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

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 beta-particle emitter, Lu-177 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 [Cu-64]Cu-DOTA-panitumumab F(ab')(2) to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [Lu-177]Lu-DOTA-panitumumab F(ab')(2). Results Panitumumab F(ab')(2) were conjugated to DOTA and complexed to Cu-64 or Lu-177 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 x 10(- 9) mol/L). Biodistribution (BOD) studies at 6, 24 or 48 h post-injection (p.i.) of [Cu-64]Cu-DOTA-panitumumab F(ab')(2) (5.5-14.0 MBq; 50 mu g) or [Lu-177]Lu-DOTA-panitumumab F(ab')(2) (6.5 MBq; 50 mu g) 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 [Cu-64]Cu-DOTA-panitumumab F(ab')(2) or microSPECT/CT with [Lu-177]Lu-DOTA-panitumumab F(ab')(2) but not with irrelevant [Lu-177]Lu-DOTA-trastuzumab F(ab')(2). Tumour uptake at 24 h p.i. of [Cu-64]Cu-DOTA-panitumumab F(ab')(2) [14.9 +/- 1.1% injected dose/gram (%ID/g) and [Lu-177]Lu-DOTA-panitumumab F(ab')(2) (18.0 +/- 0.4%ID/g) were significantly higher (P < 0.05) than [Lu-177]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 [Lu-177]Lu-DOTA-panitumumab F(ab')(2) based on the BOD of [Cu-64]Cu-DOTA-panitumumab F(ab')(2) compared to those estimated directly from the BOD of [Lu-177]Lu-DOTA-panitumumab F(ab')(2) except for the liver and whole body which were modestly underestimated by [Cu-64]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 [Lu-177]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 [Cu-64]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 [Lu-177]Lu-DOTA-panitumumab F(ab')(2) is feasible. RIT with [Lu-177]Lu-DOTA-panitumumab F(ab')(2) may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR.

Automated summary

The study assessed the feasibility of a theranostic strategy using [Cu-64]Cu-DOTA-panitumumab F(ab')(2) for imaging HNSCC tumors and predicting radiation doses from RIT with [Lu-177]Lu-DOTA-panitumumab F(ab')(2). Results showed promising potential for RIT in HNSCC treatment, highlighting the need for further research to confirm the findings.