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.

项目摘要 几十年来，癌症的治疗一直依赖于手术切除，化学疗法和/或放疗。 最近，许多基于免疫的疗法为癌症治疗提供了新的方法。 其中包括阻塞T细胞抑制（例如抗PD-1）的检查点抑制剂，双特异性抗体 交联的T细胞与癌细胞（例如Bi特异性T细胞工程师 - 咬合）和设计表达的T细胞 抗原受体特有的癌细胞（例如嵌合抗原受体T细胞或CAR T）。这三个 方法诱导T细胞介导的癌细胞杀死。但是，双特异性的宽度开发 抗体和CAR T细胞受到足够多的已知细胞表面蛋白的限制 特定于癌症，可以安全地通过抗体靶向。对于固体癌症而言，尤其如此 造血恶性肿瘤，健康细胞的丧失不能被干细胞祖细胞复制。一个 解决此问题的方法是靶向癌症特定的聚糖抗原，而不是蛋白质抗原。确实，改变了 糖基化是癌症几乎普遍的特征，代表了最丰富，最广泛的细胞 表面癌抗原，同时在正常组织中也有限或没有表达。但是，产生 事实证明，针对复杂的碳水合物特异性的单克隆抗体非常挑战，极大地限制了 它们作为癌症免疫疗法的靶标有用。在这里，我们建议解决这些问题， 开发一种新型的免疫治疗药，该免疫疗法针对N连接的碳水化合物抗原 绝大多数固体和造血癌。我们称这些分子为聚糖 依赖的T细胞招聘器（Glytr）技术。至关重要的是，Glytr技术不利用抗体 靶碳水化合物癌抗原。初步数据表明Glytr Bi特异性蛋白1） 2）仅在存在的情况下强化T细胞 癌细胞的3）诱导T细胞依赖于EC50低至5pm的癌细胞杀死癌细胞，4）抑制 人源化NSG小鼠中已建立的结肠癌异种移植物的体内生长并没有触发产生 小鼠的抗体。为了进一步扩展这种方法，提出了以下目标。目标1意志 表征靶向N-聚糖的人和小鼠反应性Glytr Bi特异性蛋白。 AIM 2意志 检查使用人源化NSG小鼠靶向N-聚糖的Glytr蛋白的效率和安全性。 AIM 3将检查使用与A的小鼠靶向N-聚糖的Glytr蛋白的效率和安全性 正常免疫系统。如果成功，这些实验将为整个新的新事物提供主要数据证明 杀死免疫治疗的癌症类别能够靶向多种固体和造血癌 最小的毒性。