SBIR Phase I: Endogenously secreted bispecific natural killer cell engagers (BIKEs) for therapy of solid tumors

SBIR I 期：用于治疗实体瘤的内源性分泌双特异性自然杀伤细胞接合剂 (BIKE)

• 批准号: 2322959
• 负责人: Rampyari Walia
• 金额: $ 27.5万
• 依托单位: WALIA, RAMPYARI
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2322959&HistoricalAwards=false
• 关键词: SBIR; Phase; Endogenously; secreted; bispecific

This Small Business Innovation Research (SBIR) Phase I project provides a novel, intramuscular gene delivery platform that supports sustained expression of any therapeutic protein, a capability yet to be commercially realized. The ability to provide sustained expression and endogenous secretion of bispecific natural killer cell engager (BiKE) therapeutics is expected to be paradigm shifting by providing a solution that bypasses current immunotherapy treatments for solid tumors. This approach, which is less invasive than the current state-of-the art, could eliminate the need for continuous/frequent repeated infusions of therapeutics and would circumvent the need for hospitalization during administration. The approach has a lower price point, potentially reducing the cost of therapy by tens to hundreds of thousands of dollars compared to other immunotherapies, and is amenable to low resource settings, significantly increasing the availability of treatment. The proof-of-concept therapeutic will target hepatocellular carcinoma, a solid tumor that accounts for 90% of liver cancers. The platform has broad applications, supporting delivery of any gene therapy application (e.g., monogenic disease) that can benefit from systemic expression of a secreted protein, including bi-specific antibody T cell engagers, therapeutic antibodies, and vaccine candidates (e.g., endogenous therapeutic antibody production, delivery of DNA vaccines, and expression of therapeutic proteins to treat monogenic rare diseases). Anticipated impacts of the platform include improved treatment efficacy and improved patient quality of life. This project seeks to advance the development of a safe, efficient intramuscular gene delivery system for redosable gene delivery as well as the demonstration of the platform’s ability to express endogenously secreted bispecific natural killer cell engagers (BIKEs) in vivo for treatment of hepatocellular carcinoma (HCC), a solid tumor. To date, gene therapy approaches to cancer treatment have been costly, labor intensive, and limited in efficacy. This platform is expected to enhance gene delivery by over 1,000-fold compared to the injection of naked DNA and to enable efficient secretion of the gene product into the blood stream, thereby allowing for systemic expression. Specific aims are to establish a cell expression system for production, purification, and functional validation of the recombinant BiKE in vitro and to make bioluminescent hepatoma cell lines transduced with a commercialized lentivirus co-expressing RedFLuc and secreted GLuc for more sensitive detection of tumor survival. The project will also validate the efficacy of the BiKE expression construct in a humanized, orthotopic hepatocellular carcinoma (HCC) mouse model. Proof of concept will be established with the demonstration of sustained systemic expression of the secretable BiKE for ≥ 1 month at serum levels of ≥100-500 ng/ml, as evaluated by enzyme-linked immunosorbent assay (ELISA) assays at days 3-60 post-intramuscular delivery.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项小型企业创新研究（SBIR）I期项目提供了一个新型的肌内基因输送平台，该平台支持任何治疗蛋白的持续表达，这是尚未商业实现的能力。通过提供绕过当前的实体瘤免疫疗法治疗的溶液，预计双特异性天然杀伤细胞参与者（Bike）治疗的持续表达和内源性秘密的能力将是范式转移的能力。这种方法比当前的最新技术不那么侵入性，可以消除对治疗剂的连续/频繁反复输注的需求，并会规避在给药过程中住院的需求。与其他免疫疗法相比，该方法的价格较低，可能会将治疗​​成本降低至数十万美元，并且可以适合低资源设置，从而大大增加了治疗的可用性。概念验证治疗将靶向肝细胞癌，肝细胞癌占肝癌的90％。该平台具有广泛的应用，支持任何基因疗法应用（例如单基因疾病）可以从全身表达中受益于分泌蛋白的全身表达，包括双特异性抗体T细胞交易者，治疗性抗体和候选疫苗的候选者（例如，源自培养基抗体的生产，对DNA的剂量均能治疗蛋白质的蛋白质，以及表达蛋白质的蛋白质，表达蛋白质，并表达疾病）。该平台的严重影响包括提高治疗效率和改善患者生活质量。该项目旨在推动开发安全，有效的肌内基因输送系统，以进行可恢复的基因输送，并证明该平台在体内表达内源性分泌的双特异性自然杀伤细胞探空剂（BIKES），用于治疗肝细胞癌（HCC），固体肿瘤。迄今为止，癌症治疗的基因治疗方法已经昂贵，劳动力密集并且效率有限。与注射裸DNA相比，该平台有望将基因递送增强1,000倍以上，并能够有效地分泌该基因产物为血流，从而允许全身表达。具体的目的是建立一个细胞表达系统，用于在体外重组自行车的生产，纯化和功能验证，并使生物发光的肝癌细胞系与商业化的慢病毒一起转化，并共表达重新荧光和分泌的Gluc，以对肿瘤存活更敏感。该项目还将验证人源化的，原位的肝细胞癌（HCC）小鼠模型中自行车表达构建体的效率。概念证明将在表现出≥1个月的持续系统性表达≥100-500ng/ml的水平上，通过酶联免疫吸收测定（ELISA）测定法进行评估。优点和更广泛的影响审查标准。