Asif Noor, Emily R. McGowan, Jessica K. Van Zuylekom, Carleen Cullinane, Peter D. Roselt, Rodney J. Hicks, Michael P. Wheatcroft, Paul S. Donnelly
{"title":"用于碳酸酐酶 IX 阳性肿瘤诊断成像的 [89Zr]ZrDFOSquaramide-girentuximab 的临床前评估和自动合成","authors":"Asif Noor, Emily R. McGowan, Jessica K. Van Zuylekom, Carleen Cullinane, Peter D. Roselt, Rodney J. Hicks, Michael P. Wheatcroft, Paul S. Donnelly","doi":"10.1186/s41181-024-00310-x","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Carbonic Anhydrase IX (CAIX) is a zinc metalloenzyme that is over-expressed in many cancers making it a valid target for targeted diagnostic imaging with Positron Emission Tomography (PET). The monoclonal antibody girentuximab binds to CAIX and when radiolabelled with positron-emitting zirconium-89 can be used for diagnostic PET imaging of CAIX positive tumours.</p><h3>Results</h3><p>Reaction of desferrioxamine squaramide ethyl ester with girentuximab allowed isolation of a conjugate with desferrioxamine squaramide (DFOSq) covalently attached to girentuximab through stable vinylogous amide linkages to give DFOSq-girentuximab. This conjugate was radiolabelled with zirconium-89 to give [<sup>89</sup>Zr]ZrDFOSq-girentuximab and the tumour uptake of the tracer was evaluated in CAIX positive HT29 tumour-bearing mice. Analysis of the PET images and biodistribution studies showed that the tracer displays high tumour uptake. An automated process for production of [<sup>89</sup>Zr]ZrDFOSq-girentuximab was developed, using [<sup>89</sup>Zr]ZrCl<sub>4</sub> as a starting material that was also synthesized in an automated process. This automated process allows isolation of [<sup>89</sup>Zr]ZrDFOSq-girentuximab in radiochemical yields of 80–90% and in > 95% radiochemical purity.</p><h3>Conclusions</h3><p>[<sup>89</sup>Zr]ZrDFOSq-girentuximab has high uptake in CAIX positive tumours. An automated procedure for the synthesis of [<sup>89</sup>Zr]ZrDFOSq-girentuximab using [<sup>89</sup>Zr]ZrCl<sub>4</sub> as a starting material has been developed. This automated process could be readily adapted to other antibodies.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00310-x","citationCount":"0","resultStr":"{\"title\":\"Preclinical evaluation and automated synthesis of [89Zr]ZrDFOSquaramide-girentuximab for diagnostic imaging of carbonic anhydrase IX positive tumours\",\"authors\":\"Asif Noor, Emily R. McGowan, Jessica K. Van Zuylekom, Carleen Cullinane, Peter D. Roselt, Rodney J. Hicks, Michael P. Wheatcroft, Paul S. Donnelly\",\"doi\":\"10.1186/s41181-024-00310-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Carbonic Anhydrase IX (CAIX) is a zinc metalloenzyme that is over-expressed in many cancers making it a valid target for targeted diagnostic imaging with Positron Emission Tomography (PET). The monoclonal antibody girentuximab binds to CAIX and when radiolabelled with positron-emitting zirconium-89 can be used for diagnostic PET imaging of CAIX positive tumours.</p><h3>Results</h3><p>Reaction of desferrioxamine squaramide ethyl ester with girentuximab allowed isolation of a conjugate with desferrioxamine squaramide (DFOSq) covalently attached to girentuximab through stable vinylogous amide linkages to give DFOSq-girentuximab. This conjugate was radiolabelled with zirconium-89 to give [<sup>89</sup>Zr]ZrDFOSq-girentuximab and the tumour uptake of the tracer was evaluated in CAIX positive HT29 tumour-bearing mice. Analysis of the PET images and biodistribution studies showed that the tracer displays high tumour uptake. An automated process for production of [<sup>89</sup>Zr]ZrDFOSq-girentuximab was developed, using [<sup>89</sup>Zr]ZrCl<sub>4</sub> as a starting material that was also synthesized in an automated process. This automated process allows isolation of [<sup>89</sup>Zr]ZrDFOSq-girentuximab in radiochemical yields of 80–90% and in > 95% radiochemical purity.</p><h3>Conclusions</h3><p>[<sup>89</sup>Zr]ZrDFOSq-girentuximab has high uptake in CAIX positive tumours. An automated procedure for the synthesis of [<sup>89</sup>Zr]ZrDFOSq-girentuximab using [<sup>89</sup>Zr]ZrCl<sub>4</sub> as a starting material has been developed. This automated process could be readily adapted to other antibodies.</p></div>\",\"PeriodicalId\":534,\"journal\":{\"name\":\"EJNMMI Radiopharmacy and Chemistry\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-11-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00310-x\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EJNMMI Radiopharmacy and Chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://link.springer.com/article/10.1186/s41181-024-00310-x\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, INORGANIC & NUCLEAR\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EJNMMI Radiopharmacy and Chemistry","FirstCategoryId":"1085","ListUrlMain":"https://link.springer.com/article/10.1186/s41181-024-00310-x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, INORGANIC & NUCLEAR","Score":null,"Total":0}
Preclinical evaluation and automated synthesis of [89Zr]ZrDFOSquaramide-girentuximab for diagnostic imaging of carbonic anhydrase IX positive tumours
Background
Carbonic Anhydrase IX (CAIX) is a zinc metalloenzyme that is over-expressed in many cancers making it a valid target for targeted diagnostic imaging with Positron Emission Tomography (PET). The monoclonal antibody girentuximab binds to CAIX and when radiolabelled with positron-emitting zirconium-89 can be used for diagnostic PET imaging of CAIX positive tumours.
Results
Reaction of desferrioxamine squaramide ethyl ester with girentuximab allowed isolation of a conjugate with desferrioxamine squaramide (DFOSq) covalently attached to girentuximab through stable vinylogous amide linkages to give DFOSq-girentuximab. This conjugate was radiolabelled with zirconium-89 to give [89Zr]ZrDFOSq-girentuximab and the tumour uptake of the tracer was evaluated in CAIX positive HT29 tumour-bearing mice. Analysis of the PET images and biodistribution studies showed that the tracer displays high tumour uptake. An automated process for production of [89Zr]ZrDFOSq-girentuximab was developed, using [89Zr]ZrCl4 as a starting material that was also synthesized in an automated process. This automated process allows isolation of [89Zr]ZrDFOSq-girentuximab in radiochemical yields of 80–90% and in > 95% radiochemical purity.
Conclusions
[89Zr]ZrDFOSq-girentuximab has high uptake in CAIX positive tumours. An automated procedure for the synthesis of [89Zr]ZrDFOSq-girentuximab using [89Zr]ZrCl4 as a starting material has been developed. This automated process could be readily adapted to other antibodies.
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