title: H(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.
abstract: A bifunctional derivative of the versatile acyclic chelator H4octapa, 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 (111)In and (177)Lu. 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 (111)In- and (177)Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for (111)In- and (177)Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for (111)In- and (177)Lu-octapa-trastuzumab compared to (111)In- and (177)Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada, V6T 1Z1.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Price
authors.forename: Brian M
authors.initials: BM
authors.lastname: Zeglis
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.forename: Caterina F
authors.initials: CF
authors.lastname: Ramogida
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ramos
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Adam
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use; D005021:Ethylamines / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry / Q000627:therapeutic use; D008187:Lutetium / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000188:drug therapy; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000627:therapeutic use; D014018:Tissue Distribution; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002614:Chelating Agents; D005021:Ethylamines; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; C000596870:N,N'-((6-carboxylato)pyridin-2-yl)methyl)-N,N'-diacetic acid-1,2-diaminoethane; D011725:Pyridines; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; D000068878:Trastuzumab
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