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

摘要

BackgroundEpidermal 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 .ResultsPanitumumab F(ab') 2 were conjugated to DOTA and complexed to 64 Cu or 177 Lu in high radiochemical purity (95.6?±?2.1% and 96.7?±?3.5%, respectively) and exhibited high affinity EGFR binding (K d ?=?2.9?±?0.7?×?10 ??9 ?mol/L). Biodistribution (BOD) studies at 6, 24 or 48?h post-injection (p.i.) of [ 64 Cu]Cu-DOTA-panitumumab F(ab') 2 (5.5–14.0?MBq; 50?μg) or [ 177 Lu]Lu-DOTA-panitumumab F(ab') 2 (6.5?MBq; 50?μg) 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?h p.i. of [ 64 Cu]Cu-DOTA-panitumumab F(ab') 2 [14.9?±?1.1% injected dose/gram (%ID/g) and [ 177 Lu]Lu-DOTA-panitumumab F(ab') 2 (18.0?±?0.4%ID/g) were significantly higher ( P ?0.05) than [ 177 Lu]Lu-DOTA-trastuzumab F(ab') 2 (2.6?±?0.5%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?cm diameter HNSCC tumour in a patient would receive 1.1–1.5?mSv/MBq and the whole body dose would be 0.15–0.22?mSv/MBq.ConclusionA 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.