H4octapa-trastuzumab: Versatile acyclic chelate system for 111In and 177Lu imaging and therapy Journal Article
| Authors: | Price, E. W.; Zeglis, B. M.; Cawthray, J. F.; Ramogida, C. F.; Ramos, N.; Lewis, J. S.; Adam, M. J.; Orvig, C. |
| Article Title: | H4octapa-trastuzumab: Versatile acyclic chelate system for 111In and 177Lu imaging and therapy |
| Abstract: | A bifunctional derivative of the versatile acyclic chelator H 4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ∼94-95%) than those based on DOTA-trastuzumab (60 min, 37 C, ∼50-88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. © 2013 American Chemical Society. |
| Keywords: | unclassified drug; human cell; nonhuman; mouse; complex formation; cancer immunotherapy; computer assisted tomography; ovary cancer; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; immunoreactivity; monoclonal antibodies; kinetics; isotope labeling; nude mouse; tissue distribution; geometry; cancer cell; thermodynamics; chemical structure; radioisotope; tumor growth; trastuzumab; radioimmunotherapy; single photon emission computer tomography; indium 111; density functional theory; chemical reaction; drug conjugation; synthesis; chelation; radiochemistry; specific activity; ovarian cancers; single photon emission computed tomography; radioimmunoconjugate; chelating agent; radiochemical purity; target organ; spectrophotometry; lutetium 177; tetraxetan; radioimmunoconjugates; activity ratios; bi-functional; radiolabeling; spect imaging; octapa trastuzumab in 111; octapa trastuzumab lu 177; pentetic acid derivative; tetraxetan trastuzumab in 111; tetraxetan trastuzumab lu 177 |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 135 |
| Issue: | 34 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 2013-08-28 |
| Start Page: | 12707 |
| End Page: | 12721 |
| Language: | English |
| DOI: | 10.1021/ja4049493 |
| PROVIDER: | scopus |
| PMCID: | PMC3787943 |
| PUBMED: | 23901833 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 October 2013" - "CODEN: JACSA" - "Source: Scopus" |
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