Biodistribution, Imaging and Metabolism Studies of 64-Copper Radiolabelled Monoclonal Antibody : Comparison of DOTA and TE1PA Chelating Agents in a Murine Model of Multiple Myeloma - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue European Journal of Nuclear Medicine and Molecular Imaging Année : 2018

Biodistribution, Imaging and Metabolism Studies of 64-Copper Radiolabelled Monoclonal Antibody : Comparison of DOTA and TE1PA Chelating Agents in a Murine Model of Multiple Myeloma

Résumé

Purpose: TE1PA is a C-functionalized monopicolinate cyclam designed for 64-copper chelation. It was proven to have excellent Cu(II) and Cu(I) chelation properties, with fast kinetics, high thermodynamic stability and resistance to transchelation in vitro, and a usefulness for phenotypic imagery when coupled to antibodies. This work presents in vivo studies (biodistribution, metabolism and imaging) of TE1PA in a syngenic multiple myeloma model on mice, compared to DOTA, its main competitor. Materials and methods: p-SCN-Bn-TE1PA and DOTA-NHS ester were grafted on 9E7.4 rat IgG2a antibody, targeting murine CD-138. Immunoconjugates were then radiolabelled with 64Cu. Both 64Cu-9E7.4-p-SCN-Bn-TE1PA and 64Cu-9E7.4-NHS-DOTA were injected in 12 mice previously grafted with 5T33 cells, allowing the development of subcutaneous tumors expressing CD-138. Each mouse was injected with 100 μg of radioimmunoconjugates corresponding to 10 MBq of 64Cu. For each time studied (2h, 24h and 48h post-injection), a biodistribution and a liver metabolism studies were conducted on mice for both radiolabelled antibodies. Additionally, a micro-PET scan was performed on 4 mice injected with 64Cu-9E7.4-p-SCN-Bn-TE1PA at those 3 times. Results: Biodistribution study shows an excellent hepatic clearance of the 64Cu-9E7.4-p-SCN-Bn-TE1PA over time. Significantly higher radioactivity was found in blood, lungs and heart at 48h PI for 64Cu-9E7.4-NHS-DOTA, which suggests a release of 64Cu from antibody, in parallel with a higher intestinal elimination. This was correlated by the liver metabolism study, which shows a better in vivo resistance to transchelation for 64Cu-9E7.4-p-SCN-Bn-TE1PA. The imaging study of 64Cu-9E7.4-p-SCN-Bn-TE1PA shows an increasing targeting of the tumors over time and confirms the hepatic clearance at 24h and 48h PI. Conclusion: 64Cu-9E7.4-p-NCS-Bn-TE1PA has shown a very high tumor targeting, associated to an increasing of tumor-to-tissues ratio over time that suggests an overall clearance from healthy tissues. Compared to DOTA, TE1PA displays an in vivo stability and resistance to transchelation significantly superior. This confirms the previous results obtained in vitro and 64Cu-labelled TE-1PA proved once again its usefulness for immuno-PET imaging in a preclinical model.

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Cancer
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Dates et versions

inserm-02344286 , version 1 (04-11-2019)

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  • HAL Id : inserm-02344286 , version 1

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A. Navarro, T. Le Bihan, Patricia Remaud-Le Saëc, Sébastien Gouard, N. Le Bris, et al.. Biodistribution, Imaging and Metabolism Studies of 64-Copper Radiolabelled Monoclonal Antibody : Comparison of DOTA and TE1PA Chelating Agents in a Murine Model of Multiple Myeloma. European Journal of Nuclear Medicine and Molecular Imaging, 2018, 45 (1), pp.S119-S120. ⟨inserm-02344286⟩
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