Natalia Magro , Marta Oteo , Eduardo Romero , Marta Ibáñez-Moragues , Victor Manuel Lujan , Laura Martínez , Oscar Vela , Maria Elena López-Melero , Alicia G. Arroyo , Guillermo Garaulet , Jorge Luis Martínez-Torrecuadrada , Francisca Mulero , Miguel Angel Morcillo
{"title":"用于三阴性乳腺癌 PET 成像和 beta 治疗的抗 MT1-MMP 抗体的靶点接合","authors":"Natalia Magro , Marta Oteo , Eduardo Romero , Marta Ibáñez-Moragues , Victor Manuel Lujan , Laura Martínez , Oscar Vela , Maria Elena López-Melero , Alicia G. Arroyo , Guillermo Garaulet , Jorge Luis Martínez-Torrecuadrada , Francisca Mulero , Miguel Angel Morcillo","doi":"10.1016/j.nucmedbio.2024.108930","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><p>Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with <sup>89</sup>Zr for PET and <sup>177</sup>Lu for therapy in a TNBC murine model.</p></div><div><h3>Methods</h3><p>The LEM2/15 antibody and IgG isotype control were radiolabelled with <sup>89</sup>Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (γH2AX) in MDA 231-BrM2-831 tumours.</p></div><div><h3>Results</h3><p>At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-blood ratio for [<sup>89</sup>Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15-based treatments. A similar uptake was found for [<sup>89</sup>Zr]Zr-Df-LEM2/15 and [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 ± 1.31 vs. 5.61 ± 0.66 %ID/g). Tumour doubling time was longer in the [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with γH2AX-foci was higher in tumours treated with [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4–5 %).</p></div><div><h3>Conclusions</h3><p>The results showed that the <sup>89</sup>Zr/<sup>177</sup>Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.</p></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"136 ","pages":"Article 108930"},"PeriodicalIF":3.6000,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969805124000568/pdfft?md5=405b7a48670d167c2e5b1df9dbb1e4ce&pid=1-s2.0-S0969805124000568-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy\",\"authors\":\"Natalia Magro , Marta Oteo , Eduardo Romero , Marta Ibáñez-Moragues , Victor Manuel Lujan , Laura Martínez , Oscar Vela , Maria Elena López-Melero , Alicia G. Arroyo , Guillermo Garaulet , Jorge Luis Martínez-Torrecuadrada , Francisca Mulero , Miguel Angel Morcillo\",\"doi\":\"10.1016/j.nucmedbio.2024.108930\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Purpose</h3><p>Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with <sup>89</sup>Zr for PET and <sup>177</sup>Lu for therapy in a TNBC murine model.</p></div><div><h3>Methods</h3><p>The LEM2/15 antibody and IgG isotype control were radiolabelled with <sup>89</sup>Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (γH2AX) in MDA 231-BrM2-831 tumours.</p></div><div><h3>Results</h3><p>At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-blood ratio for [<sup>89</sup>Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15-based treatments. A similar uptake was found for [<sup>89</sup>Zr]Zr-Df-LEM2/15 and [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 ± 1.31 vs. 5.61 ± 0.66 %ID/g). Tumour doubling time was longer in the [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with γH2AX-foci was higher in tumours treated with [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [<sup>177</sup>Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4–5 %).</p></div><div><h3>Conclusions</h3><p>The results showed that the <sup>89</sup>Zr/<sup>177</sup>Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.</p></div>\",\"PeriodicalId\":19363,\"journal\":{\"name\":\"Nuclear medicine and biology\",\"volume\":\"136 \",\"pages\":\"Article 108930\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-05-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0969805124000568/pdfft?md5=405b7a48670d167c2e5b1df9dbb1e4ce&pid=1-s2.0-S0969805124000568-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nuclear medicine and biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0969805124000568\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nuclear medicine and biology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969805124000568","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy
Purpose
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with 89Zr for PET and 177Lu for therapy in a TNBC murine model.
Methods
The LEM2/15 antibody and IgG isotype control were radiolabelled with 89Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [177Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [177Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (γH2AX) in MDA 231-BrM2-831 tumours.
Results
At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-blood ratio for [89Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15-based treatments. A similar uptake was found for [89Zr]Zr-Df-LEM2/15 and [177Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 ± 1.31 vs. 5.61 ± 0.66 %ID/g). Tumour doubling time was longer in the [177Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with γH2AX-foci was higher in tumours treated with [177Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [177Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4–5 %).
Conclusions
The results showed that the 89Zr/177Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.
期刊介绍：
Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized.
These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field.
Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.
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