of a current therapeutic on the market that, while very effective, can cause significant side effects in a number of patients. We will generate an antibody-based therapeutic that addresses problematic toxicity associated with the existing therapeutic. We will use a novel immunogen platform and methodology, termed GTI, to generate mAbs with high affinity and specificity for proteins. These mAbs will be developed in such that they only recognize target proteins when modified with the tumor-specific aberrant glycans. Not only will novel and improved therapeutics result from this project, it will serve as proof of a principle that employing tumor-specific aberrant glycosylation in the context of over-expressed tumor-associated proteins is a defining methodology for the generation of truly tumor-specific therapeutic agents.

项目摘要 使用单抗治疗癌症已经取得了相当大的成功，领先 在治疗多种癌症方面取得突破。在大多数情况下，癌症单抗的作用是通过区分 正常和肿瘤细胞受肿瘤细胞上靶蛋白表达升高的程度影响。就像现在一样 在正常细胞和肿瘤细胞上看不到结合表位的结构差异，mAbs仍然能够结合和 影响正常细胞，即使目标蛋白表达水平较低。因此，现有的单抗 市场可能会有严重的副作用，这不允许许多患者使用。发展中的众多 针对新的肿瘤靶点的单抗由于靶外效应而遇到了不可逾越的障碍。 该项目目标是开发以单抗为基础的治疗药物，显示出更好的选择性和有效性 通过联合靶向癌细胞过度表达的蛋白质和肿瘤的存在- 相关的异常糖基化。为了达到肿瘤特异性靶向的目标，我们专注于开发 一种特殊的糖链结构，存在于包括乳腺在内的大多数实体肿瘤的细胞表面， 肺和结肠。这种异常的葡聚糖暴露了癌细胞上的蛋白质表位，而这些表位通常是 健康的组织。有许多细胞表面蛋白有很高的潜力展示这些 异常的葡聚糖，已知在主要癌症中过度表达。 对于这项提议，我们专注于目前市场上一种治疗药物的目标，虽然非常 有效，可在许多患者中引起显著的副作用。我们将产生一种基于抗体的 治疗，解决与现有治疗相关的有问题的毒性。 我们将使用一种新的免疫原平台和方法，称为GTI，以产生高质量的单抗 蛋白质的亲和力和专一性。这些单抗的发展将使它们只能识别目标 当用肿瘤特异性变异多聚糖修饰蛋白质时。不仅是新的和改进的疗法 这一项目的结果将证明使用肿瘤特异性异常糖基化的原理 在肿瘤相关蛋白过度表达的背景下，是产生真正意义上的 肿瘤特异性治疗剂。