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

这个小企业创新研究(SBIR)第一阶段项目的更广泛的影响/商业潜力是制造一种新的基于抗体的免疫疗法，这种疗法可以普遍适用于肿瘤患者。对于选定的癌症患者，免疫疗法可以通过重新激活他们的自然免疫系统来对抗他们的癌症来起到治愈的作用。不幸的是，癌症经常会发生突变，以躲避目前已获批准的免疫疗法的小规模资料库。许多有希望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，而且往往会通过非靶标损害健康器官而导致严重的副作用。抗体可以用来帮助将药物直接运送到癌症部位，但目前受到限制。该项目提出了一种新技术，可将抗体药物负载量增加一个数量级，每个抗体最多可增加100个药物。这些新型抗体刷状聚合物结合物(ABC)将使免疫疗法能够治疗臭名昭著的免疫耐药癌症，如结肠癌。这项小型企业创新研究(SBIR)第一阶段项目将通过抗体-刷状聚合物结合物(ABC)的研究和开发创建下一代抗体-药物结合物(ADC)免疫疗法。由于化学处理的限制，ADC的药物负载量很低，迫使使用细胞毒性药物有效载荷，如导致患者严重不良事件的金葡素。该项目将开发结合技术，将导致药物抗体比率高达100的ABC。刷状聚合物通过聚乙二醇屏蔽和靶向药物释放的组合，实现了更高的药物负载量，这将导致对癌症低表达抗原靶标的更大疗效，并使具有更多作用机制的药物得到应用。具体地说，该项目将创建加载免疫刺激分子(如TLR和STING激动剂)的ABC库，尽管这些分子在临床前有重要的前景，但由于治疗窗口狭窄和靶向性有限，这些分子在临床开发中停滞不前。优化的免疫刺激ABC将在传统免疫治疗耐药的结直肠癌动物模型中进行体内耐受性、药代动力学、生物分布、疗效和治疗潜力的评估。这项SBIR第一阶段研究将使新型免疫疗法进一步发展为临床应用。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.