Preclinical Comparison of [111In]In- and [225Ac]Ac-DOTA-Trastuzumab IgG, F(ab')2 and Fab for Theranostic SPECT/CT Imaging and α-Particle Radioimmunotherapy of HER2-Positive Human Breast Cancer.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Molecular Pharmaceutics Pub Date : 2025-01-06 Epub Date: 2024-12-12 DOI:10.1021/acs.molpharmaceut.4c01071
Misaki Kondo, Zhongli Cai, Conrad Chan, Madeline K Brown, Raymond M Reilly
{"title":"Preclinical Comparison of [<sup>111</sup>In]In- and [<sup>225</sup>Ac]Ac-DOTA-Trastuzumab IgG, F(ab')<sub>2</sub> and Fab for Theranostic SPECT/CT Imaging and α-Particle Radioimmunotherapy of HER2-Positive Human Breast Cancer.","authors":"Misaki Kondo, Zhongli Cai, Conrad Chan, Madeline K Brown, Raymond M Reilly","doi":"10.1021/acs.molpharmaceut.4c01071","DOIUrl":null,"url":null,"abstract":"<p><p>Radioimmunotherapy (RIT) with α-particle-emitting, <sup>225</sup>Ac complexed to trastuzumab may offer an alternative treatment for patients who progress on HER2-targeted therapies. Moreover, RIT with [<sup>225</sup>Ac]Ac-DOTA-trastuzumab could be combined with SPECT/CT imaging with [<sup>111</sup>In]In-DOTA-trastuzumab in a theranostic approach. In this study, we compared DOTA-conjugated trastuzumab IgG, F(ab')<sub>2</sub> or Fab complexed to <sup>111</sup>In or <sup>225</sup>Ac for SPECT/CT imaging and α-particle RIT of subcutaneous (s.c.) HER2-positive 164/8-1B/H2N.luc<sup>+</sup> human BC tumors in NRG mice. SPECT/CT imaging and tumor and normal tissue uptake were compared in NRG or NOD-SCID mice coinjected i.v. with [<sup>111</sup>In]In-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab and [<sup>225</sup>Ac]Ac-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab. Radiation absorbed doses in the tumor and normal organs for [<sup>225</sup>Ac]Ac-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab were estimated based on the biodistribution of the [<sup>111</sup>In]In-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab. Normal tissue toxicity was assessed by hematology and blood biochemistry analyses and monitoring body weight in NRG mice injected i.v. with 2 and 4 kBq of [<sup>225</sup>Ac]Ac-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab separated by 8 d. RIT studies were performed in NRG mice with s.c. 164/8-1B/H2N.luc<sup>+</sup> tumors injected i.v. with 2 kBq and 4 kBq of [<sup>225</sup>Ac]Ac-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab separated by 8 d or irrelevant [<sup>225</sup>Ac]Ac-DOTA-IgG<sub>1</sub>, two doses of unlabeled trastuzumab IgG or 0.9% NaCl. A tumor growth index (TGI) was plotted vs time (d) and Kaplan-Meier median survival estimated. [<sup>111</sup>In]In-DOTA-trastuzumab IgG or F(ab')<sub>2</sub> exhibited 4.1-fold and 3.3-fold significantly greater tumor uptake at 2 d postinjection (p.i.) than Fab at 24 h p.i. However, spleen uptake at 2 d p.i. for [<sup>111</sup>In]In-DOTA-trastuzumab IgG was 3.3-fold significantly higher than F(ab')<sub>2</sub> and 13.2-fold higher than Fab at 24 h p.i. [<sup>111</sup>In]In-DOTA-trastuzumab F(ab')<sub>2</sub> and Fab exhibited higher kidney uptake than IgG. Tumors were imaged by SPECT/CT with [<sup>111</sup>In]In-DOTA-trastuzumab IgG and F(ab')<sub>2</sub> but were not well-visualized with [<sup>111</sup>In]In-DOTA-trastuzumab Fab. The absorbed dose in the tumor was 2.2-fold greater for [<sup>225</sup>Ac]Ac-DOTA-trastuzumab F(ab')<sub>2</sub> than IgG and 3.4-fold greater than Fab. Hematological toxicity was observed for [<sup>225</sup>Ac]Ac-DOTA-trastuzumab IgG but not for [<sup>225</sup>Ac]Ac-DOTA-trastuzumab F(ab')<sub>2</sub> or Fab. No kidney or liver toxicity or decreased body weight was observed for any RIT agent. Tumor growth was significantly inhibited by [<sup>225</sup>Ac]Ac-DOTA-trastuzumab IgG, F(ab')<sub>2</sub> or Fab but [<sup>225</sup>Ac]Ac-DOTA-trastuzumab F(ab')<sub>2</sub> was most effective for increasing median survival (46 d vs 22 d for IgG and 29 d for Fab). We conclude that [<sup>111</sup>In]In- and [<sup>225</sup>Ac]Ac-DOTA-trastuzumab F(ab')<sub>2</sub> exhibited superior properties for theranostic imaging and α-particle RIT of HER2-positive human BC xenografts in NRG mice.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"474-487"},"PeriodicalIF":4.5000,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11708818/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.molpharmaceut.4c01071","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/12 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Radioimmunotherapy (RIT) with α-particle-emitting, 225Ac complexed to trastuzumab may offer an alternative treatment for patients who progress on HER2-targeted therapies. Moreover, RIT with [225Ac]Ac-DOTA-trastuzumab could be combined with SPECT/CT imaging with [111In]In-DOTA-trastuzumab in a theranostic approach. In this study, we compared DOTA-conjugated trastuzumab IgG, F(ab')2 or Fab complexed to 111In or 225Ac for SPECT/CT imaging and α-particle RIT of subcutaneous (s.c.) HER2-positive 164/8-1B/H2N.luc+ human BC tumors in NRG mice. SPECT/CT imaging and tumor and normal tissue uptake were compared in NRG or NOD-SCID mice coinjected i.v. with [111In]In-DOTA-trastuzumab IgG, F(ab')2 or Fab and [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab. Radiation absorbed doses in the tumor and normal organs for [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab were estimated based on the biodistribution of the [111In]In-DOTA-trastuzumab IgG, F(ab')2 or Fab. Normal tissue toxicity was assessed by hematology and blood biochemistry analyses and monitoring body weight in NRG mice injected i.v. with 2 and 4 kBq of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab separated by 8 d. RIT studies were performed in NRG mice with s.c. 164/8-1B/H2N.luc+ tumors injected i.v. with 2 kBq and 4 kBq of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab separated by 8 d or irrelevant [225Ac]Ac-DOTA-IgG1, two doses of unlabeled trastuzumab IgG or 0.9% NaCl. A tumor growth index (TGI) was plotted vs time (d) and Kaplan-Meier median survival estimated. [111In]In-DOTA-trastuzumab IgG or F(ab')2 exhibited 4.1-fold and 3.3-fold significantly greater tumor uptake at 2 d postinjection (p.i.) than Fab at 24 h p.i. However, spleen uptake at 2 d p.i. for [111In]In-DOTA-trastuzumab IgG was 3.3-fold significantly higher than F(ab')2 and 13.2-fold higher than Fab at 24 h p.i. [111In]In-DOTA-trastuzumab F(ab')2 and Fab exhibited higher kidney uptake than IgG. Tumors were imaged by SPECT/CT with [111In]In-DOTA-trastuzumab IgG and F(ab')2 but were not well-visualized with [111In]In-DOTA-trastuzumab Fab. The absorbed dose in the tumor was 2.2-fold greater for [225Ac]Ac-DOTA-trastuzumab F(ab')2 than IgG and 3.4-fold greater than Fab. Hematological toxicity was observed for [225Ac]Ac-DOTA-trastuzumab IgG but not for [225Ac]Ac-DOTA-trastuzumab F(ab')2 or Fab. No kidney or liver toxicity or decreased body weight was observed for any RIT agent. Tumor growth was significantly inhibited by [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab but [225Ac]Ac-DOTA-trastuzumab F(ab')2 was most effective for increasing median survival (46 d vs 22 d for IgG and 29 d for Fab). We conclude that [111In]In- and [225Ac]Ac-DOTA-trastuzumab F(ab')2 exhibited superior properties for theranostic imaging and α-particle RIT of HER2-positive human BC xenografts in NRG mice.

[111In]In-和[225Ac] ac - dota -曲妥珠单抗IgG、F(ab')2和Fab在her2阳性人乳腺癌SPECT/CT显像和α-粒子放射免疫治疗中的临床前比较
放射免疫疗法(RIT)与α-颗粒发射,225Ac复合曲妥珠单抗可能为her2靶向治疗进展的患者提供替代治疗。此外,RIT与[225Ac] ac - dota -曲妥珠单抗可以联合SPECT/CT成像与[111In] in - dota -曲妥珠单抗进行治疗。在这项研究中,我们比较了dota偶联曲妥珠单抗IgG、F(ab’)2或Fab与111In或225Ac配合用于SPECT/CT成像和皮下α-颗粒RIT (s.c。)her2阳性164/8-1B / H2N。luc+人BC肿瘤在NRG小鼠中的作用比较NRG或NOD-SCID小鼠共静脉注射[111In] in - dota -曲妥珠单抗IgG, F(ab')2或Fab和[225Ac] ac - dota -曲妥珠单抗IgG, F(ab')2或Fab的SPECT/CT成像和肿瘤及正常组织摄取情况。根据[111In] in - dota -曲妥珠单抗IgG、F(ab’)2或Fab的生物分布,估计[225Ac] ac - dota -曲妥珠单抗IgG、F(ab’)2或Fab在肿瘤和正常器官中的辐射吸收剂量。通过血液学和血液生化分析评估NRG小鼠正常组织毒性,并监测体重,分别静脉注射2和4 kBq的[225Ac] ac - dota -曲妥珠单抗IgG、F(ab')2或Fab,分离8 d。NRG小鼠采用sc . 164/8-1B/H2N进行RIT研究。luc+肿瘤静脉注射2 kBq和4 kBq的[225Ac] ac - dota -曲妥珠单抗IgG, F(ab')2或Fab分离8 d或不相关的[225Ac]Ac-DOTA-IgG1,两剂未标记的曲妥珠单抗IgG或0.9% NaCl。绘制肿瘤生长指数(TGI)与时间(d)的关系图,并估计Kaplan-Meier中位生存期。[111In] in - dota -曲妥珠单抗IgG或F(ab’)2在注射后第2天的肿瘤摄取比Fab在注射后24小时的肿瘤摄取高4.1倍和3.3倍。然而,在注射后第2天,in - dota -曲妥珠单抗IgG的脾脏摄取比F(ab’)2高3.3倍,比Fab在注射后24小时的脾脏摄取高13.2倍。[111In] in - dota -曲妥珠单抗F(ab’)2和Fab的肾脏摄取比IgG高。用[111In] in - dota -曲妥珠单抗IgG和F(ab')2对肿瘤进行SPECT/CT成像,但用[111In] in - dota -曲妥珠单抗Fab不能很好地显示肿瘤。[225Ac] ac - dota -曲妥珠单抗F(ab’)2在肿瘤中的吸收剂量比IgG高2.2倍,比Fab高3.4倍。观察到[225Ac] ac - dota -曲妥珠单抗IgG的血液学毒性,但未观察到[225Ac] ac - dota -曲妥珠单抗F(ab')2或Fab的血液毒性。没有观察到任何RIT药物的肾或肝毒性或体重下降。[225Ac] ac - dota -曲妥珠单抗IgG、F(ab')2或Fab显著抑制肿瘤生长,但[225Ac] ac - dota -曲妥珠单抗F(ab')2对提高中位生存期最有效(46天,IgG 22天,Fab 29天)。我们得出结论,[111In]In-和[225Ac] ac - dota -曲妥珠单抗F(ab')2在NRG小鼠her2阳性人BC异种移植物的治疗成像和α-颗粒RIT方面具有优越的性能。
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 求助全文
来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信