90Y/177Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation

Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG(1) mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (similar to 2.22GBq) of Y-90-labelled Cetuximab and Lu-177-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N,N,N-pentaacetic acid (CHX-A-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 +/- 0.27GBq/mg for Y-90-CHX-A-DTPA-Cetuximab and 1.14 +/- 0.15GBq/mg for Lu-177-CHX-A-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both Y-90-CHX-A-DTPA-Cetuximab and Lu-177-CHX-A-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (similar to 16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of Y-90-CHX-A-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation.