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Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy
CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either (177)Lu or (131)I as th...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919712/ https://www.ncbi.nlm.nih.gov/pubmed/29658563 http://dx.doi.org/10.3892/ijo.2018.4364 |
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author | Mortensen, Anja C. Spiegelberg, Diana Haylock, Anna-Karin Lundqvist, Hans Nestor, Marika |
author_facet | Mortensen, Anja C. Spiegelberg, Diana Haylock, Anna-Karin Lundqvist, Hans Nestor, Marika |
author_sort | Mortensen, Anja C. |
collection | PubMed |
description | CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either (177)Lu or (131)I as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with (177)Lu, (125)I or (131)I. The therapeutic effects of (177)Lu-AbN44v6 and (131)I-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for (177)Lu-AbN44v6 and (125)I-AbN44v6/(131)I-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro. In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both (177)Lu-AbN44v6 and (131)I-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of (177)Lu-AbN44v6 in the liver, spleen and bone, compared to (125)I-AbN44v6, whereas (125)I-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for (177)Lu-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for (131)I-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically and with high affinity to CD44v6. Furthermore, in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates, demonstrating that both (177)Lu-AbN44v6 and (131)I-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro, combined with the beneficial dosimetry in vivo, render AbN44v6 a potential candidate for RIT. |
format | Online Article Text |
id | pubmed-5919712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-59197122018-05-03 Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy Mortensen, Anja C. Spiegelberg, Diana Haylock, Anna-Karin Lundqvist, Hans Nestor, Marika Int J Oncol Articles CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either (177)Lu or (131)I as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with (177)Lu, (125)I or (131)I. The therapeutic effects of (177)Lu-AbN44v6 and (131)I-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for (177)Lu-AbN44v6 and (125)I-AbN44v6/(131)I-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro. In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both (177)Lu-AbN44v6 and (131)I-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of (177)Lu-AbN44v6 in the liver, spleen and bone, compared to (125)I-AbN44v6, whereas (125)I-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for (177)Lu-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for (131)I-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically and with high affinity to CD44v6. Furthermore, in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates, demonstrating that both (177)Lu-AbN44v6 and (131)I-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro, combined with the beneficial dosimetry in vivo, render AbN44v6 a potential candidate for RIT. D.A. Spandidos 2018-04-11 /pmc/articles/PMC5919712/ /pubmed/29658563 http://dx.doi.org/10.3892/ijo.2018.4364 Text en Copyright: © Mortensen et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Mortensen, Anja C. Spiegelberg, Diana Haylock, Anna-Karin Lundqvist, Hans Nestor, Marika Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy |
title | Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy |
title_full | Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy |
title_fullStr | Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy |
title_full_unstemmed | Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy |
title_short | Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy |
title_sort | preclinical evaluation of a novel engineered recombinant human anti-cd44v6 antibody for potential use in radio-immunotherapy |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919712/ https://www.ncbi.nlm.nih.gov/pubmed/29658563 http://dx.doi.org/10.3892/ijo.2018.4364 |
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