N-glycosylation and Immunotherapy for cancer

N-糖基化和癌症免疫治疗

• 批准号: 10005189
• 负责人: MICHAEL DEMETRIOU
• 金额: $ 68.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005189
• 关键词: Address; Antibodies; Antibody Formation; Antigen Receptors; Antigens; Binding; Binding Proteins; Bite; CD3 Antigens; Carbohydrates; Cell Surface Proteins; Cell surface; Cells; Colon Carcinoma; Complex; Data; Development; Engineering; Excision; Generations; Genes; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Lectin; Link; Malignant Neoplasms; Mediating; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; PD-1 inhibitors; Phaseolus vulgaris; Plant Lectins; Polysaccharides; Production; Proteins; Radiation therapy; Safety; Sensitivity and Specificity; Solid; T-Lymphocyte; Technology; Therapeutic; Time; Toxic effect; Tumor Antigens; Tumor Immunity; Tumor-Associated Carbohydrate Antigens; Xenograft procedure; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-cancer; antibody engineering; base; bi-specific T cell engager; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chemotherapy; chimeric antigen receptor T cells; cost; crosslink; engineered T cells; experimental study; glycosylation; in vivo; new technology; novel; novel strategies; stem cells; sugar; tumor growth

Project Summary For decades, the treatment of cancer has relied on surgical resection, chemotherapy and/or radiotherapy. Recently, a number of immune based therapies have provided promising new approaches for cancer treatment. These include checkpoint inhibitors that block T cell suppression (eg anti-PD-1), bi-specific antibodies that cross-link T cells to cancer cells (eg Bi-specific T cell engagers – BiTE) and T cells engineered to express antigen receptors specific to cancer cells (eg Chimeric Antigen Receptor T cells or CAR T). All three approaches induce T cell mediated killing of cancer cells. However, widespread development of bi-specific antibodies and CAR T cells is limited by the small number of known cell-surface proteins that are sufficiently specific to cancer to safely allow targeting by antibodies. This is particularly true for solid cancers, where unlike hematopoietic malignancies, loss of healthy cells cannot be readily replenished by stem cell progenitors. A solution to this issue is to target cancer specific glycan antigens rather than protein antigens. Indeed, altered glycosylation is a near universal feature of cancer and represent the most abundant and widely expressed cell surface cancer antigens, while also having limited or no expression in normal tissue. However, generation of monoclonal antibodies specific to complex carbohydrates has proven to be very challenging, greatly limiting their usefulness as targets for cancer immunotherapy. Here we propose to address these issues and develop a novel class of immunotherapeutics that target an N-linked carbohydrate antigen common to the vast majority of solid and hematopoietic cancers. We have termed these molecules as Glycan- dependent T cell Recruiter (GlyTR) technology. Critically, GlyTR technology does not utilize antibodies to target carbohydrate cancer antigens. Preliminary data demonstrates that the GlyTR bi-specific protein 1) specifically bound to both human CD3 and its N-glycan target, 2) robustly activated T cells only in the presence of cancer cells, 3) induced T cell dependent killing of cancer cells with an EC50 as low as 5pM, 4) inhibited in vivo growth of established colon cancer xenografts in humanized NSG mice and 5) did not trigger production of antibodies in mice. To further expand on this approach, the following Aims are proposed. Aim 1 will characterize human and mouse reactive GlyTR bi-specific proteins targeting N-glycans. Aim 2 will examine the efficacy and safety of GlyTR proteins targeting N-glycans using humanized NSG mice. Aim 3 will examine the efficacy and safety of GlyTR proteins targeting N-glycans using mice with a normal immune system. If successful, these experiments will provide proof of principal data for an entire new class of cancer killing immunotherapeutic's capable of targeting multiple solid and hematopoietic cancers with minimal toxicity.

项目概要 几十年来，癌症的治疗一直依赖于手术切除、化疗和/或放疗。 最近，许多基于免疫的疗法为癌症治疗提供了有希望的新方法。 其中包括阻止 T 细胞抑制的检查点抑制剂（例如抗 PD-1）、双特异性抗体 将 T 细胞与癌细胞交联（例如双特异性 T 细胞接合器 – BiTE）以及经过工程改造的 T 细胞 癌细胞特异性抗原受体（例如嵌合抗原受体 T 细胞或 CAR T）。全部三个 方法诱导 T 细胞介导的癌细胞杀伤。然而，双特异性技术的广泛发展 抗体和 CAR T 细胞受到少量已知细胞表面蛋白的限制，这些蛋白足以 特异性针对癌症，以安全地允许抗体靶向。对于实体癌尤其如此，与实体癌不同 造血系统恶性肿瘤，健康细胞的损失不能轻易地由干细胞祖细胞补充。一个 解决这个问题的方法是针对癌症特异性聚糖抗原而不是蛋白质抗原。确实，改了 糖基化是癌症的一个近乎普遍的特征，代表了最丰富和最广泛表达的细胞 表面癌抗原，同时在正常组织中也有有限的表达或没有表达。然而，一代 事实证明，针对复杂碳水化合物的单克隆抗体非常具有挑战性，极大地限制了 它们作为癌症免疫治疗靶标的有用性。在此我们建议解决这些问题 开发一类新型免疫疗法，针对常见的 N 连接碳水化合物抗原 绝大多数实体癌和造血系统癌症。我们将这些分子称为聚糖- 依赖性 T 细胞招募剂 (GlyTR) 技术。重要的是，GlyTR 技术不利用抗体 靶向碳水化合物癌症抗原。初步数据表明 GlyTR 双特异性蛋白 1) 特异性结合人类 CD3 及其 N-聚糖靶标，2) 仅在存在时才强力激活 T 细胞 癌细胞，3) 诱导 T 细胞依赖性杀伤癌细胞，EC50 低至 5pM，4) 在 已建立的结肠癌异种移植物在人源化 NSG 小鼠中的体内生长，并且 5) 不会引发 小鼠体内产生抗体。为了进一步扩展这种方法，提出了以下目标。目标1将 表征针对 N-聚糖的人类和小鼠反应性 GlyTR 双特异性蛋白。目标2将 使用人源化 NSG 小鼠检查靶向 N-聚糖的 GlyTR 蛋白的功效和安全性。 目标 3 将使用小鼠检查针对 N-聚糖的 GlyTR 蛋白的功效和安全性 正常的免疫系统。如果成功，这些实验将为全新的技术提供主要数据的证明 能够靶向多种实体癌和造血系统癌症的一类癌症杀伤免疫治疗药物 毒性最小。