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 labe...
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SAGE Publishing
2023-01-01
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| Series: | Molecular Imaging |
| Online Access: | http://dx.doi.org/10.1155/2023/3499655 |
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| author | Elaine M. Jagoda Falguni Basuli Colleen Olkowski Ido Weiss Tim E. Phelps Karen Wong Anita Thien Ton Kelly C. Lane Steve Adler Donna Butcher Elijah F. Edmondson Sol Langermann Peter L. Choyke |
| author_facet | Elaine M. Jagoda Falguni Basuli Colleen Olkowski Ido Weiss Tim E. Phelps Karen Wong Anita Thien Ton Kelly C. Lane Steve Adler Donna Butcher Elijah F. Edmondson Sol Langermann Peter L. Choyke |
| author_sort | Elaine M. Jagoda |
| collection | DOAJ |
| description | 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 (Kd~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. |
| format | Article |
| id | doaj-art-15ff0cb633964b33b41459e8b6efa45e |
| institution | Kabale University |
| issn | 1536-0121 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | SAGE Publishing |
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| series | Molecular Imaging |
| spelling | doaj-art-15ff0cb633964b33b41459e8b6efa45e2025-01-03T00:12:41ZengSAGE PublishingMolecular Imaging1536-01212023-01-01202310.1155/2023/3499655Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318Elaine M. Jagoda0Falguni Basuli1Colleen Olkowski2Ido Weiss3Tim E. Phelps4Karen Wong5Anita Thien Ton6Kelly C. Lane7Steve Adler8Donna Butcher9Elijah F. Edmondson10Sol Langermann11Peter L. Choyke12Molecular Imaging BranchChemistry and Synthesis CenterMolecular Imaging BranchNextCureMolecular Imaging BranchMolecular Imaging BranchMolecular Imaging BranchChemistry and Synthesis CenterMolecular Imaging BranchMolecular Histopathology LabMolecular Histopathology LabNextCureMolecular Imaging BranchObjective. 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 (Kd~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.http://dx.doi.org/10.1155/2023/3499655 |
| spellingShingle | Elaine M. Jagoda Falguni Basuli Colleen Olkowski Ido Weiss Tim E. Phelps Karen Wong Anita Thien Ton Kelly C. Lane Steve Adler Donna Butcher Elijah F. Edmondson Sol Langermann Peter L. Choyke Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318 Molecular Imaging |
| title | Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318 |
| title_full | Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318 |
| title_fullStr | Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318 |
| title_full_unstemmed | Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318 |
| title_short | Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318 |
| title_sort | immuno pet imaging of siglec 15 using the zirconium 89 labeled therapeutic antibody nc318 |
| url | http://dx.doi.org/10.1155/2023/3499655 |
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