Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies
HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/1017 |
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| author | Janik Puttemans Yana Dekempeneer Jos L. Eersels Heleen Hanssens Pieterjan Debie Marleen Keyaerts Albert D. Windhorst Frank van der Aa Quentin Lecocq Karine Breckpot Alfred Morgenstern Frank Bruchertseifer Tony Lahoutte Nick Devoogdt Matthias D’Huyvetter |
| author_facet | Janik Puttemans Yana Dekempeneer Jos L. Eersels Heleen Hanssens Pieterjan Debie Marleen Keyaerts Albert D. Windhorst Frank van der Aa Quentin Lecocq Karine Breckpot Alfred Morgenstern Frank Bruchertseifer Tony Lahoutte Nick Devoogdt Matthias D’Huyvetter |
| author_sort | Janik Puttemans |
| collection | DOAJ |
| description | HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β<sup>−</sup>-emitting radionuclides for the detection and treatment of HER2<sup>pos</sup> brain lesions in a preclinical setting. 2Rs15d was radiolabeled with <sup>111</sup>In, <sup>225</sup>Ac and <sup>131</sup>I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for <sup>131</sup>I- and <sup>225</sup>Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2<sup>pos</sup> tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2<sup>pos</sup> SK-OV-3-Luc-IP1 and HER2<sup>pos</sup> MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [<sup>131</sup>I]-2Rs15d and [<sup>225</sup>Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2<sup>pos</sup> metastatic cancer. |
| first_indexed | 2024-03-10T20:20:20Z |
| format | Article |
| id | doaj.art-6ff75e5f8a484b58a4f80aef0cc1f7e0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:20:20Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6ff75e5f8a484b58a4f80aef0cc1f7e02023-11-19T22:15:42ZengMDPI AGCancers2072-66942020-04-01124101710.3390/cancers12041017Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain AntibodiesJanik Puttemans0Yana Dekempeneer1Jos L. Eersels2Heleen Hanssens3Pieterjan Debie4Marleen Keyaerts5Albert D. Windhorst6Frank van der Aa7Quentin Lecocq8Karine Breckpot9Alfred Morgenstern10Frank Bruchertseifer11Tony Lahoutte12Nick Devoogdt13Matthias D’Huyvetter14In vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumAmsterdam UMC (Universitair Medische Centra), Department of Radiology & Nuclear Medicine, Cancer Center Amsterdam, VU University, 1081 HV Amsterdam, The NetherlandsAmsterdam UMC (Universitair Medische Centra), Department of Radiology & Nuclear Medicine, Cancer Center Amsterdam, VU University, 1081 HV Amsterdam, The NetherlandsLaboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, 1090 Brussels, BelgiumLaboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, 1090 Brussels, BelgiumEuropean Commission, Joint Research Centre, Department for Nuclear Safety and Security, P.O. Box 2340, 76125 Karlsruhe, GermanyEuropean Commission, Joint Research Centre, Department for Nuclear Safety and Security, P.O. Box 2340, 76125 Karlsruhe, GermanyIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumIn vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, BelgiumHER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β<sup>−</sup>-emitting radionuclides for the detection and treatment of HER2<sup>pos</sup> brain lesions in a preclinical setting. 2Rs15d was radiolabeled with <sup>111</sup>In, <sup>225</sup>Ac and <sup>131</sup>I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for <sup>131</sup>I- and <sup>225</sup>Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2<sup>pos</sup> tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2<sup>pos</sup> SK-OV-3-Luc-IP1 and HER2<sup>pos</sup> MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [<sup>131</sup>I]-2Rs15d and [<sup>225</sup>Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2<sup>pos</sup> metastatic cancer.https://www.mdpi.com/2072-6694/12/4/1017single-domain antibody fragmenttargeted radionuclide therapybrain metastasisHER2 |
| spellingShingle | Janik Puttemans Yana Dekempeneer Jos L. Eersels Heleen Hanssens Pieterjan Debie Marleen Keyaerts Albert D. Windhorst Frank van der Aa Quentin Lecocq Karine Breckpot Alfred Morgenstern Frank Bruchertseifer Tony Lahoutte Nick Devoogdt Matthias D’Huyvetter Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies Cancers single-domain antibody fragment targeted radionuclide therapy brain metastasis HER2 |
| title | Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies |
| title_full | Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies |
| title_fullStr | Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies |
| title_full_unstemmed | Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies |
| title_short | Preclinical Targeted α- and β<sup>−</sup>-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies |
| title_sort | preclinical targeted α and β sup sup radionuclide therapy in her2 positive brain metastasis using camelid single domain antibodies |
| topic | single-domain antibody fragment targeted radionuclide therapy brain metastasis HER2 |
| url | https://www.mdpi.com/2072-6694/12/4/1017 |
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