PURPOSE: The L1 cell adhesion protein is overexpressed in tumors, such as neuroblastomas, renal cell carcinomas, ovarian carcinomas, and endometrial carcinomas, and represents a target for tumor diagnosis and therapy with anti-L1-CAM antibody chCE7. Divalent fragments of this internalizing antibody labeled with 67/64Cu and 177Lu were evaluated to establish a chCE7 antibody fragment for radioimmunotherapy and positron emission tomography imaging, which combines high-yield production with improved clearance and biodistribution properties. EXPERIMENTAL DESIGN: chCE7F(ab')2 fragments were produced in high amounts (0.2 g/L) in HEK-293 cells, substituted with the peptide-linked tetraazamacrocycle 3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycyl-L-p-isothiocyanato-phenylalanine, and labeled with 67Cu and 177Lu. In vivo bioevaluation involved measuring kinetics of tumor and tissue uptake in nude mice with SK-N-BE2c xenografts and NanoPET (Oxford Positron Systems, Oxford, United Kingdom) imaging with 64Cu-3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycine-chCE7F(ab')2. RESULTS: The 177Lu- and 67Cu-labeled immunoconjugates reached maximal tumor accumulation at 24 hours after injection with similar levels of 12%ID/g to 14%ID/g. Blood levels dropped to 1.0%ID/g for the 177Lu fragment and 2.3%ID/g for the 67Cu fragment at 24 hours. The most striking difference concerned radioactivity present in the kidneys, being 34.5%ID/g for the 177Lu fragment and 16.0%ID/g for the 67Cu fragment at 24 hours. Positron emission tomography imaging allowed clear visualization of s.c. xenografts and peritoneal metastases and a detailed assessment of whole-body tracer distribution. CONCLUSIONS: 67/64Cu- and 177Lu-labeled recombinant chCE7F(ab')2 revealed suitable in vivo characteristics for tumor imaging and therapy but displayed higher kidney uptake than the intact monoclonal antibody. The 67Cu- and 177Lu-labeled immunoconjugates showed different in vivo behavior, with 67/64Cu-3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycine-F(ab')2 appearing as the more favorable conjugate due to superior tumor/kidney ratios.
PURPOSE: The L1 cell adhesion protein is overexpressed in tumors, such as neuroblastomas, renal cell carcinomas, ovarian carcinomas, and endometrial carcinomas, and represents a target for tumor diagnosis and therapy with anti-L1-CAM antibody chCE7. Divalent fragments of this internalizing antibody labeled with 67/64Cu and 177Lu were evaluated to establish a chCE7 antibody fragment for radioimmunotherapy and positron emission tomography imaging, which combines high-yield production with improved clearance and biodistribution properties. EXPERIMENTAL DESIGN: chCE7F(ab')2 fragments were produced in high amounts (0.2 g/L) in HEK-293 cells, substituted with the peptide-linked tetraazamacrocycle 3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycyl-L-p-isothiocyanato-phenylalanine, and labeled with 67Cu and 177Lu. In vivo bioevaluation involved measuring kinetics of tumor and tissue uptake in nude mice with SK-N-BE2c xenografts and NanoPET (Oxford Positron Systems, Oxford, United Kingdom) imaging with 64Cu-3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycine-chCE7F(ab')2. RESULTS: The 177Lu- and 67Cu-labeled immunoconjugates reached maximal tumor accumulation at 24 hours after injection with similar levels of 12%ID/g to 14%ID/g. Blood levels dropped to 1.0%ID/g for the 177Lu fragment and 2.3%ID/g for the 67Cu fragment at 24 hours. The most striking difference concerned radioactivity present in the kidneys, being 34.5%ID/g for the 177Lu fragment and 16.0%ID/g for the 67Cu fragment at 24 hours. Positron emission tomography imaging allowed clear visualization of s.c. xenografts and peritoneal metastases and a detailed assessment of whole-body tracer distribution. CONCLUSIONS: 67/64Cu- and 177Lu-labeled recombinant chCE7F(ab')2 revealed suitable in vivo characteristics for tumor imaging and therapy but displayed higher kidney uptake than the intact monoclonal antibody. The 67Cu- and 177Lu-labeled immunoconjugates showed different in vivo behavior, with 67/64Cu-3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycine-F(ab')2 appearing as the more favorable conjugate due to superior tumor/kidney ratios.
Authors: Jürgen Grünberg; Dennis Lindenblatt; Holger Dorrer; Susan Cohrs; Konstantin Zhernosekov; Ulli Köster; Andreas Türler; Eliane Fischer; Roger Schibli Journal: Eur J Nucl Med Mol Imaging Date: 2014-05-24 Impact factor: 9.236
Authors: Karen J Wong; Kwamena E Baidoo; Tapan K Nayak; Kayhan Garmestani; Martin W Brechbiel; Diane E Milenic Journal: EJNMMI Res Date: 2011-06-07 Impact factor: 3.138
Authors: Jason L J Dearling; Stephan D Voss; Patricia Dunning; Erin Snay; Frederic Fahey; Suzanne V Smith; James S Huston; Claude F Meares; S Ted Treves; Alan B Packard Journal: Nucl Med Biol Date: 2010-10-27 Impact factor: 2.408
Authors: Ru Chen; Sheng Pan; Kelly Cooke; Kara White Moyes; Mary P Bronner; David R Goodlett; Ruedi Aebersold; Teresa A Brentnall Journal: Pancreas Date: 2007-01 Impact factor: 3.327
Authors: Arutselvan Natarajan; Gayatri Gowrishankar; Carsten H Nielsen; Sen Wang; Andrei Iagaru; Michael L Goris; Sanjiv Sam Gambhir Journal: Mol Imaging Biol Date: 2012-10 Impact factor: 3.488
Authors: Stephan D Voss; Suzanne V Smith; Nadine DiBartolo; Lacey J McIntosh; Erika M Cyr; Ali A Bonab; Jason L J Dearling; Edward A Carter; Alan J Fischman; S Ted Treves; Stephen D Gillies; Alan M Sargeson; James S Huston; Alan B Packard Journal: Proc Natl Acad Sci U S A Date: 2007-10-22 Impact factor: 11.205
Authors: Haiming Luo; Reinier Hernandez; Hao Hong; Stephen A Graves; Yunan Yang; Christopher G England; Charles P Theuer; Robert J Nickles; Weibo Cai Journal: Proc Natl Acad Sci U S A Date: 2015-09-28 Impact factor: 11.205
Authors: Shiloh M Martin; Robert T O'Donnell; David L Kukis; Craig K Abbey; Hayes McKnight; Julie L Sutcliffe; Joseph M Tuscano Journal: Mol Imaging Biol Date: 2008-10-24 Impact factor: 3.488