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Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu.
Single-chain Fv (scFv) molecules exhibit highly specific tumour-targeting properties in tumour-bearing mice. However, because of their smaller size and monovalent binding, the quantities of radiolabelled scFv retained in tumours limit their therapeutic applications. Diabodies are dimeric antibody-ba...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
1998
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150193/ https://www.ncbi.nlm.nih.gov/pubmed/9652755 |
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author | Adams, G. P. Schier, R. McCall, A. M. Crawford, R. S. Wolf, E. J. Weiner, L. M. Marks, J. D. |
author_facet | Adams, G. P. Schier, R. McCall, A. M. Crawford, R. S. Wolf, E. J. Weiner, L. M. Marks, J. D. |
author_sort | Adams, G. P. |
collection | PubMed |
description | Single-chain Fv (scFv) molecules exhibit highly specific tumour-targeting properties in tumour-bearing mice. However, because of their smaller size and monovalent binding, the quantities of radiolabelled scFv retained in tumours limit their therapeutic applications. Diabodies are dimeric antibody-based molecules composed of two non-covalently associated scFv that bind to antigen in a divalent manner. In vitro, diabodies produced from the anti-HER2/neu (c-erbB-2) scFv C6.5 displayed approximately 40-fold greater affinity for HER2/neu by surface plasmon resonance biosensor measurements and significantly prolonged association with antigen on the surface of SK-OV-3 cells (t1/2 cell surface retention of > 5 h vs 5 min) compared with C6.5 scFv. In SK-OV-3 tumour-bearing scid mice, radioiodinated C6.5 diabody displayed a highly favourable balance of quantitative tumour retention and specificity. By as early as 4 h after i.v. administration, significantly more diabody was retained in tumour (10 %ID g(-1)) than in blood (6.7 %ID ml(-1)) or normal tissue (liver, 2.8 %ID g(-1); lung, 7.1 %ID g(-1); kidney, 5.2 %ID g(-1)). Over the next 20 h, the quantity present in blood and most tissues dropped approximately tenfold, while the tumour retained 6.5 %ID g(-1) or about two-thirds of its 4-h value. In contrast, the 24-h tumour retention of radioiodinated C6.5 scFv monomer was only 1 %ID g(-1). When diabody retentions were examined over the course of a 72-h study and cumulative area under the curve (AUC) values were determined, the resulting tumor-organ AUC ratios were found to be superior to those previously reported for other monovalent or divalent scFv molecules. In conclusion, the diabody format provides the C6.5 molecule with a distinct in vitro and in vivo targeting advantage and has promise as a delivery vehicle for therapeutic agents. |
format | Text |
id | pubmed-2150193 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1998 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-21501932009-09-10 Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Adams, G. P. Schier, R. McCall, A. M. Crawford, R. S. Wolf, E. J. Weiner, L. M. Marks, J. D. Br J Cancer Research Article Single-chain Fv (scFv) molecules exhibit highly specific tumour-targeting properties in tumour-bearing mice. However, because of their smaller size and monovalent binding, the quantities of radiolabelled scFv retained in tumours limit their therapeutic applications. Diabodies are dimeric antibody-based molecules composed of two non-covalently associated scFv that bind to antigen in a divalent manner. In vitro, diabodies produced from the anti-HER2/neu (c-erbB-2) scFv C6.5 displayed approximately 40-fold greater affinity for HER2/neu by surface plasmon resonance biosensor measurements and significantly prolonged association with antigen on the surface of SK-OV-3 cells (t1/2 cell surface retention of > 5 h vs 5 min) compared with C6.5 scFv. In SK-OV-3 tumour-bearing scid mice, radioiodinated C6.5 diabody displayed a highly favourable balance of quantitative tumour retention and specificity. By as early as 4 h after i.v. administration, significantly more diabody was retained in tumour (10 %ID g(-1)) than in blood (6.7 %ID ml(-1)) or normal tissue (liver, 2.8 %ID g(-1); lung, 7.1 %ID g(-1); kidney, 5.2 %ID g(-1)). Over the next 20 h, the quantity present in blood and most tissues dropped approximately tenfold, while the tumour retained 6.5 %ID g(-1) or about two-thirds of its 4-h value. In contrast, the 24-h tumour retention of radioiodinated C6.5 scFv monomer was only 1 %ID g(-1). When diabody retentions were examined over the course of a 72-h study and cumulative area under the curve (AUC) values were determined, the resulting tumor-organ AUC ratios were found to be superior to those previously reported for other monovalent or divalent scFv molecules. In conclusion, the diabody format provides the C6.5 molecule with a distinct in vitro and in vivo targeting advantage and has promise as a delivery vehicle for therapeutic agents. Nature Publishing Group 1998-05 /pmc/articles/PMC2150193/ /pubmed/9652755 Text en https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Adams, G. P. Schier, R. McCall, A. M. Crawford, R. S. Wolf, E. J. Weiner, L. M. Marks, J. D. Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. |
title | Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. |
title_full | Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. |
title_fullStr | Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. |
title_full_unstemmed | Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. |
title_short | Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. |
title_sort | prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human her2/neu. |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150193/ https://www.ncbi.nlm.nih.gov/pubmed/9652755 |
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