title: Immuno-PET Using Anticarcinoembryonic Antigen Bispecific Antibody and 68Ga-Labeled Peptide in Metastatic Medullary Thyroid Carcinoma: Clinical Optimization of the Pretargeting Parameters in a First-in-Human Trial.
abstract: Earlier clinical studies reported a high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anticarcinoembryonic antigen (CEA) bispecific antibody (BsMAb) and peptides labeled with111In or131I in medullary thyroid carcinoma (MTC). Preclinical studies showed that new-generation humanized recombinant anti-CEA × antihistamine-succinyl-glycine (HSG) trivalent BsMAb TF2 and radiolabeled HSG peptide (IMP288) present good features for PET. This study aimed at optimizing molar doses and pretargeting interval of TF2 and68Ga-labeled IMP288 for immuno-PET in relapsed MTC patients with calcitonin serum levels greater than 150 pg/mL.
  
  
  METHODS
  Five cohorts (C1-C5) of 3 patients received variable molar doses of TF2 and approximately 150 MBq of68Ga-IMP288 after different pretargeting time intervals (C1: 120 nmol TF2, 6 nmol IMP288, 24 h; C2: 120 nmol TF2, 6 nmol IMP288, 30 h; C3: 120 nmol TF2, 6 nmol IMP288, 42 h; C4: 120 nmol TF2, 3 nmol IMP288, 30 h; and C5: 60 nmol TF2, 3 nmol IMP288, 30 h). TF2 and68Ga-IMP288 pharmacokinetics were monitored. Whole-body PET was recorded 60 and 120 min after68Ga-IMP288 injection. Tumor maximal SUV (T-SUVmax) and T-SUVmax-to-mediastinum blood-pool (MBP) SUVmeanratios (T/MBP) were determined.
  
  
  RESULTS
  In C1, T-SUVmaxand T/MBP ranged from 4.09 to 8.93 and 1.39 to 3.72 at 60 min and 5.14 to 11.25 and 2.73 to 5.38 at 120 min, respectively. Because of the high MBP, the delay was increased to 30 h in C2, increasing T-SUVmaxand T/MBP. Further increasing the delay to 42 h in C3 decreased T-SUVmaxand T/MBP, showing that 30 h was the most favorable delay. In C4, the TF2-to-peptide mole ratio was increased to 40 (delay 30 h), resulting in high T-SUVmaxbut with higher MBP than in C2. In C5, the molar dose of TF2 was reduced, resulting in lower imaging performance. Pharmacokinetics demonstrated a fast TF2 clearance and a clear relationship between blood activity clearance and the ratio between the molar amount of injected peptide to the molar amount of circulating TF2 at the time of peptide injection.
  
  
  CONCLUSIONS
  High tumor uptake and contrast can be obtained with pretargeted anti-CEA immuno-PET in relapsed MTC patients, especially using optimized pretargeting parameters: a BsMAb-to-peptide mole ratio of 20 and 30 h pretargeting delay.
authors.affiliation: Nuclear Medicine Department, University Hospital, Nantes, France CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France caroline.milin@chu-nantes.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bodet-Milin
authors.affiliation: Nuclear Medicine Department, University Hospital, Nantes, France CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Faivre-Chauvet
authors.affiliation: Nuclear Medicine Department, University Hospital, Nantes, France CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carlier
authors.affiliation: CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France Nuclear Medicine, ICO Cancer Center, Saint-Herblain, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Rauscher
authors.affiliation: Nuclear Medicine Department, University Hospital, Nantes, France CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Bourgeois
authors.affiliation: Nuclear Medicine Department, University Hospital, Nantes, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Cerato
authors.affiliation: Endocrinology Department, University Hospital, Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Rohmer
authors.affiliation: Nuclear Medicine, University Hospital, Angers, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Couturier
authors.affiliation: Endocrinology Department, University Hospital, Nantes, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Drui
authors.affiliation: IBC Pharmaceuticals, Inc., Morris Plains, New Jersey Immunomedics, Inc., Morris Plains, New Jersey; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey; and.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.affiliation: CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France GIP Arronax, Saint-Herblain, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbet
authors.affiliation: Nuclear Medicine Department, University Hospital, Nantes, France CRCNA, Inserm U892, CNRS UMR 6299, Nantes, France Nuclear Medicine, ICO Cancer Center, Saint-Herblain, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Kraeber-Bodere
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D018278:Carcinoma, Neuroendocrine / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D016719:Radioimmunodetection / Q000379:methods*; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018033:Antibodies, Bispecific; D002272:Carcinoembryonic Antigen; C515662:DOTA-tyrosyl-lysyl(histaminyl-succinyl-glycyl)-glutamyl-lysyl(histaminyl-succinyl-glycyl)amide; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides
keywords: 68Ga; bispecific antibody; immuno-PET; medullary thyroid carcinoma; pharmacokinetics; pretargeting