抗体-药物偶联物
曲妥珠单抗
医学
药理学
洛伐他汀
药代动力学
癌症研究
癌症
抗体
乳腺癌
单克隆抗体
内科学
免疫学
胆固醇
作者
Emma Brown,Shayla Shmuel,Komal Mandleywala,Sandeep Surendra Panikar,Neil Berry,Yi Rao,Abbey Zidel,Jason S. Lewis,Patrícia M. R. Pereira
标识
DOI:10.2967/jnumed.122.265172
摘要
The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the 89Zr-labeled or 64Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.
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