Preclinical Targeted α- and β−-Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies
| Autor: | Pieterjan Debie, Quentin Lecocq, Matthias D'Huyvetter, Tony Lahoutte, Janik Puttemans, Heleen Hanssens, Marleen Keyaerts, Albert D. Windhorst, Frank Bruchertseifer, Yana Dekempeneer, Frank van der Aa, Nick Devoogdt, Karine Breckpot, Jos L E Eersels, Alfred Morgenstern |
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| Přispěvatelé: | Supporting clinical sciences, Medical Imaging, Faculty of Medicine and Pharmacy, Nuclear Medicine, Basic (bio-) Medical Sciences, Translational Imaging Research Alliance, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class Monoclonal antibody lcsh:RC254-282 radiation therapy Metastasis 03 medical and health sciences 0302 clinical medicine Breast cancer In vivo Trastuzumab HER2 Medicine brain metastasis skin and connective tissue diseases Cancer business.industry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease targeted radionuclide therapy single-domain antibody fragment 030104 developmental biology Oncology 030220 oncology & carcinogenesis Radionuclide therapy Cancer research business medicine.drug Brain metastasis |
| Zdroj: | Puttemans, J, Dekempeneer, Y, Eersels, J L, Hanssens, H, Debie, P, Keyaerts, M, Windhorst, A D, van der Aa, F, Lecocq, Q, Breckpot, K, Morgenstern, A, Bruchertseifer, F, Lahoutte, T, Devoogdt, N & D'Huyvetter, M 2020, ' Preclinical Targeted α-and β--Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies ', Cancers, vol. 12, no. 4, 1017 . https://doi.org/10.3390/cancers12041017 Cancers Volume 12 Issue 4 Cancers, 12(4):1017. Multidisciplinary Digital Publishing Institute (MDPI) Cancers, Vol 12, Iss 1017, p 1017 (2020) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12041017 |
| Popis: | 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 &gamma and therapeutic &alpha and &beta &minus emitting radionuclides for the detection and treatment of HER2pos brain lesions in a preclinical setting. 2Rs15d was radiolabeled with 111In, 225Ac and 131I 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 131I- and 225Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2pos tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2pos SK-OV-3-Luc-IP1 and HER2pos MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [131I]-2Rs15d and [225Ac]-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 HER2pos metastatic cancer. |
| Databáze: | OpenAIRE |
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