(90) Y/(177) Lu-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 IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-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 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~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 (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h 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.
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Rubel
R
Chakravarty
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Sudipta
S
Chakraborty
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Haladhar Dev
HD
Sarma
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
K V Vimalnath
KV
Nair
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Ardhi
A
Rajeswari
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Ashutosh
A
Dash
D000818:Animals; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000737:chemistry*; D004339:Drug Compounding; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008187:Lutetium / Q000737:chemistry*; D051379:Mice; D057054:Molecular Imaging; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000737:chemistry*
D018796:Immunoconjugates; D015021:Yttrium Radioisotopes; D008187:Lutetium; D000068818:Cetuximab
EGFR; cancer; cetuximab; lutetium-177; theranostics; yttrium-90