ImmunoGen, Waltham, Massachusetts.
Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
Mol Cancer Ther. 2021 Jan;20(1):203-212. doi: 10.1158/1535-7163.MCT-20-0451. Epub 2020 Nov 11.
Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRα was generated and tested in an animal model where the antibody/ADC bind both human tumor FRα and mouse FRα in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRα antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the co-administered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.
几种在实体瘤中显示出强烈临床反应的抗体药物偶联物（ADC）针对高表达抗原（HER2、TROP2、Nectin-4 和叶酸受体 alpha/FRα）。高表达的肿瘤抗原在正常组织中通常有明显的低水平表达，导致潜在的靶向介导药物处置（TMDD）和清除增加。然而，ADC 通常不会与用于测试疗效的动物模型（通常是小鼠）中的正常组织发生交叉反应，并且 ADC 与正常组织抗原结合对肿瘤反应的影响仍不清楚。生成了一种与人和鼠 FRα 交叉反应的抗体，并在一种动物模型中进行了测试，该模型中抗体/ADC 结合人肿瘤 FRα 和正常组织中的鼠 FRα。以前的工作已经表明，未缀合抗体的“载体”剂量可以改善高表达靶抗原的 ADC 的肿瘤穿透性。载体剂量用于研究对交叉反应性 ADC 清除率、分布和疗效的影响。与 ADC 联合使用未缀合的抗 FRα 抗体可提高疗效，即使在低表达模型中，联合使用通常会降低疗效。通过减少正常组织中靶抗原介导的清除，联合使用的抗体增加了系统暴露，改善了肿瘤组织穿透性，减少了正常组织中靶抗原介导的摄取，并提高了 ADC 的疗效。然而，有效载荷效力和肿瘤抗原饱和度对疗效也很关键，如使用过高的载体剂量会降低疗效所示。明智地使用更高剂量的抗体，无论是通过降低 DAR 还是载体剂量，都可以通过提高疗效同时降低正常组织中的靶介导毒性来增加治疗窗口。
