Enhancement of ADC selectivity by inverse targeting: Mechanistic studies and optimization

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9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 Vedotin、belantamab mafodotin、trastuzumab deruxtecan和saituzumab gov.itecan)，ADC疗法通常 与严重的非靶向毒性、狭窄的治疗窗口和高临床失败率相关 测试。本项目介绍了一种新的药物动力学策略，以提高抗体的肿瘤选择性- 定向投放抗癌药物。在我们的方法中，有效载荷结合的抗体片段，称为有效载荷- 结合选择性增强剂(PbSe)与ADC联合使用，以减少健康人群的暴露 组织到有效载药剂，从而减少了靶外毒性的发展，增加了耐受量 提高了ADC的效率。该战略的基础是认识到非现场ADC的毒性是 主要归因于释放的有效载荷分子，以及PbSe可能是 用于防止游离有效载荷分子进入非靶向细胞(通过防止扩散 质膜)，而不改变ADC进入靶细胞(通过受体介导的过程 内吞作用)。该项目的工作将集中在开发和评估一系列新颖的PbSe 已证明可降低游离SN38和DXD的细胞毒性。这些药物是喜树碱的衍生物。 它们被用作saituzumab gov.itecan和trastuzumab deruxtecan的有效载荷，最近批准了两个 在临床研究中，ADC分子已显示出一定的疗效，但毒性很大。机械论 在Aim#1和Aim#2中提出的研究检查PbSe分子属性之间的关系(例如，亲和力， 分子形态[即：Ig G、Fab、ScFv、sdAb]、对非结合有效载荷的选择性、分子电荷等。和 PbSe在提高ADC治疗的药代动力学和药效学选择性方面的效用。这些发现 将通过使用机械数学建模来集成，以帮助选择最优的 用于评价AIM#3疗效和毒性的药剂和给药方案。 这项工作可能适合于立即翻译成saituzumab gov.itecan和trastuzumab的最优化 地塞替康治疗难治性和耐药性乳腺癌。

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 9 anti-cancer ADCs approved for use in the US (brentuximab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, 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. This project introduces a new pharmacokinetic 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 in this project will focus on the development and evaluation of a novel series of PBSE that have been shown to decrease the cytotoxicity of free SN38 and Dxd. These agents are camptothecin derivatives that are employed as payloads for sacituzumab govitecan and trastuzumab deruxtecan, two recently approved ADC molecules that have shown some efficacy, but substantial toxicity, in clinical investigations. Mechanistic studies proposed in Aim #1 and Aim #2 examine relationships between PBSE molecular attributes (e.g., affinity, molecular modality [i.e., IgG, Fab, scFv, sdAb], selectivity for unconjugated payload, molecular charge, etc.) and PBSE utility in enhancing the pharmacokinetic and pharmacodynamic selectivity of ADC therapy. These findings will be integrated through the use of mechanistic mathematical modeling to assist in the selection of an optimal agent and dosing regimen for evaluation of efficacy and toxicity in Aim #3. The novel agents developed in this work may be suitable for immediate translation toward optimization of sacituzumab govitecan and trastuzumab deruxtecan therapy of refractory and resistant breast cancer.