Cancer Immunotherapy Targeting Tn Antigen

针对 Tn 抗原的癌症免疫疗法

• 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
• 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

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 癌症免疫治疗性双特异性蛋白和工程嵌合抗原受体T细胞（CAR） T）显示出了显着的临床活性，B细胞恶性肿瘤的完全缓解率高达90％。 但是，将这两种治疗方法应用于绝大多数癌症类型是限制的 由多个因素。首先，只有少数已知的细胞表面蛋白足够 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；干细胞祖细胞不能轻易复制健康细胞的丧失。第二， 由于每个单独的双特异性蛋白质和/或CAR T细胞仅针对单一癌症类型，因此不同的双特异性 和/或CAR T细胞需要为每种癌症类型开发。这大大增加了发展时间和 费用。第三，这两种疗法都能够有效地瞄准最丰富和广泛表达的细胞表面 癌症抗原已知，即肿瘤相关的碳水化合物抗原（TACA）。许多癌症 抗原不是蛋白质，而是在正常组织中有限或没有表达的复杂碳氢化物。 实际上，糖基化改变是癌症几乎普遍的特征。虽然塔卡（Taca）几十年来一直闻名 事实证明，生成有效的单克隆抗体对复杂的碳氢化物很非常 具有挑战性，极大地限制了它们作为癌症免疫疗法的靶标。在这里我们建议解决 这些问题并开发了针对TN抗原的新型免疫治疗剂，一种异常 在许多固体和造血癌上常见的O连接碳水化合物，但在正常情况下不存在 组织。我们将这项技术称为聚糖依赖性T细胞招聘器（Glytr，发音为 '闪光'）。我们已经生成并优化了一种Glytr Bi特异性蛋白，该蛋白是1）专门结合了两个TN 抗原和CD3，2）在存在但不存在TN+癌细胞的情况下激活T细胞，3）诱导T细胞 在体外和体内依赖杀死潜水员固体和液体癌细胞。但是，血清半衰期约为2小时， 类似于FDA批准的双特异性蛋白蓝色，该蛋白需要连续静脉输注 （通过泵）在28天（医院前9天）。为了避免这种繁琐的治疗方案， 在这里，我们建议通过添加人类白蛋白（HSA）域来扩展半衰期。 HSA的半衰期 约为3周，已成功融合到治疗蛋白中，以明显增加半衰期，其中包括两个 FDA批准的治疗。在这里，我们建议将HSA遗传融合到Glytr（HSA-Glytr）并确认 与TN抗原，杀癌活性和半衰期的结合。具体来说，我们提出以下两个 目标。 AIM 1优化了用于活性和药物开发的HSA-GLYTR BI特异性蛋白。 AIM 2探索 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使研究能够开发一类新的癌症，以杀死免疫治疗的独特性 能够通过一种疗法靶向多种固体和造血癌。