Extended half-life GlyTR1 combined with checkpoint blockade for Cancer Immunotherapy

延长半衰期的 GlyTR1 与检查点阻断相结合用于癌症免疫治疗

• 批准号: 10766646
• 负责人: MICHAEL DEMETRIOU
• 金额: $ 40万
• 依托单位: GLYTR THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10766646
• 关键词: Address; Antibodies; Antigen Targeting; Antigens; B-Cell Neoplasm; B-Lymphocytes; Binding; Binding Proteins; Biological Assay; Bispecific Antibodies; Bite; CD3 Antigens; CTLA4 gene; Cancer Center; Cancer Patient; Carbohydrates; Cell Surface Proteins; Cell surface; Cells; Clinical Trials; Combined Modality Therapy; Complex; Data; Detection; Development; Disease; Disease Progression; Dose; Drug Kinetics; FDA approved; Fc domain; Funding; Future; Half-Life; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunoglobulin Fragments; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Intravenous infusion procedures; Invaded; Investigational Therapies; Lectin; Malignant Neoplasms; Metastatic/Recurrent; National Cancer Institute; National Cancer Program; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Patients; Phase; Phase I Clinical Trials; Phosphatidylinositols; Phosphotransferases; Polysaccharides; Prognosis; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Regulatory T-Lymphocyte; Relapse; Safety; Sequential Treatment; Serum; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Specificity; Surface; Surface Antigens; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Tumor Antigens; Work; bi-specific T cell engager; cancer cell; cancer immunotherapy; cell motility; cost; driver mutation; first-in-human; humanized mouse; immune checkpoint blockade; in vitro activity; in vivo; manufacture; mouse model; neonatal Fc receptor; neonatal human; new technology; novel; novel therapeutics; overexpression; palliative; phase I trial; pre-clinical; preclinical development; prevent; programmed cell death protein 1; programs; safety assessment; stable cell line; sugar; tumor growth

Abstract Treatment of non-resectable recurrent/metastatic solid cancers is currently palliative only and there is an urgent unmet need for novel mechanisms of action and additional paradigm shifting therapeutic options. Antigen- targeting cancer immunotherapies such as bi-specific antibodies (eg Bi-specific T cell engager or BiTE’s) provide a unique approach for cancer immunotherapy. However, applying this therapeutic tactic to solid cancers has been restricted by a limited number of protein antigens safe for targeting. Moreover, even if safe cell-surface antigens are identified, different bi-specific antibodies will likely be needed for each different antigen/cancer. This would greatly increase development time and costs. Thus, there remains a great need for additional safe antigen- specific immunotherapies, particularly for those with refractory/metastatic solid cancers who have few therapeutic options. Many cell surface cancer-specific antigens are not proteins but rather complex carbohydrates that have limited or no expression in normal tissues. For example, β1,6GlcNAc-branched N- glycans constitute a small subset of the complex-type N-glycans expressed at the surface of normal human cells but are markedly up-regulated in diverse solid cancers by driver mutations in the receptor tyrosine kinase/RAS/phosphoinositide-3-kinase(PI3K) signaling pathway. Aberrant over-expression of β1,6GlcNAc- branched N-glycans in solid tumors drives RTK signaling, tumor growth, motility, invasion, and metastasis. As both a marker and driver of many diverse cancers, β1,6 GlcNAc-branched N-glycans provide an excellent target for antigen-specific immunotherapies. However, an antibody to β1,6GlcNAc-branched N-glycans has never been generated. To address this issue, we generated a novel class of immunotherapeutics that readily target abnormal glycan antigens with high specificity. We have termed this technology ‘Glycan-dependent T cell Recruiter’ (GlyTR, pronounced ‘glitter’). With funding from the Biden Cancer Moonshot program of the National Cancer Institute, we developed and optimized the GlyTR1 bi-specific protein that binds both β1,6GlcNAc-branched N- glycans and CD3 in T cells. The GlyTR1 bi-specific protein induces T cell-dependent killing of a wide diversity of solid cancers in vitro and in vivo with EC50’s as low as ~50 femtomolar, yet does not kill normal cells or trigger “on-target, off-cancer” toxicity in humanized mouse models. GlyTR1 is undergoing late-stage IND-enabling studies and upon FDA approval, the UC Irvine Cancer Center will perform a dose-escalation Phase 1 clinical trial in relapsed/metastatic solid cancer. However, as GlyTR1 has a short half-life of ~2.5hrs and requires constant intravenous infusion, herein we propose to develop a longer half-life version of GlyTR1. We also propose to examine for potential additive/synergistic activity with checkpoint inhibitors. Data from this proposal will be used to inform future clinical trials following confirmation of safety of GlyTR1 in our Phase 1 trial, namely whether a longer half-life GlyTR1 and/or co-treatment with checkpoint inhibitors should be pursued.

摘要 不可切除的复发性/转移性实体癌的治疗目前仅是姑息性的， 对新的作用机制和额外的范式转变治疗选择的迫切未满足的需求。抗原- 靶向癌症免疫疗法，例如双特异性抗体（例如双特异性T细胞增殖剂或BiTE）， 癌症免疫治疗的独特方法。然而，将这种治疗策略应用于实体癌， 受到可安全靶向的蛋白质抗原数量有限的限制。此外，即使安全的细胞表面 当抗原被鉴定时，对于每种不同的抗原/癌症可能需要不同的双特异性抗体。这 将大大增加开发时间和成本。因此，仍然非常需要额外的安全抗原- 特异性免疫疗法，特别是对于那些患有难治性/转移性实体癌的人， 治疗选择许多细胞表面的癌症特异性抗原不是蛋白质而是复杂的 在正常组织中表达有限或不表达的碳水化合物。例如，β1，6 GlcNAc-支链的N- 聚糖构成在正常人细胞表面表达的复合型N-聚糖的一个小子集 但在多种实体癌中通过受体酪氨酸的驱动突变而显著上调 激酶/RAS/磷酸肌醇-3-激酶（PI 3 K）信号通路。β1，6 GlcNAc异常过表达 实体瘤中的分支N-聚糖驱动RTK信号传导、肿瘤生长、运动性、侵袭和转移。作为 作为许多不同癌症的标志物和驱动因素，β 1，6 GlcNAc分支的N-聚糖提供了一个极好的靶点， 用于抗原特异性免疫疗法。然而，针对β1，6 GlcNAc分支的N-聚糖的抗体从未被发现。 生成的.为了解决这个问题，我们产生了一类新的免疫治疗药物， 具有高特异性的聚糖抗原。我们将这项技术称为“聚糖依赖性T细胞招募” （GlyTR，发音为“闪光”）。在国家癌症中心拜登癌症登月计划的资助下， 研究所，我们开发并优化了GlyTR 1双特异性蛋白，该蛋白结合β1，6 GlcNAc分支的N- 聚糖和T细胞中的CD 3。GlyTR 1双特异性蛋白诱导T细胞依赖性杀伤多种 体外和体内实体癌的EC 50低至~50飞摩尔，但不杀死正常细胞或触发 在人源化小鼠模型中的“中靶，脱癌”毒性。GlyTR 1正在经历后期IND启用 研究和FDA批准后，加州大学欧文分校癌症中心将进行剂量递增的1期临床试验， 复发/转移性实体癌的临床试验。然而，由于GlyTR 1的半衰期很短，约为2.5小时， 恒定静脉输注，在此我们提出开发GlyTR 1的更长半衰期版本。我们也 建议检查检查点抑制剂的潜在加和/协同活性。数据从该 在我们的I期试验中确认GlyTR 1的安全性后，该提案将用于通知未来的临床试验， 即是否应该追求更长的半衰期GlyTR 1和/或与检查点抑制剂的共同治疗。