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，有180万例，60万癌症 预计2020年死亡。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靶向的疗法，包括开发抗体-药物缀合物 （ADC）。ADC采用对肿瘤相关抗原具有特异性的单克隆抗体，以增加肿瘤相关抗原的表达。 抗癌毒素递送的效率和选择性（即，payloads）到癌细胞。虽然这 该方法已被证明是成功的，8种抗癌ADC在美国获批使用（维布妥昔单抗， 曲妥珠单抗emtansine、吉妥珠单抗ozogamicin、inotuzumab ozogamicin、polatuzumab vedotin、enfortumab vedotin、曲妥珠单抗deruxtecan和sacituzumab govitecan），ADC治疗通常与 在临床试验中存在大量脱靶毒性、狭窄的治疗窗和高失败率。审议 FDA批准的ADC的研究表明，这些药物通常可以适度延长平均生存时间， 但他们很少能治愈癌症患者不良事件的发生阻止了 在一些实施方案中，可以以实现肿瘤根除所必需的剂量施用ADC。这个项目追求一个新的 这是一种提高抗癌药物的抗体导向递送的肿瘤选择性的策略。在我们的方法中， 将称为有效载荷结合选择性增强剂（PBSE）的有效载荷结合抗体片段 与ADC一起使用，以减少健康组织对有效载荷试剂的暴露，从而减少 脱靶毒性、增加ADC的耐受剂量和增加ADC功效。战略基于 认识到非原位ADC毒性主要归因于释放的（“游离”）有效负载分子，并且还 假设PBSE可用于防止非靶向细胞中游离有效载荷分子进入细胞， 细胞（通过防止跨质膜扩散），而不改变ADC进入靶细胞（其 通过受体介导的内吞作用进行）。在这个项目上的工作重点是新的铅优化 开发了抗SN 38 PBSE，预期可增加SN 38 ADC的安全性和有效性，包括 sacituzumab govitecan。该项目将开发我们的主要抗SN 38 PBSE的优化衍生物，评估其生物学活性。 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， 携带人乳腺癌异种移植物的小鼠。总而言之，第一阶段项目的拟议工作将使 鉴定优化的先导抗SN 38 PBSE，然后通过IND使能临床前 调查事务所

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.