Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours
While radiolabelled antibodies have found great utility as PET and SPECT imaging agents in oncological investigations, a notable shortcoming of these agents is their propensity to accumulate non-specifically within tumour tissue. The degree of this non-specific contribution to overall tumour uptake...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
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Elsevier
2019
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| _version_ | 1797068936779399168 |
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| author | Knight, J Mosley, M Kersemans, V Dias, G Allen, D Smart, S Cornelissen, B |
| author_facet | Knight, J Mosley, M Kersemans, V Dias, G Allen, D Smart, S Cornelissen, B |
| author_sort | Knight, J |
| collection | OXFORD |
| description | While radiolabelled antibodies have found great utility as PET and SPECT imaging agents in oncological investigations, a notable shortcoming of these agents is their propensity to accumulate non-specifically within tumour tissue. The degree of this non-specific contribution to overall tumour uptake is highly variable and can ultimately lead to false conclusions. Therefore, in an effort to obtain a reliable measure of inter-individual differences in non-specific tumour uptake of radiolabelled antibodies, we demonstrate that the use of dual-isotope imaging overcomes this issue, enables true quantification of epitope expression levels, and allows non-invasive in vivo immunohistochemistry. The approach involves co-administration of (i) an antigen-targeting antibody labelled with zirconium-89 (89Zr), and (ii) an isotype-matched non-specific control IgG antibody labelled with indium-111 (111In). As an example, the anti-HER2 antibody trastuzumab was radiolabelled with 89Zr, and co-administered intravenously together with its 111In-labelled non-specific counterpart to mice bearing human breast cancer xenografts with differing HER2 expression levels (MDA-MB-468 [HER2-negative], MDA-MB-231 [low-HER2], MDA-MB-231/H2N [medium-HER2], and SKBR3 [high-HER2]). Simultaneous PET/SPECT imaging using a MILabs Vector4 small animal scanner revealed stark differences in the intratumoural distribution of [89Zr]Zr-trastuzumab and [111In]In-IgG, highlighting regions of HER2-mediated uptake and non-specific uptake, respectively. Normalisation of the tumour uptake values and tumour-to-blood ratios obtained with [89Zr]Zr-trastuzumab against those obtained with [111In]In-IgG yielded values which were most strongly correlated (R = 0.94; P = 0.02) with HER2 expression levels for each breast cancer type determined by Western blot and in vitro saturation binding assays, but not non-normalised uptake values. Normalised intratumoural distribution of [89Zr]Zr-trastuzumab correlated well with intratumoural heterogeneity HER2 expression. |
| first_indexed | 2024-03-06T22:17:11Z |
| format | Journal article |
| id | oxford-uuid:53c5109f-2c44-450c-b691-b7ad9b929b1b |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:17:11Z |
| publishDate | 2019 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:53c5109f-2c44-450c-b691-b7ad9b929b1b2022-03-26T16:33:48ZDual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumoursJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:53c5109f-2c44-450c-b691-b7ad9b929b1bSymplectic Elements at OxfordElsevier2019Knight, JMosley, MKersemans, VDias, GAllen, DSmart, SCornelissen, BWhile radiolabelled antibodies have found great utility as PET and SPECT imaging agents in oncological investigations, a notable shortcoming of these agents is their propensity to accumulate non-specifically within tumour tissue. The degree of this non-specific contribution to overall tumour uptake is highly variable and can ultimately lead to false conclusions. Therefore, in an effort to obtain a reliable measure of inter-individual differences in non-specific tumour uptake of radiolabelled antibodies, we demonstrate that the use of dual-isotope imaging overcomes this issue, enables true quantification of epitope expression levels, and allows non-invasive in vivo immunohistochemistry. The approach involves co-administration of (i) an antigen-targeting antibody labelled with zirconium-89 (89Zr), and (ii) an isotype-matched non-specific control IgG antibody labelled with indium-111 (111In). As an example, the anti-HER2 antibody trastuzumab was radiolabelled with 89Zr, and co-administered intravenously together with its 111In-labelled non-specific counterpart to mice bearing human breast cancer xenografts with differing HER2 expression levels (MDA-MB-468 [HER2-negative], MDA-MB-231 [low-HER2], MDA-MB-231/H2N [medium-HER2], and SKBR3 [high-HER2]). Simultaneous PET/SPECT imaging using a MILabs Vector4 small animal scanner revealed stark differences in the intratumoural distribution of [89Zr]Zr-trastuzumab and [111In]In-IgG, highlighting regions of HER2-mediated uptake and non-specific uptake, respectively. Normalisation of the tumour uptake values and tumour-to-blood ratios obtained with [89Zr]Zr-trastuzumab against those obtained with [111In]In-IgG yielded values which were most strongly correlated (R = 0.94; P = 0.02) with HER2 expression levels for each breast cancer type determined by Western blot and in vitro saturation binding assays, but not non-normalised uptake values. Normalised intratumoural distribution of [89Zr]Zr-trastuzumab correlated well with intratumoural heterogeneity HER2 expression. |
| spellingShingle | Knight, J Mosley, M Kersemans, V Dias, G Allen, D Smart, S Cornelissen, B Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
| title | Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
| title_full | Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
| title_fullStr | Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
| title_full_unstemmed | Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
| title_short | Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
| title_sort | dual isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours |
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