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

这个小型企业创新研究（SBIR）I期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，可普遍适用于肿瘤患者。对于特定的癌症患者，免疫疗法可以通过重新激活他们的天然免疫系统来对抗癌症。不幸的是，癌症经常发生突变，以逃避目前批准的免疫疗法的小库。许多有希望的实验性小分子免疫疗法不能使用，因为它们不能以足够高的浓度有效地在癌症部位积累，并且经常通过对健康器官的脱靶损伤引起严重的副作用。抗体可用于帮助将药物直接运送到癌症部位，但目前受到限制。该项目推进了一项新技术，将抗体载药量提高了一个数量级，每个抗体最多可载100种药物。这些新型抗体刷聚合物偶联物（ABC）将使免疫疗法能够治疗众所周知的免疫疗法耐药性癌症，例如结直肠癌。这个小企业创新研究（SBIR）I期项目将通过研究创建下一代抗体药物偶联物（ADC）抗体刷聚合物偶联物（ABC）的研究和开发。由于有限的化学处理，ADC具有低的药物负载，这迫使使用细胞毒性药物有效载荷，如在患者中引起严重不良事件的奥瑞他汀。该项目将开发偶联技术，使ABC的药物抗体比高达100。刷状聚合物通过PEG屏蔽和靶向药物释放的组合，实现了这种更高的载药量，这将导致对癌症中低表达抗原靶标的更大功效和具有更多样化作用机制的药物的应用。具体来说，该项目将创建装载有TLR和STING激动剂等免疫刺激分子的ABC库，尽管这些分子具有重要的临床前前景，但由于治疗窗口狭窄和靶向能力有限，在临床开发中停滞不前。优化的免疫刺激ABC将在传统免疫疗法耐药的结直肠癌动物模型中体内评价耐受性、药代动力学、生物分布、功效和治愈潜力。该SBIR第一阶段研究将使新型免疫疗法的进一步发展成为临床应用。该奖项反映了NSF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。

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.