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

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 ± 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. 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41181-021-00140-1.