Jason P. Holland

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

AbstractRadioimmunotherapy (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.