E. Jagoda, F. Basuli, C. Olkowski, Ido D. Weiss, Tim E. Phelps, Karen J. Wong, Anita T. Ton, Kelly C. Lane, S. Adler, D. Butcher, E. Edmondson, S. Langermann, P. Choyke
{"title":"使用锆标记的治疗性抗体NC318对Siglec-15进行免疫PET成像","authors":"E. Jagoda, F. Basuli, C. Olkowski, Ido D. Weiss, Tim E. Phelps, Karen J. Wong, Anita T. Ton, Kelly C. Lane, S. Adler, D. Butcher, E. Edmondson, S. Langermann, P. Choyke","doi":"10.1155/2023/3499655","DOIUrl":null,"url":null,"abstract":"Objective. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is overexpressed in various cancers which has led to the development of therapeutic anti-Siglec-15 monoconal antibodies (mAbs). In these preclinical studies, the therapeutic mAb, NC318 (antihuman/murine Siglec-15 mAb), was labeled with zirconium-89 and evaluated in human Siglec-15 expressing cancer cells and mouse xenografts for potential use as a clinical diagnostic imaging agent. Methods. Desferrioxamine-conjugated NC318 was radiolabeled with zirconium-89 to synthesize [89Zr]Zr-DFO-NC318. Cancer cell lines expressing variable Siglec-15 levels were used for in vitro cell binding studies and tumor xenograft mouse models for biodistributions. [89Zr]Zr-DFO-NC318 biodistribution and PET imaging studies to determine tissue uptakes (tissue : muscle ratios, T : M) included pharmacokinetic evaluation in Siglec-15+tumor xenografts and immunocompetent mice, blocking with nonradioactive NC318 (20, 100, and 300 μg) and xenografts with low/negligible Siglec-15 expressing tumors. Results. [89Zr]Zr-DFO-NC318 exhibited high affinity (\n \n \n \n K\n \n \n d\n \n \n \n ~4 nM) for Siglec-15 and distinguished between moderate and negligible Siglec-15 expression levels in cancer cell lines. The highest [89Zr]Zr-DFO-NC318 uptakes occurred in the spleen and lymph nodes of the Siglec-15+tumor xenografts at all time points followed by Siglec-15+tumor uptake which was lower although highly retained. In immunocompetent mice, the spleen and lymph nodes exhibited lower uptakes indicating that the athymic xenografts had increased Siglec-15+ immune cells. Specific [89Zr]Zr-DFO-NC318 binding to Siglec-15 was proven with NC318 blocking studies in which dose-dependent decreases in Siglec-15+tumor T : Ms were observed. Higher than expected, tumor T : Ms were seen in lower expressing tumors likely due to the contribution of murine Siglec-15+ immune cells in the tumor microenvironment as confirmed by immunohistochemistry. Siglec-15+tumors were identified on PET images whereas low/negligible expressing tumors showed lower uptakes. Conclusions. In vitro and in vivo [89Zr]Zr-DFO-NC318 uptakes correlated with Siglec-15 expression levels in target tissues. Despite uptake in immune cell subsets in the tumor microenvironment, these results suggest that clinical [89Zr]Zr-DFO-NC318 PET imaging may have value in selecting patients for Siglec-15-targeted therapies.","PeriodicalId":49796,"journal":{"name":"Molecular Imaging","volume":" ","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2023-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318\",\"authors\":\"E. Jagoda, F. Basuli, C. Olkowski, Ido D. Weiss, Tim E. Phelps, Karen J. Wong, Anita T. Ton, Kelly C. Lane, S. Adler, D. Butcher, E. Edmondson, S. Langermann, P. Choyke\",\"doi\":\"10.1155/2023/3499655\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Objective. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is overexpressed in various cancers which has led to the development of therapeutic anti-Siglec-15 monoconal antibodies (mAbs). In these preclinical studies, the therapeutic mAb, NC318 (antihuman/murine Siglec-15 mAb), was labeled with zirconium-89 and evaluated in human Siglec-15 expressing cancer cells and mouse xenografts for potential use as a clinical diagnostic imaging agent. Methods. Desferrioxamine-conjugated NC318 was radiolabeled with zirconium-89 to synthesize [89Zr]Zr-DFO-NC318. Cancer cell lines expressing variable Siglec-15 levels were used for in vitro cell binding studies and tumor xenograft mouse models for biodistributions. [89Zr]Zr-DFO-NC318 biodistribution and PET imaging studies to determine tissue uptakes (tissue : muscle ratios, T : M) included pharmacokinetic evaluation in Siglec-15+tumor xenografts and immunocompetent mice, blocking with nonradioactive NC318 (20, 100, and 300 μg) and xenografts with low/negligible Siglec-15 expressing tumors. Results. [89Zr]Zr-DFO-NC318 exhibited high affinity (\\n \\n \\n \\n K\\n \\n \\n d\\n \\n \\n \\n ~4 nM) for Siglec-15 and distinguished between moderate and negligible Siglec-15 expression levels in cancer cell lines. The highest [89Zr]Zr-DFO-NC318 uptakes occurred in the spleen and lymph nodes of the Siglec-15+tumor xenografts at all time points followed by Siglec-15+tumor uptake which was lower although highly retained. In immunocompetent mice, the spleen and lymph nodes exhibited lower uptakes indicating that the athymic xenografts had increased Siglec-15+ immune cells. Specific [89Zr]Zr-DFO-NC318 binding to Siglec-15 was proven with NC318 blocking studies in which dose-dependent decreases in Siglec-15+tumor T : Ms were observed. Higher than expected, tumor T : Ms were seen in lower expressing tumors likely due to the contribution of murine Siglec-15+ immune cells in the tumor microenvironment as confirmed by immunohistochemistry. Siglec-15+tumors were identified on PET images whereas low/negligible expressing tumors showed lower uptakes. Conclusions. In vitro and in vivo [89Zr]Zr-DFO-NC318 uptakes correlated with Siglec-15 expression levels in target tissues. Despite uptake in immune cell subsets in the tumor microenvironment, these results suggest that clinical [89Zr]Zr-DFO-NC318 PET imaging may have value in selecting patients for Siglec-15-targeted therapies.\",\"PeriodicalId\":49796,\"journal\":{\"name\":\"Molecular Imaging\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2023-02-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Imaging\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1155/2023/3499655\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/2023/3499655","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318
Objective. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is overexpressed in various cancers which has led to the development of therapeutic anti-Siglec-15 monoconal antibodies (mAbs). In these preclinical studies, the therapeutic mAb, NC318 (antihuman/murine Siglec-15 mAb), was labeled with zirconium-89 and evaluated in human Siglec-15 expressing cancer cells and mouse xenografts for potential use as a clinical diagnostic imaging agent. Methods. Desferrioxamine-conjugated NC318 was radiolabeled with zirconium-89 to synthesize [89Zr]Zr-DFO-NC318. Cancer cell lines expressing variable Siglec-15 levels were used for in vitro cell binding studies and tumor xenograft mouse models for biodistributions. [89Zr]Zr-DFO-NC318 biodistribution and PET imaging studies to determine tissue uptakes (tissue : muscle ratios, T : M) included pharmacokinetic evaluation in Siglec-15+tumor xenografts and immunocompetent mice, blocking with nonradioactive NC318 (20, 100, and 300 μg) and xenografts with low/negligible Siglec-15 expressing tumors. Results. [89Zr]Zr-DFO-NC318 exhibited high affinity (
K
d
~4 nM) for Siglec-15 and distinguished between moderate and negligible Siglec-15 expression levels in cancer cell lines. The highest [89Zr]Zr-DFO-NC318 uptakes occurred in the spleen and lymph nodes of the Siglec-15+tumor xenografts at all time points followed by Siglec-15+tumor uptake which was lower although highly retained. In immunocompetent mice, the spleen and lymph nodes exhibited lower uptakes indicating that the athymic xenografts had increased Siglec-15+ immune cells. Specific [89Zr]Zr-DFO-NC318 binding to Siglec-15 was proven with NC318 blocking studies in which dose-dependent decreases in Siglec-15+tumor T : Ms were observed. Higher than expected, tumor T : Ms were seen in lower expressing tumors likely due to the contribution of murine Siglec-15+ immune cells in the tumor microenvironment as confirmed by immunohistochemistry. Siglec-15+tumors were identified on PET images whereas low/negligible expressing tumors showed lower uptakes. Conclusions. In vitro and in vivo [89Zr]Zr-DFO-NC318 uptakes correlated with Siglec-15 expression levels in target tissues. Despite uptake in immune cell subsets in the tumor microenvironment, these results suggest that clinical [89Zr]Zr-DFO-NC318 PET imaging may have value in selecting patients for Siglec-15-targeted therapies.
期刊介绍:
Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.