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Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma
BACKGROUND: Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarc...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077112/ https://www.ncbi.nlm.nih.gov/pubmed/27776176 http://dx.doi.org/10.1371/journal.pone.0165382 |
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author | Westrøm, Sara Bønsdorff, Tina B. Abbas, Nasir Bruland, Øyvind S. Jonasdottir, Thora J. Mælandsmo, Gunhild M. Larsen, Roy H. |
author_facet | Westrøm, Sara Bønsdorff, Tina B. Abbas, Nasir Bruland, Øyvind S. Jonasdottir, Thora J. Mælandsmo, Gunhild M. Larsen, Roy H. |
author_sort | Westrøm, Sara |
collection | PubMed |
description | BACKGROUND: Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo. METHODS AND RESULTS: A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of (125)I-labeled OI-3 antibody variants was compared with (125)I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI-3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, (177)Lu, and their biodistributions were studied in the nude mouse model. The (177)Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant. CONCLUSION: Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies. |
format | Online Article Text |
id | pubmed-5077112 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50771122016-11-04 Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma Westrøm, Sara Bønsdorff, Tina B. Abbas, Nasir Bruland, Øyvind S. Jonasdottir, Thora J. Mælandsmo, Gunhild M. Larsen, Roy H. PLoS One Research Article BACKGROUND: Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo. METHODS AND RESULTS: A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of (125)I-labeled OI-3 antibody variants was compared with (125)I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI-3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, (177)Lu, and their biodistributions were studied in the nude mouse model. The (177)Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant. CONCLUSION: Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies. Public Library of Science 2016-10-24 /pmc/articles/PMC5077112/ /pubmed/27776176 http://dx.doi.org/10.1371/journal.pone.0165382 Text en © 2016 Westrøm et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Westrøm, Sara Bønsdorff, Tina B. Abbas, Nasir Bruland, Øyvind S. Jonasdottir, Thora J. Mælandsmo, Gunhild M. Larsen, Roy H. Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma |
title | Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma |
title_full | Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma |
title_fullStr | Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma |
title_full_unstemmed | Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma |
title_short | Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma |
title_sort | evaluation of cd146 as target for radioimmunotherapy against osteosarcoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077112/ https://www.ncbi.nlm.nih.gov/pubmed/27776176 http://dx.doi.org/10.1371/journal.pone.0165382 |
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