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

Abstract

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.

Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes

“…E. coli BL21(DE3) cells were obtained from New England Biolabs (NEB). NMR spectra ( 1 H, 13 C) were collected on a 700 MHz Advance III Bruker instrument at 25 1C and processed using TopSpin 4.0.7. Chemical shifts are reported as parts per million (ppm).…”

“…This must be addressed by combining such targeting vectors with bifunctional chelators that form inert complexes at <40 °C with high radiochemical yield and purity – a challenge which remains pertinent, especially for lanthanide isotopes. 12–14…”

Optical Imaging of Ionizing Radiation from Clinical Sources

“…2A). Quantification of tumor uptake using CLI correlated with ex vivo measurements, thus offering means for dosimetry as well as an alternative to PET imaging of the very low amount of positrons emitted from 90 Y. Cetuximab labeled with either 90 Y or 177 Lu was also imaged ex vivo using CLI, again showing the utility of CL for radionuclides that are often difficult to image using traditional methods (18). Therapeutically, 90 Y was combined with a PDT agent for a synergistic system of both radiotherapy and PDT excited by CL (19).…”

Immunoscintigraphy for Therapy Decision Making and Follow - Up of Biological Therapies

“…Lu are also emerging in the last years aiming to explore the feasibility of radiolabelled Cetuximab as radioimmunotherapy [35] but of course they require more extensive studies.…”