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.

中文翻译：

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抗体联合给药可以改善抗体药物缀合物的全身和局部分布，从而提高体内疗效


几种抗体药物偶联物 (ADC) 在实体瘤中表现出强烈的临床反应，靶向高表达抗原（HER2、TROP2、Nectin-4 和叶酸受体 α/FRα）。高表达的肿瘤抗原通常在正常组织中具有显着的低水平表达，从而导致靶点介导的药物处置（TMDD）和清除增加的潜力。然而，在用于测试疗效的动物模型（通常是小鼠）中，ADC 通常不会与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。生成了与人和鼠 FRα 交叉反应的抗体，并在动物模型中进行了测试，其中抗体/ADC 与正常组织中的人肿瘤 FRα 和小鼠 FRα 结合。先前的工作已经证明，“载体”剂量的未缀合抗体可以提高具有高表达靶抗原的 ADC 的肿瘤渗透性。采用载体剂量来研究对交叉反应 ADC 清除、分布和功效的影响。未缀合的抗 FRα 抗体与 ADC 的共同给药可提高功效，即使在共同给药通常会降低功效的低表达模型中也是如此。通过减少正常组织中靶标抗原介导的清除，共同施用的抗体增加了全身暴露，改善了肿瘤组织渗透，减少了正常组织中靶标抗原介导的摄取，并提高了 ADC 功效。然而，有效负载效力和肿瘤抗原饱和度对于功效也至关重要，如使用过高的载体剂量会降低功效所示。通过降低 DAR 或载体剂量，明智地使用较高的抗体剂量，可以通过提高疗效同时降低正常组织中靶标介导的毒性来改善治疗窗。