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

International audienceEarlier clinical studies reported a high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anticarcinoembryonic antigen (CEA) bispecific antibody (BsMAb) and peptides labeled with 111 In or 131 I 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 and 68 Ga-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 of 68 Ga-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 and 68 Ga-IMP288 phar-macokinetics were monitored. Whole-body PET was recorded 60 and 120 min after 68 Ga-IMP288 injection. Tumor maximal SUV (T-SUV max) and T-SUV max –to–mediastinum blood-pool (MBP) SUV mean ratios (T/ MBP) were determined. Results: In C1, T-SUV max and 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-SUV max and T/MBP. Further increasing the delay to 42 h in C3 decreased T-SUV max and 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-SUV max but with higher MBP than in C2. In C5, the molar dose of TF2 was reduced, resulting in lower imaging performance. Pharmaco-kinetics 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. Conclusion: 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 pretar-geting delay. Medul lary thyroid carcinoma (MTC) is relatively infrequent, accounting for less than 10% of all thyroid cancers (1). After initial surgery, serum calcitonin is still detectable in nearly 20% of patients , suggesting residual disease, and imaging including neck ultrasonography, neck and chest CT, liver contrast-enhanced CT or MRI, and spine and pelvic bone MRI is recommended when serum calcitonin is higher than 150 pg/mL (1,2). With the ability to characterize and quantify cancer molecular processes, 18 F-DOPA or 18 F-FDG PET/CT also show high performance in relapsed MTC patients and great potential as surrogate biomarkers, useful for early response evaluation and prediction of clinical outcome (3–6). MTC is characterized by an intense expression of CEA, and previous clinical trials showed the high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anti-CEA bispecific antibody (BsMAb) and pretargeted haptens-peptides labeled with 111 In or 131 I (5,7,8). These results and the high potential of immuno-PET reported in other solid tumors using different radioimmuno-conjugates suggested that pretargeted haptens labeled with PET emitters would allow high-sensitivity and-specificity imaging under good conditions of radiation protection and dosimetry (9,10). Today, new pretargeting reagents have been designed (11–15). TF2 is an engineered trivalent BsMAb composed of a humanized anti–histamine-succinyl-glycine Fab fragment derived from the murine 679 antibody and 2 humanized anti-CEA Fab fragments derived from the hMN-14 antibody, formed into a 157-kD protein by the dock-and-lock procedure (11). IMP288 is a bivalent histamine-succinyl-glycine hapten that can be labeled with a variety of radionuclides for therap