Evaluation of Candidate Theranostics for Th/Zr Paired Radioimmunotherapy of Lymphoma.

Fiche publication

Date publication

juillet 2023

Journal

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

Auteurs

Membres identifiés du Cancéropôle Est :
Dr CHAMBRON Jean-Claude

Tous les auteurs :
Abou DS, Longtine M, Fears A, Benabdallah N, Unnerstall R, Johnston H, Shim K, Hasson A, Zhang H, Ulmert D, Mangin F, Ozen S, Raibaut L, Brandès S, Meyer M, Chambron JC, Tatum DS, Magda D, Wahl RL, Thorek DLJ

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/37142300

Résumé

Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved Ra as its first daughter. There is an ample supply of Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent -block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of Th for α-particle-emitting and radiotheranostic applications. We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (-SCN-Bn-HEHA), -isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-Phe-NCS), and macrocyclic 1,2-HOPO -hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion Zr-labeled PET agent. Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. Th-HEHA-ofatumumab showed moderate in vitro stability. Th-DFOcyclo*-ofatumumab presented excellent Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). Th-L804-ofatumumab coordinated Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, Zr-L804-ofatumumab, showed organ distribution matching that of Th to delineate SU-DHL-6 tumors. Commercially available and novel chelators for Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for Zr/Th quantitative imaging and α-particle therapy.