Cancer Immunotherapy Targeting Tn Antigen

针对 Tn 抗原的癌症免疫疗法

基本信息

批准号：
10326021
负责人：
MICHAEL DEMETRIOU
金额：
$ 39.82万
依托单位：
GLYTR THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326021
关键词：
Address Antibodies Antigens B lymphoid malignancy Binding Binding Proteins Bite Blood group antigen S CD3 Antigens Carbohydrates Cell Line Cell Surface Proteins Cell surface Cells Clinical Complex Continuous Intravenous Infusion Development Engineering FDA approved Galactose Generations Growth Half-Life Hematologic Neoplasms Hematopoietic Neoplasms Hospitals Human Human Activities Immune Immune system Immunotherapeutic agent Immunotherapy In Vitro In complete remission Individual Lectin Link Liquid substance Liver Location Lymphocyte Malignant Neoplasms Mediating Monoclonal Antibodies Mus Normal tissue morphology Parents Polysaccharides Protein Engineering Proteins Pump Recycling Risk Safety Sensitivity and Specificity Serum Serum Albumin Solid T-Lymphocyte Technology Therapeutic Time Tn antigen Toxic effect Treatment Protocols Tumor Antigens Tumor-Associated Carbohydrate Antigens Xenograft procedure base bi-specific T cell engager cancer cell cancer immunotherapeutics cancer immunotherapy cancer type chimeric antigen receptor T cells clinical candidate cost drug development experimental study glycosylation improved in vitro activity in vivo macrophage meetings neonatal Fc receptor new technology nonhuman primate novel pharmacokinetics and pharmacodynamics preclinical development stem cells sugar therapeutic protein treatment duration

项目摘要

Abstract Cancer immunotherapeutic bi-specific proteins and engineered Chimeric Antigen Receptor T cells (CAR T) have shown remarkable clinical activity, with complete response rates as high as ~90% for B cell malignancies. However, applying these two therapeutic approaches to the vast majority of cancer types is restricted by multiple factors. First, there are only a 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. Second, as each individual bi-specific protein and/or CAR T cell only target a single cancer type, different bi-specific and/or CAR T cells will need to be developed for each cancer type. This greatly increases development time and costs. Third, neither therapy is able to effectively target the most abundant and widely expressed cell surface cancer antigens known, namely Tumor associated carbohydrate antigens (TACA’s). Many cancer specific antigens are not proteins, but rather complex carbohydrates that have limited or no expression in normal tissues. Indeed, altered glycosylation is a near universal feature of cancer. While TACA’s have been known for decades, generation of effective 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 the Tn antigen, an abnormal O-linked carbohydrate common on many solid and hematopoietic cancers but not present on normal tissue. We have termed this technology as Glycan-dependent T cell Recruiter (GlyTR, pronounced ‘glitter’). We have generated and optimized a GlyTR bi-specific protein that 1) specifically binds to both Tn antigen and CD3, 2) activated T cells in the presence but not absence of Tn+ cancer cells and 3) induced T cell dependent killing of diverse solid and liquid cancer cells in vitro and in vivo. However, serum half-life was ~2 hrs, which is similar to the FDA approved bi-specific protein Blincyto that requires continuous intravenous infusion (via a pump) over 28-days (first 9 days in hospital). To avoid this cumbersome treatment regimen for GlyTR, here we propose to extend the half-life by adding a human-serum albumin (HSA) domain. The half-life of HSA is ~3 weeks and has been successfully fused to therapeutic proteins to markedly increase half-life, including two FDA approved therapeutics. Here we propose to genetically fuse HSA to GlyTR (HSA-GlyTR) and confirm binding to Tn antigen, cancer-killing activity and improved half-life. Specifically, we propose the following two Aims. Aim 1 optimizes the HSA-GlyTR bi-specific protein for activity and drug development. Aim 2 explores the efficacy and safety of the optimized HSA-GlyTR bi-specific protein. If successful, these experiments will allow subsequent IND enabling studies to develop an entire new class of cancer killing immunotherapeutic’s uniquely capable of targeting multiple solid and hematopoietic cancers with a single therapeutic.

抽象的癌症免疫治疗双特异性蛋白和工程嵌合抗原受体 T 细胞 (CAR T）已显示出显着的临床活性，对 B 细胞恶性肿瘤的完全缓解率高达约 90%。然而，将这两种治疗方法应用于绝大多数癌症类型受到限制首先，只有少数已知的细胞表面蛋白质能够充分发挥作用。特定于癌症以安全地允许抗体靶向，这对于实体癌尤其如此，这与实体癌不同。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。由于每个单独的双特异性蛋白和/或 CAR T 细胞仅针对单一癌症类型，因此不同的双特异性蛋白和/或 CAR T 细胞需要针对每种癌症类型进行开发，这大大增加了开发时间。第三，这两种疗法都不能有效地靶向最丰富和最广泛表达的细胞表面。已知的癌症抗原，即肿瘤相关碳水化合物抗原（TACA）是许多癌症特异性的。抗原不是蛋白质，而是在正常组织中表达有限或不表达的复杂碳水化合物。事实上，糖基化的改变几乎是癌症的一个普遍特征，尽管 TACA 已经为人所知数十年了。事实证明，产生针对复杂碳水化合物的有效单克隆抗体非常有效具有挑战性，极大地限制了它们作为癌症免疫治疗靶标的用途。这些问题并开发了一类针对 Tn 抗原的新型免疫治疗药物，Tn 抗原是一种异常的抗原。 O-连接碳水化合物常见于许多实体癌和造血系统癌症，但不存在于正常癌症中我们将这种技术称为聚糖依赖性 T 细胞招募程序（GlyTR，发音为 Glycan-dependent T cell Recruiter）。 “glitter”）。我们生成并优化了一种 GlyTR 双特异性蛋白，它 1) 与 Tn 特异性结合。抗原和 CD3，2) 在 Tn+ 癌细胞存在但不存在的情况下激活 T 细胞，3) 诱导 T 细胞体外和体内不同固体和液体癌细胞的依赖性杀伤然而，血清半衰期约为 2 小时，类似于FDA批准的双特异性蛋白Blincyto，需要持续静脉输注（通过泵）超过 28 天（住院前 9 天）为了避免这种繁琐的 GlyTR 治疗方案，在这里，我们建议通过添加人血清白蛋白 (HSA) 结构域来延长 HSA 的半衰期。大约 3 周，并已成功与治疗蛋白融合，显着延长半衰期，包括两种 FDA 批准的疗法在此我们建议将 HSA 与 GlyTR 进行基因融合（HSA-GlyTR）并进行确认。具体来说，我们提出以下两个建议：与 Tn 抗原结合、抗癌活性和改善半衰期。目标 1 优化 HSA-GlyTR 双特异性蛋白的活性和药物开发。优化的 HSA-GlyTR 双特异性蛋白的功效和安全性如果成功，这些实验将允许。随后的 IND 使研究能够开发出一种全新的独特的癌症免疫治疗药物能够用单一疗法靶向多种实体癌和造血系统癌症。