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Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent
High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the developm...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732808/ https://www.ncbi.nlm.nih.gov/pubmed/29262642 http://dx.doi.org/10.18632/oncotarget.22228 |
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author | Marquez-Nostra, Bernadette V. Lee, Supum Laforest, Richard Vitale, Laura Nie, Xingyu Hyrc, Krzysztof Keler, Tibor Hawthorne, Thomas Hoog, Jeremy Li, Shunqiang Dehdashti, Farrokh Ma, Cynthia X. Lapi, Suzanne E. |
author_facet | Marquez-Nostra, Bernadette V. Lee, Supum Laforest, Richard Vitale, Laura Nie, Xingyu Hyrc, Krzysztof Keler, Tibor Hawthorne, Thomas Hoog, Jeremy Li, Shunqiang Dehdashti, Farrokh Ma, Cynthia X. Lapi, Suzanne E. |
author_sort | Marquez-Nostra, Bernadette V. |
collection | PubMed |
description | High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using (89)Zr-labeled glembatumumab ([(89)Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [(89)Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [(89)Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [(89)Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [(89)Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [(89)Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC. |
format | Online Article Text |
id | pubmed-5732808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57328082017-12-19 Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent Marquez-Nostra, Bernadette V. Lee, Supum Laforest, Richard Vitale, Laura Nie, Xingyu Hyrc, Krzysztof Keler, Tibor Hawthorne, Thomas Hoog, Jeremy Li, Shunqiang Dehdashti, Farrokh Ma, Cynthia X. Lapi, Suzanne E. Oncotarget Research Paper High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using (89)Zr-labeled glembatumumab ([(89)Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [(89)Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [(89)Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [(89)Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [(89)Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [(89)Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC. Impact Journals LLC 2017-11-01 /pmc/articles/PMC5732808/ /pubmed/29262642 http://dx.doi.org/10.18632/oncotarget.22228 Text en Copyright: © 2017 Marquez-Nostra et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Marquez-Nostra, Bernadette V. Lee, Supum Laforest, Richard Vitale, Laura Nie, Xingyu Hyrc, Krzysztof Keler, Tibor Hawthorne, Thomas Hoog, Jeremy Li, Shunqiang Dehdashti, Farrokh Ma, Cynthia X. Lapi, Suzanne E. Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
title | Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
title_full | Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
title_fullStr | Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
title_full_unstemmed | Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
title_short | Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
title_sort | preclinical pet imaging of glycoprotein non-metastatic melanoma b in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732808/ https://www.ncbi.nlm.nih.gov/pubmed/29262642 http://dx.doi.org/10.18632/oncotarget.22228 |
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