SBIR Phase I: Cell-penetrating monobodies targeting oncogenic KRAS

SBIR 第一阶段：针对致癌 KRAS 的细胞穿透单体

• 批准号: 2321926
• 负责人: Johnathan Rabb
• 金额: $ 27.5万
• 依托单位: COVALABIO INC.
• 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: 2024-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2321926&HistoricalAwards=false
• 关键词: SBIR; Phase; Cell; penetrating; monobodies

The broader impact of this Small Business Innovation Research (SBIR) Phase I project lies in technological development of a new pharmaceutical intervention called cell-penetrating monobodies (CPM). The validation of this new CPM intervention will be demonstrated by designing potent and selective CPM-based inhibitors targeting certain cancers. The success of this project will establish a powerful pharmaceutical technology for designing personalized therapies to treat the oncogenic mutant-driven lung, pancreatic, and colorectal cancers, where treatment options are extremely limited. This project will also enhance the academia-industry partnership, strengthen a burgeoning life science ecosystem in the Buffalo area, and develop a globally competitive STEM workforce for the Western New York region.The proposed project addresses a critical barrier in the clinical translation of monobodies - a class of powerful tool biologics that are not cell-permeable despite their small size. The CPM technology overcomes this barrier by combining orthogonal crosslinking  a proprietary method to rigidify monobody structure through site-specific inter-strand crosslinking - with monobody surface supercharging. As a result, the CPM technology potentially possesses several innovative features: 1) genetic modifications facilitate recombinant production of CPM in bacteria both at research scale and for manufacturing; 2) high binding affinity and specificity toward intracellular oncogene targets can be readily obtained using well-established display technologies; and 3) robust cytosolic transport efficiency can be obtained owing to the rigid scaffold and tunable surface charge. This project aims to unlock the commercial value of CPM technology by identifying potent and selective inhibitors oncogenic KRAS mutants that proved to be elusive with the small-molecule approach. Extensive optimizations of charge distribution and physicochemical properties will be performed using a reported monobody-based KRAS inhibitor as a template, with a goal to identify one CPM with sub-micromolar inhibitory activity in the KRAS mutant-harboring cell lines.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.

这项小企业创新研究（SBIR）第一阶段项目的更广泛影响在于一种称为细胞穿透单体（CPM）的新型药物干预的技术开发。这种新的CPM干预的有效性将通过设计针对某些癌症的有效和选择性的CPM抑制剂来证明。该项目的成功将建立一种强大的制药技术，用于设计个性化治疗方案，以治疗由致癌突变驱动的肺癌、胰腺癌和结直肠癌，这些癌症的治疗方案极其有限。该项目还将加强学术界与工业界的合作伙伴关系，加强布法罗地区蓬勃发展的生命科学生态系统，并为纽约西部地区培养具有全球竞争力的STEM劳动力。拟议的项目解决了单体临床翻译中的一个关键障碍-一类强大的工具生物制剂，尽管它们的体积小，但却不能渗透细胞。CPM技术克服了这一障碍，将正交交联（一种专有方法）与单体表面增压相结合，通过特定位点的链间交联使单体结构刚性。因此，CPM技术可能具有以下几个创新特征：1)基因修饰有助于在研究规模和生产规模上重组细菌生产CPM；2)利用成熟的展示技术，可以很容易地获得对细胞内癌基因靶点的高结合亲和力和特异性；3)由于支架的刚性和表面电荷的可调，可以获得强大的细胞质运输效率。该项目旨在通过鉴定小分子方法难以捉摸的强效和选择性抑制剂来释放CPM技术的商业价值。将使用一种基于单体的KRAS抑制剂作为模板，对电荷分布和物理化学性质进行广泛的优化，目的是在KRAS突变细胞系中鉴定出一种具有亚微摩尔抑制活性的CPM。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。