Lead Optimization and Evaluation of Anti-SN38 Payload Binding Selectivity Enhancers

癌症是美国发病率和死亡率的主要原因，美国有180万病例和60万癌症 预计2020年将有死亡人数。在过去的二十年里，癌症治疗取得了实质性的进展， 主要是通过开发高度针对性的疗法，包括开发抗体-药物结合物 (ADC)。ADC使用对肿瘤相关抗原具有特异性的单抗来增加 向癌细胞输送抗癌毒素(即有效载荷)的效率和选择性。虽然这件事 该方法已被证明是成功的，有8种抗癌ADC被批准在美国使用(Brentuximab vedotin， 曲妥珠单抗恩坦辛、吉图珠单抗奥佐米星、诺图珠单抗奥佐米星、波拉图单抗维多丁、恩福单抗 维多丁、曲妥珠单抗、曲妥珠单抗和saituzum单抗政府技术)，ADC疗法通常与 严重的非靶向毒性，治疗窗口狭窄，临床试验失败率高。考虑事项 FDA批准的ADC的研究表明，这些药物通常会适度延长平均生存时间， 但他们很少治愈病人的癌症。不良事件的发展会阻止 以达到肿瘤根除所需的剂量给予ADC。这个项目追求的是一种新的 提高抗体导向的抗癌药物的肿瘤选择性的策略。在我们的方法中， 有效载荷结合抗体片段，称为有效载荷结合选择性增强剂(PbSe)，联合给药 使用ADC来减少健康组织对有效载荷制剂的暴露，从而减少 脱靶毒性，增加ADC的耐受量，并提高ADC的疗效。该战略的基础是 认识到场外ADC毒性主要归因于释放的有效载荷分子，以及 PbSe可能被用来阻止自由有效载荷分子进入非靶向细胞的假设 细胞(通过防止跨质膜扩散)，而不改变ADC进入目标细胞(这 通过受体介导的内吞作用进行)。该项目的工作重点是新产品的销售线索优化 开发了抗SN38 PbSe，预计将提高SN38 ADC的安全性和有效性，包括 Sacituzumab政府技术。该项目将开发我们的领先反SN38 PbSe的优化衍生品，评估 PbSe构建用于血浆、组织和肿瘤处置，并进行安全性和有效性评估 荷人乳腺癌异种移植的小鼠。总而言之，这个第一阶段项目中提出的工作将使 鉴定一种优化的抗SN38PbSe先导抗体，然后它将在启用IND的临床前阶段取得进展 调查。

Cancer is a major cause of morbidity and mortality in the US, with 1.8 million cases and 600 thousand cancer deaths projected for 2020. Substantial progress in cancer treatment has been made in the past two decades, largely through the development of highly targeted therapies, including development of antibody-drug conjugates (ADCs). ADCs employ monoclonal antibodies with specificity for tumor-associated antigens to increase the efficiency and selectivity of the delivery of anti-cancer toxins (i.e., payloads) to cancer cells. Although this approach has proven to be successful, with 8 anti-cancer ADCs approved for use in the US (brentuximab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, and sacituzumab govitecan), ADC therapies are often associated with substantial off-target toxicity, narrow therapeutic windows, and high failure rates in clinical testing. Consideration of the FDA-approved ADCs shows that these agents often allow a modest extension in average survival time, but they very rarely cure a patient from their cancer. The development of adverse events prevents the administration of ADC at dosages that are necessary to achieve tumor eradication. This project pursues a new strategy to increase the tumor-selectivity of antibody-directed delivery of anti-cancer drugs. In our approach, payload-binding antibody fragments, termed payload-binding selectivity enhancers (PBSE), are co-administered with ADCs to decrease the exposure of healthy tissues to payload agents, thereby reducing the development of off-target toxicity, increasing the tolerable dose of ADCs, and increasing ADC efficacy. The strategy is based on the recognition that off-site ADC toxicity is primarily attributed to the released (“free”) payload molecule, and also on the hypothesis that PBSE may be employed to prevent cellular entry of free payload molecules in non-targeted cells (by preventing diffusion across plasma membranes) without altering entry of ADCs into targeted cells (which proceeds via receptor mediated endocytosis). Work on this project focuses on lead optimization for newly developed anti-SN38 PBSE, which are expected to increase the safety and efficacy of SN38 ADC, including sacituzumab govitecan. The project will develop optimized derivatives of our lead anti-SN38 PBSE, evaluate the PBSE constructs for plasma, tissue, and tumor disposition, and conduct assessments of safety and efficacy in mice bearing human breast cancer xenografts. In sum, work proposed in this Phase 1 project will enable the identification of an optimized lead anti-SN38 PBSE, which will then advance through IND-enabling preclinical investigations.