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人被诊断患有肛门癌。5年生存率 转移性肛门癌在标准治疗化疗中仅占~30%。FDA尚未批准任何治疗方案- 在化疗失败后获得批准，并且单药免疫仅显示出有限的益处 检查点封锁（ICB）。迫切需要新的治疗方案来改善患者的预后。目标 该直接进入II期项目的目的是开发TAGE-201，一种肿瘤内给药的抗体（Ab）- 指导CRISPR基因编辑器敲除TME免疫细胞中的阿达尔以与ICB组合使用。 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） 平台TAGE是一种非病毒、非纳米颗粒的递送方式，由工程化的CRISPR-Cas9 核糖核蛋白（RNP）融合到抗体，使细胞靶向递送和体内基因敲除。阿达尔 （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，这可以驱动肿瘤微环境（TME）的状态转变为免疫许可， 克服了用ICB产生最佳抗肿瘤免疫应答的主要障碍。TAGE使 阿达尔的基因敲除，尽管有令人信服的临床前证据，但ADAR很难用药。初步 使用优化的Ab和CRISPR-Cas的TAGE-201的鼠替代原型的数据表明，阿达尔 基因敲除联合ICB治疗介导同基因小鼠肿瘤的全身抗肿瘤应答 这些模型不仅对ICB有反应。该直接进入第二阶段项目旨在：1）确定TAGE-201电极导线 通过优化RNP结构和指导RNA组分，2）生成临床前数据包 证明了在直接局部注射小鼠肿瘤后，小鼠肿瘤的TME免疫细胞中的阿达尔敲除 TAGE-201替代物（msTAGE-201），在多种鼠和PDX肿瘤模型中的抗肿瘤功效， 与阿达尔生物学一致的药效学效应，以及 证明安全性可接受，3）与FDA召开INTERACT会议， 临床前、可制造性评估和初步配方数据包以及IND支持 学习计划。在成功完成直接进入第二阶段项目后，TAGE-201开发项目 候选人将准备启动IND使能研究，然后进行临床试验，目标是提供一个 目前没有FDA批准的治疗药物的患者群体的有效治疗选择 改善总体结果和生活质量的战略。