SBIR Phase I: Antibody Brush Polymer Conjugates with High Drug Antibody Ratios and Immunostimulatory Payloads for Treatment of Late-Stage Cancers

SBIR 第一期：具有高药物抗体比率和免疫刺激有效负载的抗体刷聚合物缀合物，用于治疗晚期癌症

• 批准号: 2136667
• 负责人: Hung Nguyen
• 金额: $ 25.6万
• 依托单位: WINDOW THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2136667&HistoricalAwards=false
• 关键词: SBIR; Phase; Antibody; Brush; Polymer

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to make a new class of antibody-based immunotherapies that can be generally applicable to oncology patients. For select cancer patients, immunotherapies can serve as a cure by reactivating their natural immune systems to fight against their cancers. Unfortunately, cancers are often mutated to evade the small library of currently approved immunotherapies. Many promising experimental small molecule immunotherapies cannot be used because they cannot effectively accumulate in cancer sites at high enough concentrations and often cause severe side effects through off-target damage to healthy organs. Antibodies can be used to help shuttle drugs directly to cancer sites but are currently limited. This project advances a novel technology that increases antibody drug loading over an order of magnitude, up to 100 drugs per antibody. These novel Antibody Brush polymer Conjugates (ABCs) will enable immunotherapies to treat notoriously immunotherapy resistant cancers, such as colorectal cancer.This Small Business Innovation Research (SBIR) Phase I project will create the next-generation of Antibody-Drug Conjugate (ADC) immunotherapies through the research and development of Antibody-Brush polymer Conjugates (ABCs). Due to limited chemical handles, ADCs have low drug loadings that force the use of cytotoxic drug payloads like auristatins that cause severe adverse events in patients. This project will develop conjugation techniques that will lead to ABCs with drug-antibody ratios as high as 100. Brush polymers, through a combination of PEG shielding and targeted drug release, enable this higher drug loading that will lead to both greater efficacy against low expression antigen targets in cancer and application of drugs with more diverse mechanisms of action. Specifically, this project will create libraries of ABCs loaded with immunostimulating molecules like TLR and STING agonists that, despite significant preclinical promise, have stagnated in clinical development due to narrow therapeutic windows and limited targetability. Optimized immunostimulatory ABCs will be evaluated in vivo for tolerability, pharmacokinetics, biodistribution, efficacy, and curative potential in traditionally immunotherapy-resistant colorectal cancer animal models. This SBIR Phase I research will enable further development of the novel immunotherapies into clinical applications.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阶段项目的更广泛的影响/商业潜力是制造一类新的基于抗体的免疫疗法，通常适用于肿瘤学患者。对于某些癌症患者，免疫疗法可以通过重新激活其自然免疫系统与癌症作斗争来作为治愈方法。不幸的是，癌症经常被突变以逃避当前批准的免疫疗法的小图书馆。许多有前途的实验性小分子免疫疗法无法使用，因为它们不能在足够高的浓度下有效地积聚在癌症部位，并且经常通过对健康器官的脱靶损害引起严重的副作用。抗体可用于帮助直接穿梭到癌症部位，但目前受到限制。该项目推进了一项新型技术，该技术可将抗体药物载荷增加到一个数量级，每抗体高达100种药物。这些新型抗体刷聚合物共轭物（ABC）将使免疫疗法能够治疗众所周知的抗免疫疗法的抗药性癌症，例如结直肠癌。这项小型企业创新研究（SBIR）I期项目将通过研究和抗生素的研究（ABC）创建抗体 - 吸水偶联物（ADC）免疫疗法的下一代。由于化学处理有限，ADC的药物负荷较低，迫使使用细胞毒性药物有效载荷（例如auristatins）在患者中造成严重不良事件。该项目将通过通过PEG屏蔽和靶向药物释放的组合来开发具有药物抗体比的ABC高达100。刷聚合物的ABC，这使得这种较高的药物载荷将导致对低表达抗原靶标在癌症中的低表达抗原和具有更多不同动作机制的药物的应用。具体而言，该项目将创建带有免疫刺激分子（如TLR）和刺痛激动剂的ABC的图书馆，尽管临床前的承诺很大，但由于狭窄的治疗窗口和有限的目标性，在临床开发中仍然停滞不前。优化的免疫刺激性ABC将在体内评估，用于传统抗性免疫疗法的大肠癌动物模型中的耐受性，药代动力学，生物分布，疗效和治愈潜力。这项SBIR I期研究将使新型免疫疗法进一步开发到临床应用中。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的评估标准通过评估来支持的。