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
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
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DOI：
10.2967/jnumed.116.172221
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发表时间：
2016-10-01
影响因子：
9.3
通讯作者：
Kraeber-Bodere, Francoise
中科院分区：
文献类型：
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作者：
Bodet-Milin, Caroline;Faivre-Chauvet, Alain;Kraeber-Bodere, Francoise
早期的临床研究报道了使用鼠或嵌合抗癌胚抗原（CEA）双特异性抗体（BsMAb）和In-111或I-131标记的肽在甲状腺髓样癌（MTC）中的高灵敏度的预靶向免疫闪烁成像。临床前研究表明，新一代人源化重组抗CEA x抗组胺-琥珀酰甘氨酸（HSG）三价BsMAb TF 2和放射性标记的HSG肽（IMP 288）对PET具有良好的特性。本研究旨在优化TF 2和Ga-68标记的IMP 288的摩尔剂量和预靶向间隔，用于降钙素血清水平大于150 pg/mL的复发性MTC患者的免疫PET。研究方法：在不同的预靶向时间间隔后，5个队列（C1-C5）的3名患者接受了不同摩尔剂量的TF 2和约150 MBq的Ga-68-IMP 288（C1：120 nmol TF2，6 nmol IMP 288，24 h; C2：120 nmol TF2，6 nmol IMP 288，30 h; C3：120 nmol TF2，6 nmol IMP 288，42 h; C4：120 nmol TF2，3 nmol IMP 288，30 h;和C5：60 nmol TF 2，3 nmol IMP 288，30 h）。监测TF 2和Ga-68-IMP 288的药代动力学。在Ga-68-IMP 288注射后60和120分钟记录全身PET。测定肿瘤最大SUV（T-SUVmax）及T-SUVmax与纵隔血池（MBP）SUV均值比值（T/MBP）。结果：C1组T-SUVmax和T/MBP在60 min时分别为4.09 ~ 8.93和1.39 ~ 3.72，在120 min时分别为5.14 ~ 11.25和2.73 ~ 5.38;由于高MBP，C2延迟增加至30 h，增加T-SUVmax和T/MBP。C3延迟42 h后，T-SUVmax和T/ MBP均下降，以30 h为最佳。在C4中，TF 2与肽的摩尔比增加至40（延迟30小时），导致高T-SUVmax，但具有比C2中更高的MBP。在C5中，TF 2的摩尔剂量减少，导致成像性能降低。药代动力学证明了快速的TF 2清除率和血液活性清除率与肽注射时注射肽的摩尔量与循环TF 2的摩尔量之间的比率之间的明确关系。结论：在复发性MTC患者中，可以使用预靶向抗CEA免疫PET获得高肿瘤摄取和对比度，特别是使用优化的预靶向参数：20和30小时预靶向延迟的BsMAb与肽摩尔比。
Earlier clinical studies reported a high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anticarcinoembryonic antigen (CEA) bispecific antibody (BsMAb) and peptides labeled with In-111 or I-131 in medullary thyroid carcinoma (MTC). Preclinical studies showed that new-generation humanized recombinant anti-CEA x 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 Ga-68-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 Ga-68-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 Ga-68-IMP288 pharmacokinetics were monitored. Whole-body PET was recorded 60 and 120 min after Ga-68-IMP288 injection. Tumor maximal SUV (T-SUVmax) and T-SUVmax-to-mediastinum blood-pool (MBP) SUVmean ratios (T/MBP) were determined. Results: In C1, T-SUVmax 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-SUVmax and T/MBP. Further increasing the delay to 42 h in C3 decreased T-SUVmax 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-SUVmax but 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. 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 pretargeting delay.