90Y/177Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation
| Autor: | Rubel Chakravarty, Haladhar Dev Sarma, Sudipta Chakraborty, Ashutosh Dash, K. V. Vimalnath Nair, A. Rajeswari |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Biodistribution
medicine.drug_class Pharmacology Monoclonal antibody Biochemistry 030218 nuclear medicine & medical imaging Analytical Chemistry law.invention 03 medical and health sciences 0302 clinical medicine law Drug Discovery medicine Radiology Nuclear Medicine and imaging Epidermal growth factor receptor Fibrosarcoma neoplasms Spectroscopy biology Cetuximab Chemistry Organic Chemistry medicine.disease digestive system diseases In vitro 030220 oncology & carcinogenesis biology.protein Recombinant DNA Ex vivo medicine.drug |
| Zdroj: | Journal of Labelled Compounds and Radiopharmaceuticals. 59:354-363 |
| ISSN: | 0362-4803 |
| DOI: | 10.1002/jlcr.3413 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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