In vivo delivery of Ab-directed CRISPR ribonucleoproteins for anal cancer immunotherapy

用于肛门癌免疫治疗的 Ab 定向 CRISPR 核糖核蛋白的体内递送

• 批准号: 10821884
• 负责人: Mary Haak-Frendscho
• 金额: $ 104.38万
• 依托单位: SPOTLIGHT THERAPEUTICS
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10821884
• 关键词: Adenosine; Aftercare; Antibodies; Antitumor Response; Architecture; Biological; Biology; CRISPR/Cas technology; Cancer Patient; Cell Line; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Diagnosis; Disease; Dose; Double-Stranded RNA; Drug Kinetics; Engineering; FDA approved; Feedback; Formulation; Genes; Genomics; Goals; Guide RNA; Human; Human Papillomavirus; Immune; Immunologic Memory; Immunotherapy; In Vitro; Injections; Inosine; Interferon Type I; Knock-out; Leukocytes; Macrophage; Malignant neoplasm of anus; Mediating; Methods; Modality; Modeling; Monoclonal Antibodies; Mus; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Process; Quality of life; Regimen; Resistance; Ribonucleoproteins; Safety; Solid Neoplasm; Streptococcus pyogenes; Survival Rate; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Tumor Burden; anti-tumor immune response; cancer immunotherapy; cancer therapy; chemical conjugate; chemical synthesis; chemotherapy; design; dsRNA adenosine deaminase; effective therapy; humanized mouse; immune checkpoint blockade; immunogenic; improved; in vivo; knockout gene; lead candidate; lead optimization; manufacturability; meetings; microbial; neoplastic cell; novel; nuclease; patient population; permissiveness; pre-clinical; programs; prototype; response; standard of care; targeted delivery; trafficking; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY: This year in the US, 9,760 people are expected to be diagnosed with anal cancer. The 5-year survival rate for metastatic anal cancer is only ~30% with standard of care chemotherapy. No regimens have been FDA- approved after chemotherapy has failed and only limited benefit has been shown with single agent immune checkpoint blockade (ICB). New treatment options are urgently needed to improve patient outcomes. The goal of this Direct to Phase II project is to develop TAGE-201, an intratumorally administered Antibody (Ab)- directed CRISPR gene editor to knockout ADAR in TME immune cells for use in combination with ICB. This new biologic is based on Spotlight Therapeutics’ proprietary Targeted Active Gene Editor (TAGE) platform. TAGE is a non-viral, non-nanoparticle delivery modality, comprised of an engineered CRISPR-Cas9 ribonucleoprotien (RNP) fused to an Ab, enabling cell-targeted delivery and gene knockout in vivo. ADAR (adenosine deaminase acting on RNA) disruption stimulates dsRNA sensing pathways and a type I interferon response, which can drive a shift the state of the tumor microenvironments (TMEs) to be immune permissive, overcoming a major barrier to generating an optimal anti-tumor immune response with ICB. TAGE enables gene knockout of ADAR, which has been difficult to drug despite compelling preclinical evidence. Preliminary data with a murine surrogate prototype of TAGE-201, with optimized Ab and CRISPR-Cas, suggests Adar knockout in conjunction with ICB treatment mediates systemic anti-tumor responses in syngeneic murine tumor models that do not respond to ICB alone. This Direct to Phase II project aims to 1) identify a TAGE-201 lead candidate by optimizing RNP architecture and guide RNA components, 2) generate a preclinical data package demonstrating Adar knockout in TME immune cells of a murine tumor after direct local injection with murine surrogate of TAGE-201 (msTAGE-201), anti-tumor efficacy in multiple murine and PDX tumor models, pharmacodynamics effects that align with ADAR biology, and pharmacokinetics and toxicity studies that demonstrates an acceptable safety profile, and 3) conduct an INTERACT meeting with the FDA to present the preclinical, manufacturability assessment, and preliminary formulation data packages and an IND-enabling study plan. Upon successful completion of the Direct to Phase II project, the TAGE-201 development candidate will be poised to initiate IND-enabling studies, followed by clinical trials, with the goal to provide an effective treatment option for a population of patients that currently do not have FDA-approved therapeutic strategies to improve overall outcomes and quality of life.

项目概要： 今年在美国，预计将有 9,760 人被诊断出患有肛门癌，其 5 年生存率。 采用标准护理化疗后，转移性肛门癌的发病率仅为 30%。 FDA 尚未批准任何治疗方案。 化疗失败后获得批准，单药免疫仅显示有限的益处 迫切需要新的治疗方案来改善患者的治疗效果。 该直接进入 II 期项目的目的是开发 TAGE-201，一种瘤内施用的抗体 (Ab)- 指导 CRISPR 基因编辑器敲除 TME 免疫细胞中的 ADAR，以便与 ICB 联合使用。 这种新的生物制剂基于 Spotlight Therapeutics 专有的靶向活性基因编辑器 (TAGE) TAGE 是一种非病毒、非纳米粒子递送方式，由工程改造的 CRISPR-Cas9 组成。 核糖核蛋白 (RNP) 与抗体融合，可实现细胞靶向递送和体内 ADAR 基因敲除。 （腺苷脱氨酶作用于 RNA）破坏刺激 dsRNA 传感途径和 I 型干扰素 反应，这可以推动肿瘤微环境（TME）的状态转变为免疫许可状态， 通过 ICB 克服产生最佳抗肿瘤免疫反应的主要障碍。 尽管有令人信服的临床前证据，但 ADAR 基因仍难以药物化。 Adar 表示，TAGE-201 的小鼠替代原型具有优化的 Ab 和 CRISPR-Cas 的数据 敲除联合 ICB 治疗介导同基因小鼠肿瘤的全身抗肿瘤反应 不单独对 ICB 做出反应的模型 该 Direct to Phase II 项目旨在 1) 确定 TAGE-201 先导药物。 通过优化RNP架构和引导RNA组件来候选，2）生成临床前数据包 直接局部注射小鼠后，证明小鼠肿瘤的 TME 免疫细胞中 Adar 被敲除 TAGE-201 (msTAGE-201) 的替代品，在多种小鼠和 PDX 肿瘤模型中具有抗肿瘤功效， 与 ADAR 生物学一致的药效学效应，以及与 ADAR 生物学相关的药代动力学和毒性研究 展示出可接受的安全性，并且 3) 与 FDA 举行 INTERACT 会议以介绍 临床前、可制造性评估和初步配方数据包以及 IND 支持 研究计划成功完成 Direct to Phase II 项目后，TAGE-201 的开发 候选人将准备启动 IND 支持研究，然后进行临床试验，目标是提供 对于目前尚未获得 FDA 批准的治疗药物的患者群体来说，这是一种有效的治疗选择 改善整体结果和生活质量的策略。