Complete Remissions of HER2-Positive Trastuzumab-Resistant Xenografts Using a Potent [225Ac]Ac-Labeled Anti-HER2 Antibody-Drug Radioconjugate.

IF 10 1区医学 Q1 ONCOLOGY Clinical Cancer Research Pub Date : 2025-02-17 DOI:10.1158/1078-0432.CCR-24-1779

Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Alissar Monzer, Emmanuel Nwangele, Anjong Florence Tikum, Nikita Henning, Nava Hassani, Sarah Frye, Randy Perron, Chris Byrne, Candice Didychuk, Qi Qi, Laura Bannister, Alireza Doroudi, Humphrey Fonge

{"title":"Complete Remissions of HER2-Positive Trastuzumab-Resistant Xenografts Using a Potent [225Ac]Ac-Labeled Anti-HER2 Antibody-Drug Radioconjugate.","authors":"Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Alissar Monzer, Emmanuel Nwangele, Anjong Florence Tikum, Nikita Henning, Nava Hassani, Sarah Frye, Randy Perron, Chris Byrne, Candice Didychuk, Qi Qi, Laura Bannister, Alireza Doroudi, Humphrey Fonge","doi":"10.1158/1078-0432.CCR-24-1779","DOIUrl":null,"url":null,"abstract":"Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody-drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody-drug radioconjugate [225Ac]Ac-macropa-trastuzumab(T)-PEG6-emtansine (DM1), is expected to be more effective than its ADC (T-PEG6-DM1) against breast cancer.Experimental design: [89Zr]Zr-p-isothiocyanatobenzyl desferrioxamine (DFO)-T-PEG6-DM1 (imaging) and [225Ac]Ac-macropa-T-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac-macropa-T-PEG6-DM1 were carried out in non-tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-T-PEG6-DM1, and radiotherapy using [225Ac]Ac-macropa-T-PEG6-DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice.Results: After 7 days of incubation at 37°C, [225Ac]Ac-macropa-T-PEG6-DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-macropa-T-PEG6-DM1 (3 × 18 kBq) administered separately in non-tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-T-PEG6-DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1-based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T-PEG6-DM1, and [225Ac]Ac-macropa-T-PEG6-DM1, respectively.Conclusions: [225Ac]Ac-macropa-T-PEG6-DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"685-696"},"PeriodicalIF":10.0000,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.CCR-24-1779","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody-drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody-drug radioconjugate [225Ac]Ac-macropa-trastuzumab(T)-PEG6-emtansine (DM1), is expected to be more effective than its ADC (T-PEG6-DM1) against breast cancer.

Experimental design: [89Zr]Zr-p-isothiocyanatobenzyl desferrioxamine (DFO)-T-PEG6-DM1 (imaging) and [225Ac]Ac-macropa-T-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac-macropa-T-PEG6-DM1 were carried out in non-tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-T-PEG6-DM1, and radiotherapy using [225Ac]Ac-macropa-T-PEG6-DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice.

Results: After 7 days of incubation at 37°C, [225Ac]Ac-macropa-T-PEG6-DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-macropa-T-PEG6-DM1 (3 × 18 kBq) administered separately in non-tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-T-PEG6-DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1-based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T-PEG6-DM1, and [225Ac]Ac-macropa-T-PEG6-DM1, respectively.

Conclusions: [225Ac]Ac-macropa-T-PEG6-DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

使用有效的[225Ac] ac标记的抗her2抗体-药物放射偶联物完全缓解her2阳性曲妥珠单抗耐药异种移植物。

目的：人们对使用锕-225 （[225Ac]Ac）开发靶向α疗法非常感兴趣。抗体-药物偶联物（adc）具有高度的细胞毒性。[225Ac]Ac与ADC联合开发抗体-药物放射偶联物（ADR） [225Ac]Ac- macropa -曲妥珠单抗- peg6 - dm1，有望比其ADC（曲妥珠单抗- peg6 - dm1）更有效地治疗乳腺癌（BC）。实验设计：研制[89Zr] zr - dfo -曲妥珠单抗- peg6 - dm1（成像）和[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1（放疗）。[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1在非荷瘤Balb/C小鼠中的生物分布和安全性评价。使用[89Zr] zr - dfos -曲妥珠单抗- peg6 - dm1进行显微pet成像和生物分布，并使用[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1对携带曲妥珠单抗耐药HCC1954的胸腺Balb/C裸鼠和T-DM1/曲妥珠单抗耐药的JIMT-1肿瘤小鼠进行放射治疗。结果：37℃孵育7 d后，[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1在人血清（89.2±0.9%）和磷酸盐缓冲盐水（82.8±0.4%）中均保持稳定。曲妥珠单抗- peg6 - dm1 （8 mg/kg）和[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1 （3 × 18 kBq）分别给药于非肿瘤小鼠，间隔10 d的生化和血液学耐受良好。成像和生物分布显示，注射后120 h， [89Zr] zr - dvo -trastuzumab- peg6 - dm1在载瘤小鼠中的肿瘤摄取高：38.1±2.8% IA/g （HCC1954）和14.6±1% IA/g （JIMT-1）。在hcc54 -肿瘤小鼠中，所有治疗组均有完全缓解（8/8 CR），表明异种移植物对T-DM1治疗的反应性，而对于JIMT-1异种移植物（1/8 CR），在治疗后23 d，肿瘤体积分别为332.1±77.5 vs 244.6±63 vs 417.9±62.1 vs 102.4±18.5，生理盐水（阴性对照），T-DM1（阳性对照），曲妥珠单抗- peg6 - dm1和[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1。结论：[225Ac] ac - macropa -曲妥珠单抗- peg6 - dm1治疗曲妥珠单抗耐药BC比ADC更有效，需要临床翻译。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.