Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab′)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab′)2 – implications for a PET theranostic strategy

Abstract

Background Epidermal growth factor receptors (EGFR) are overexpressed on many head and neck squamous cell carcinoma (HNSCC). Radioimmunotherapy (RIT) with F(ab ) 2 of the anti-EGFR monoclonal antibody panitumumab labeled with the β-particle emitter, 177 Lu may be a promising treatment for HNSCC. Our aim was to assess the feasibility of a theranostic strategy that combines positron emission tomography (PET) with [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 . Results Panitumumab F(ab ) 2 were conjugated to DOTA and complexed to 64 Cu or 177 Lu in high radiochemical purity (95.6\u2009±\u20092.1% and 96.7\u2009±\u20093.5%, respectively) and exhibited high affinity EGFR binding (K d \u2009=\u20092.9\u2009±\u20090.7\u2009×\u200910 −\u20099 \u2009mol/L). Biodistribution (BOD) studies at 6, 24 or 48\u2009h post-injection (p.i.) of [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 (5.5–14.0\u2009MBq; 50\u2009μg) or [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 (6.5\u2009MBq; 50\u2009μg) in NRG mice with s.c. HNSCC patient-derived xenografts (PDX) overall showed no significant differences in tumour uptake but modest differences in normal organ uptake were noted at certain time points. Tumours were imaged by microPET/CT with [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 or microSPECT/CT with [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 but not with irrelevant [ 177 Lu]Lu-DOTA-trastuzumab F(ab ) 2 . Tumour uptake at 24\u2009h p.i. of [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 [14.9\xa0±\xa01.1% injected dose/gram (%ID/g) and [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 (18.0\xa0±\xa00.4%ID/g) were significantly higher ( P \u2009<\u20090.05) than [ 177 Lu]Lu-DOTA-trastuzumab F(ab ) 2 (2.6\xa0±\xa00.5%ID/g), demonstrating EGFR-mediated tumour uptake. There were no significant differences in the radiation equivalent doses in the tumour and most normal organs estimated for [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 based on the BOD of [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 compared to those estimated directly from the BOD of [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 except for the liver and whole body which were modestly underestimated by [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 . Region-of-interest (ROI) analysis of microPET/CT images provided dose estimates for the tumour and liver that were not significantly different for the two radioimmunoconjugates. Human doses from administration of [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 predicted that a 2\u2009cm diameter HNSCC tumour in a patient would receive 1.1–1.5\u2009mSv/MBq and the whole body dose would be 0.15–0.22\u2009mSv/MBq. Conclusion A PET theranostic strategy combining [ 64 Cu]Cu-DOTA-panitumumab F(ab ) 2 to image HNSCC tumours and predict the equivalent radiation doses in the tumour and normal organs from RIT with [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 is feasible. RIT with [ 177 Lu]Lu-DOTA-panitumumab F(ab ) 2 may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR.