H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

A bifunctional derivative of the versatile acyclic chelator H(4)octapa, p-SCN-Bn-H(4)octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neutargeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes In-111 and Lu-177. The in vivo behavior of the resulting radio-immunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmuno-conjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H(4)octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, similar to 94-95%) than those based on DOTA-trastuzumab (60 min, 37 degrees C, similar to 50-88%). Further, antibody integrity was better preserved in the In-111- and Lu-177-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for In-111- and Lu-177-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for In-111- and Lu-177-octapa-trastuzumab compared to In-111- and Lu-177-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios.