title: Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results.
abstract: BACKGROUND
  Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC).
  
  
  METHODS
  Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 μg). After confirmation of tumour targeting by (111)In-IMP288, patients were treated with a bsMAb/(177)Lu-IMP288 cycle.
  
  
  RESULTS
  Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-μg peptide dose. High (177)Lu-IMP288 doses (2.5-7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3-4 thrombocytopaenia in 10% of the patients who received (177)Lu-IMP288.
  
  
  CONCLUSIONS
  This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.
authors.affiliation: Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Schoffelen
authors.forename: O C
authors.initials: OC
authors.lastname: Boerman
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: C M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: G M
authors.initials: GM
authors.lastname: Franssen
authors.forename: W J
authors.initials: WJ
authors.lastname: McBride
authors.forename: C-H
authors.initials: CH
authors.lastname: Chang
authors.forename: E A
authors.initials: EA
authors.lastname: Rossi
authors.forename: W T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: W J G
authors.initials: WJ
authors.lastname: Oyen
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D006241:Haptens / Q000276:immunology*; D006573:Heterocyclic Compounds, 1-Ring / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*
chemical_list: D018033:Antibodies, Bispecific; C527875:CEACAM5 protein, human; D002272:Carcinoembryonic Antigen; C515662:DOTA-tyrosyl-lysyl(histaminyl-succinyl-glycyl)-glutamyl-lysyl(histaminyl-succinyl-glycyl)amide; D058851:GPI-Linked Proteins; D006241:Haptens; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides