N-glycosylation and Immunotherapy for cancer

N-糖基化和癌症免疫治疗

基本信息

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
项目类别：
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

项目摘要

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IMUNE的疗法为癌症治疗提供了有希望的新方法。其中包括检查点抑制剂盗贼T细胞抑制（例如抗PD-1），双特异性抗体与癌细胞（例如双特异性T细胞咬合）的交联T细胞和设计以表达的T细胞这三个方法诱导T细胞介导的癌细胞的杀伤。抗体和CAR T细胞受到少量已知细胞表面蛋白的限制特定于癌症允许抗体的靶向。造血性恶性肿瘤，健康细胞的丧失不能被干细胞祖细胞补充。解决方案是靶向癌症特异性聚糖，而不是蛋白质抗原。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。对复杂碳水化合物特异的单克隆抗体具有支撑，极大地限制了他们作为癌症免疫疗法的目标有用。开发出一种新型的侵蚀性疗法药，以靶向N连接的碳水化合物抗原绝大多数固体和造血癌。依赖的T -Cell招聘者（Glytr）技术。靶碳水化合物抗原。专门与人CD3及其N-聚糖靶标的结合，2）仅在存在的情况下稳健地激活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小鼠的既定结肠癌Xenographthogroghth的体内生长没有触发产生小鼠中的抗体表征人和小鼠反应性Glytr Bi特异性蛋白针对N-聚糖检查使用人源化NSG小鼠靶向N-聚糖的Glytr蛋白的功效和安全性。 AIM 3将检查靶向N-Glycans的Glytr蛋白的功效和安全性正常的免疫系统。杀死免疫治疗的癌症类别能够用酸性和造血剂最小的毒品。