| Autor: |
Edyta Cędrowska, Alfred Morgenstern, Matthias D'Huyvetter, Tony Lahoutte, Yana Dekempeneer, Frank Bruchertseifer, Marek Pruszynski, Magdalena Rodak |
| Přispěvatelé: |
Supporting clinical sciences, Medical Imaging, Faculty of Medicine and Pharmacy, Nuclear Medicine |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| DOI: |
10.1016/j.jmir.2019.03.023 |
| Popis: |
Objectives Nanobodies (Nbs) are the smallest antibody-derived fragments with beneficial pharmacokinetic properties for molecular imaging and radionuclide therapy. Human Epidermal Growth Factor Receptor type 2 (HER2) is overexpressed in numerous carcinomas and portends a poor prognosis. Therefore, HER2-targeting nanobodies are very attractive vectors for TRT, especially when labeled with α-particle emitters. The aim of this study was to evaluate the therapeutic potential of the anti-HER2 Nb 2Rs15d labeled with 225Ac. Methods Anti-HER2 Nb 2Rs15d was coupled with the bifunctional chelate p-SCN-Bn-DOTA and further was labeled with 225Ac. Its binding affinity and specificity for HER2, together with immunoreactive fraction (IF), were evaluated on SKOV-3 (HER2+) and MDA-MB-231 (HER2-) cells. Its in vitro cytotoxicity was assessed using MTS and clonogenic assays. In vivo, 225Ac-DOTA-Nb 2Rs15d and a non-targeting control 225Ac-DOTA-Nb R3b23 were evaluated in female athymic nude mice subcutaneously xenografted with SKOV-3 and MDAMB-231 tumors, both alone and with molar excess of unlabeled 2Rs15d. After determination of maximum tolerated dose (MTD), the therapeutic efficacy of 225Ac-DOTA-Nb 2Rs15d was investigated in mice bearing intraperitoneal SKOV-3.IP1/luciferase+ xenografted metastases against several controls, a trastuzumab regimen and a combination of both 225Ac-DOTA-Nb 2Rs15d and trastuzumab. Results The yield of DOTA-Nb 2Rs15d labeling was high (>90%), with radiochemical purity ≥95%. 225Ac-DOTA-Nb 2Rs15d bound specifically to HER2+ cells with ∼75% IF, a KD of 3.50±0.17nM and lack of competition with trastuzumab or pertuzumab in vitro. Cytotoxicity studies demonstrated that 225Ac-DOTA-Nb 2Rs15d significantly reduced SKOV-3 cell viability in a dose-dependent and HER2-mediated manner, compared to 225Ac-DOTA or 225Ac-DOTA-Nb R3b23 as controls. Tumor uptake in SKOV-3 xenografted mice was high and specific (∼8%), whereas in MDA-MB-231 was |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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