免疫PET检测与他汀类药物联合用药的抗体药物效力。

IF 9.1 1区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING Journal of Nuclear Medicine Pub Date : 2023-10-01 Epub Date: 2023-06-29 DOI:10.2967/jnumed.122.265172
Emma L Brown, Shayla Shmuel, Komal Mandleywala, Sandeep Surendra Panikar, Na-Keysha Berry, Yi Rao, Abbey Zidel, Jason S Lewis, Patrícia M R Pereira
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引用次数: 0

摘要

人表皮生长因子受体2(HER2)靶向曲妥珠单抗emtansine(T-DM1)和曲妥珠珠单抗deruxtecan(T-DXd)是临床上用于治疗HER2阳性乳腺癌症的抗体驱动药物偶联物(ADC),后者于2021年获得HER2阳性癌症的临床批准。洛伐他汀,一种降低胆固醇的药物,以增强HER2-ADC结合和内化的方式暂时升高细胞表面HER2。方法:在NCIN87胃异种移植物模型和胃患者来源的异种移植物模式中,我们使用89Zr标记或64Cu标记的抗HER2抗体曲妥珠单抗来研究ADC治疗加用和不加用洛伐他汀的给药方案。我们比较了重复临床剂量方案标准的多剂量ADC方案与单剂量方案的ADC疗效。结果:无论多次或单次给药T-DM1,T-DM1/洛伐他汀治疗均可抑制肿瘤生长。洛伐他汀与T-DM1或T-DXd单剂量联合给药增强了肿瘤生长抑制,同时伴有HER2靶向免疫PET信号的减少和HER2介导的细胞水平信号的减少。DNA损伤信号在体外ADC治疗中增加。结论:我们从癌症异种移植物获得的数据表明,HER2-靶向免疫-PET与细胞表面靶向有效性调节剂联合使用,可告知肿瘤对ADC治疗的反应。我们的研究还表明,他汀类药物在细胞系和患者来源的异种移植物模型中都能增强ADC的疗效,从而实现ADC的单剂量给药。
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Immuno-PET Detects Antibody-Drug Potency on Coadministration with Statins.

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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来源期刊
Journal of Nuclear Medicine
Journal of Nuclear Medicine 医学-核医学
CiteScore
13.00
自引率
8.60%
发文量
340
审稿时长
1 months
期刊介绍: The Journal of Nuclear Medicine (JNM), self-published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), provides readers worldwide with clinical and basic science investigations, continuing education articles, reviews, employment opportunities, and updates on practice and research. In the 2022 Journal Citation Reports (released in June 2023), JNM ranked sixth in impact among 203 medical journals worldwide in the radiology, nuclear medicine, and medical imaging category.
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