A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal 90Y

Abstract

ObjectivesTo compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal 90Y. MethodsThe bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with 90Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. ResultsHigh radiochemical yields (>95%) were obtained with 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab after 15min at room temperature. Both 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for 90Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for 90Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, 90Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. ConclusionsUltimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring 90Y.