Radiolabelled 177Lu‐Bispidine‐Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers

• Published in: Chemistry : a European journal Vol. 30; no. 14
• Main Authors: Cieslik, Patrick A., Klingler, Simon, Nolff, Mirja, Holland, Jason P.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 07.03.2024
• Subjects: Animal models; Binding; Bispidines; Cancer; cancer imaging; Chelating agents; Complexation; ErbB-2 protein; Growth factors; Irradiation; Labeling; lanthanoids; Ligands; Lutetium isotopes; Metal ions; Monoclonal antibodies; Nuclides; Ovarian cancer; photoconjugation; Radiochemistry; radiotheranostics; Room temperature; Trastuzumab; Tumors; Xenotransplantation
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202303805

Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid‐selective nonadentate bispidine ligand suitable for 177Lu3+ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN3) group as a bioconjugation handle for light‐induced labelling of proteins. Quantitative radiosynthesis of [177Lu]Lu‐1+ was accomplished in 10 minutes at 40 °C. Subsequent incubation of [177Lu]Lu‐1+ with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0–8.3, gave the radiolabelled mAb, [177Lu]Lu‐1‐azepin‐trastuzumab ([177Lu]Lu‐1‐mAb) in a decay‐corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK‐OV‐3 human ovarian cancer cells confirmed that [177Lu]Lu‐1‐mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK‐OV‐3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g−1 vs. 14.8±6.1 %ID g−1, respectively; P‐value=0.037). The data indicate that bispidine‐based ligand systems are suitable starting points for constructing novel, high‐denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides. We present the synthesis and assess the in vivo performance of a nonadentate bispidine ligand for 177Lu3+ ion complexation. Photoconjugation methods to proteins including the monoclonal antibody trastuzumab produced viable 177Lu‐radiotracers for targeting the human epidermal growth‐factor receptor HER2 in relevant mouse models of human ovarian cancer. Bispidines are a promising scaffold for developing chelates with high denticity.