Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York, USA.
NBE-PK, Research and Development, Boehringer Ingelheim Pharmaceuticals Inc, 900 Ridgebury Rd., P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA.
AAPS J. 2021 Apr 15;23(3):56. doi: 10.1208/s12248-021-00584-y.
Antibody-drug conjugates (ADCs) rely on high expression of target antigens on cancer cells to effectively enter the cell and release a cytotoxic payload. Previous studies have shown that ADC efficacy is not always tied to antigen expression. However, our recent in vitro study suggests a linear relationship between antigen expression and the intracellular levels of the ADC payload. In this study, we have explored the relationship between antigen expression and intratumoral ADC exposure in vivo. Using trastuzumab-vc-MMAE (T-vc-MMAE) and four cell lines with varying expression of human epithelial growth factor receptor 2 (HER2), the pharmacokinetics of total trastuzumab, released ("free") MMAE, and total MMAE were evaluated in a tumor xenograft model. Nude mice were implanted with tumors originating from BT-474, MDA-MB-453, MCF-7, and MDA-MB-468 cell lines and dosed with 10 mg/kg or 1 mg/kg of ADC. Observed data were mathematically characterized using a mechanism-based PK model. A strong positive correlation was observed between antigen expression levels and free/total MMAE exposure (R ≥ 0.91) (total MMAE being the sum of released and conjugated MMAE) within the tumor, but not for total trastuzumab exposure. The PK model was able to recapitulate plasma PK through simulation; however, the tumor PK was overpredicted or underpredicted in some cases potentially due to differences in tumor vasculature or extracellular matrix conditions. Our results indicate a linear relationship between antigen expression and tumor exposure of free/total ADC payload in vivo, validating our previous finding in vitro, while also revealing the need to understand complex physiology of the tumor to predict tumor PK of ADC and its components. Our findings also support the concept of antigen expression screening in patients for targeted therapies like ADCs to achieve the maximum therapeutic benefit of the treatment.
抗体药物偶联物（ADC）依赖于癌细胞上靶抗原的高表达，以有效进入细胞并释放细胞毒性有效载荷。先前的研究表明，ADC 的疗效并不总是与抗原表达相关。然而，我们最近的体外研究表明，抗原表达与 ADC 有效载荷的细胞内水平之间存在线性关系。在这项研究中，我们探讨了抗原表达与体内肿瘤内 ADC 暴露之间的关系。使用曲妥珠单抗-vc-MMAE（T-vc-MMAE）和四种表达人表皮生长因子受体 2（HER2）的细胞系，我们在肿瘤异种移植模型中评估了总曲妥珠单抗、释放的（“游离的”）MMAE 和总 MMAE 的药代动力学。裸鼠被植入源自 BT-474、MDA-MB-453、MCF-7 和 MDA-MB-468 细胞系的肿瘤，并以 10mg/kg 或 1mg/kg 的 ADC 剂量给药。使用基于机制的 PK 模型对观察到的数据进行了数学描述。在肿瘤内观察到抗原表达水平与游离/总 MMAE 暴露之间存在强烈的正相关（R≥0.91）（总 MMAE 是释放和缀合的 MMAE 的总和），但与总曲妥珠单抗暴露无关。PK 模型能够通过模拟再现血浆 PK；然而，在某些情况下，肿瘤 PK 被高估或低估，这可能是由于肿瘤血管或细胞外基质条件的差异所致。我们的结果表明，在体内，抗原表达与游离/总 ADC 有效载荷的肿瘤暴露之间存在线性关系，验证了我们之前的体外发现，同时也揭示了需要了解肿瘤的复杂生理学，以预测 ADC 及其成分的肿瘤 PK。我们的研究结果还支持在患者中进行抗原表达筛选的概念，以实现靶向治疗（如 ADC）的最大治疗获益。
