Antibody–drug conjugates (ADC) have become important scaffolds for targeted cancer therapies. However, ADC exposure–response correlation is not well characterized. We demonstrated that intratumor payload exposures correlated well with the corresponding efficacies of several disulfide-linked ADCs, bearing an DNA alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD), in HER2-expressing xenograft models. The correlation suggests that a threshold concentration of intratumor payload is required to support sustained efficacy and an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy (“Plateau” effect). In contrast to tumor PBD concentrations, related assessments of systemic exposures, plasma stability, and drug-to-antibody ratio changes of related ADCs did not consistently rationalize the observed ADC efficacies. A minimal efficacious dose could be determined by ADC dose-fractionation studies in the xenograft models. Mechanistic investigations revealed that both linker immolation and linker disulfide stability are the key factors that determine intratumor PBD concentrations. Overall, this study demonstrates how a linker design can impact ADC efficacy and that the intratumor exposure of a payload drug as the molecular mechanism quantitatively correlate with and predict the antitumor efficacy of ADCs. Mol Cancer Ther; 17(3); 677–85. ©2018 AACR.

中文翻译：

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肿瘤内有效载荷浓度与抗体药物偶联物的活性相关

抗体药物偶联物 (ADC) 已成为靶向癌症治疗的重要支架。然而，ADC 暴露-反应相关性尚未得到很好的表征。我们证明，在表达 HER2 的异种移植物中，肿瘤内有效载荷暴露与几种二硫键连接的 ADC 的相应功效密切相关，这些 ADC 带有 DNA 烷化剂吡咯并 [2,1-c][1,4] 苯并二氮杂二聚体 (PBD)楷模。这种相关性表明，需要肿瘤内有效载荷的阈值浓度来支持持续的疗效，并且 ADC 可以向肿瘤输送过多水平的有效载荷，但不会增强疗效（“高原”效应）。与肿瘤 PBD 浓度、全身暴露的相关评估、血浆稳定性、相关 ADC 的药物抗体比变化并不能始终如一地合理化观察到的 ADC 功效。最小有效剂量可以通过异种移植模型中的 ADC 剂量分级研究来确定。机理研究表明，接头燃烧和接头二硫化物稳定性是决定肿瘤内 PBD 浓度的关键因素。总体而言，这项研究证明了接头设计如何影响 ADC 功效，以及作为分子机制的有效载荷药物的肿瘤内暴露与 ADC 的抗肿瘤功效定量相关并预测其抗肿瘤功效。摩尔癌症治疗; 17(3); 677-85。©2018 AACR。机理研究表明，接头燃烧和接头二硫化物稳定性是决定肿瘤内 PBD 浓度的关键因素。总体而言，这项研究证明了接头设计如何影响 ADC 功效，以及作为分子机制的有效载荷药物的肿瘤内暴露与 ADC 的抗肿瘤功效定量相关并预测其抗肿瘤功效。摩尔癌症治疗; 17(3); 677-85。©2018 AACR。机理研究表明，接头燃烧和接头二硫化物稳定性是决定肿瘤内 PBD 浓度的关键因素。总体而言，这项研究证明了接头设计如何影响 ADC 功效，以及作为分子机制的有效载荷药物的肿瘤内暴露与 ADC 的抗肿瘤功效定量相关并预测其抗肿瘤功效。摩尔癌症治疗; 17(3); 677-85。©2018 AACR。