Radiolabelled $^{177}$Lu-Bispidine-Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers

Abstract

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 $^{177}$Lu$^{3+}$ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN$_3$) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [$^{177}$Lu]Lu-1$^{+}$ was accomplished in 10 minutes at 40 °C. Subsequent incubation of [$^{177}$Lu]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, [$^{177}$Lu]Lu-1-azepin-trastuzumab ([$^{177}$Lu]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 [$^{177}$Lu]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.