title: Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide.
abstract: We previously described a highly flexible bispecific antibody (bs-mAb) pretargeting procedure using a multivalent, recombinant anti-CEA (carcinoembryonic antigen) x anti-HSG (histamine-succinyl-glycine) fusion protein with peptides radiolabeled with 111In, 90Y, 177Lu, and 99mTc. The objective of this study was to develop a radioiodination procedure primarily to assess PET imaging with 124I.
  
  
  METHODS
  A new peptide, DOTA-D-Tyr-D-Lys(HSG)-D-Glu-D-Lys(HSG)-NH2 (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), was synthesized and conditions were established for radioiodination with yields of approximately 70% for 131I and 60% for 124I. Pretargeting with the 131I- and 124I-labeled peptide was tested in nude mice bearing LS174T human colonic tumors that were first given the anti-CEA x anti-HSG bs-mAb. Imaging (including small-animal PET) and necropsy data were collected at several intervals over 24 h. Comparisons were made between animals given 124I-anti-CEA Fab', 18F-FDG, the same peptide radiolabeled with 111In and pretargeted with the bs-mAb, and the radioiodinated peptide alone.
  
  
  RESULTS
  The radioiodinated peptide alone cleared quickly from the blood with no evidence of tumor targeting, but when pretargeted with the bs-mAb, tumor uptake increased 70-fold, with efficient and rapid clearance from normal tissues, allowing clear visualization of tumor within 1-2 h. Tumor uptake measured at necropsy was 3- to 15-fold higher and tumor-to-blood ratios were 10- to 20-fold higher than those for 124I-Fab' at 1 and 24 h, respectively. Thyroid and stomach uptake was observed with the radioiodinated peptide several hours after injection (animals were not premedicated to reduce uptake in these tissues), but gastric uptake was much more pronounced with 124I-Fab'. Tumor visualization with 18F-FDG at approximately 1.5 h was also good but showed substantially more uptake in several normal tissues, making image interpretation in the pretargeted animals less ambiguous than with 18F-FDG.
  
  
  CONCLUSIONS
  Bispecific antibody pretargeting has a significant advantage for tumor imaging over directly radiolabeled antibodies and could provide additional enhancements for oncologic imaging, particularly for improving targeting specificity as compared with 18F-FDG.
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: Carl
authors.initials: C
authors.lastname: Norén
authors.forename: Habibe
authors.initials: H
authors.lastname: Karacay
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.forename: Michele J
authors.initials: MJ
authors.lastname: Losman
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Brard
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D006241:Haptens; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D016719:Radioimmunodetection; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D051598:Whole Body Imaging
chemical_list: D018033:Antibodies, Bispecific; D002272:Carcinoembryonic Antigen; C515662:DOTA-tyrosyl-lysyl(histaminyl-succinyl-glycyl)-glutamyl-lysyl(histaminyl-succinyl-glycyl)amide; D006241:Haptens; D006573:Heterocyclic Compounds, 1-Ring; D007457:Iodine Radioisotopes; D009842:Oligopeptides