Total-Body PET and Highly Stable Chelators Together Enable Meaningful 89Zr-Antibody PET Studies up to 30 Days After Injection
Total-Body PET and Highly Stable Chelators Together Enable Meaningful 89Zr-Antibody PET Studies up to 30 Days After Injection
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DOI：
10.2967/jnumed.119.230961
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发表时间：
2020-03-01
影响因子：
9.3
通讯作者：
Tarantal, Alice F.
中科院分区：
文献类型：
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作者：
Berg, Eric;Gill, Herman;Tarantal, Alice F.
使用 Zr-89 抗体 PET 成像来测量抗体生物分布和组织药代动力学的方法已经成熟，但当前的 PET 系统缺乏研究超过 2-3 个同位素半衰期（7-10 天）的 Zr-89 标记抗体所需的灵敏度，此后信噪比差会出现问题。然而，需要进行数周的研究才能更好地匹配人类和非人类灵长类动物中的抗体循环半衰期。这些研究调查了使用灵长类迷你 EXPLORER PET 扫描仪的技术可行性，利用其高灵敏度和 45 厘米轴向视野，对注射后 30 天内的恒河猴进行 Zr-89 标记抗体的全身成像。方法：针对单纯疱疹病毒蛋白糖蛋白 D (gD) 的人源化单克隆 IgG 抗体通过 4 种螯合剂-连接体组合中的 1 种（异硫氰酸苄酯-DFO [DFO-Bz-NCS]，其中 DFO 是去铁胺 B；DFO-方酰胺；DFO"-Bz-NCS，其中 DFO* 是去铁胺*；和 DFO"-Bz-NCS）中的一种，用 Zr-89 进行放射性标记。 DFO”-方酰胺）。在 12 只健康年轻雄性恒河猴（-1-2 岁，3 只 1 kg）中比较了与这 4 种螯合剂-连接子组合相关的药代动力学。首先在每只动物的右臂外周血管中静脉注射未标记的抗体（10 mg/kg，提供治疗水平的抗体浓度），随后立即在左臂外周血管中静脉注射约 40 MBq 的 Zr-89 标记抗体之一。所有动物在 30 天内进行 6 次成像，在第 0 天（注射日）进行初始 60 分钟的动态扫描，然后在大约第 3、7、14、21 和 30 天进行 3045 分钟的静态扫描，所有图像均使用单床位置获取，并使用关闭时间列表模式有序子集期望最大化重建图像。使用手动定义的感兴趣区域从 PET 图像中提取各个器官的活性浓度。结果：获得了优异的图像质量，捕获了全身扫描的初始分布阶段；后来的时间点显示残留的Zr-89主要存在于肝脏中。即使在注射后 30 天（相当于 Zr-89 的大约 9 个半衰期）且动物体内的总残留活性仅为 20-40 kBq，图像质量也足以轻松识别肝脏、肾脏以及上肢和下肢关节的活性。螯合剂-连接子类型之间的晚期时间点肝脏摄取、骨摄取和全身清除率存在显着差异，而每种类型内观察到的差异很小（10%）。结论：这些研究表明，灵长类迷你 EXPLORER 具有高灵敏度和长轴向视场，能够在注射后 30 天内对 Zr-89 放射性标记抗体进行成像，同时保持令人满意的图像质量。定量结果表明 4 种螯合剂的行为存在潜在的重要差异。这一发现支持进一步的调查。
The use of Zr-89-antibody PET imaging to measure antibody biodistribution and tissue pharmacokinetics is well established, but current PET systems lack the sensitivity needed to study Zr-89-labeled antibodies beyond 2-3 isotope half-lives (7-10 d), after which a poor signal-to-noise ratio is problematic. However, studies across many weeks are desirable to better match antibody circulation half-life in human and nonhuman primates. These studies investigated the technical feasibility of using the primate mini-EXPLORER PET scanner, making use of its high sensitivity and 45-cm axial field of view, for total-body imaging of Zr-89-labeled antibodies in rhesus monkeys up to 30 d after injection. Methods: A humanized monoclonal IgG antibody against the herpes simplex viral protein glycoprotein D (gD) was radiolabeled with Zr-89 via 1 of 4 chelator-linker combinations (benzyl isothiocyanate-DFO [DFO-Bz-NCS], where DFO is desferrioxamine B; DFO-squaramide; DFO"-Bz-NCS, where DFO* is desferrioxamine*; and DFO"-squaramide). The pharmacokinetics associated with these 4 chelator-linker combinations were compared in 12 healthy young male rhesus monkeys (-1-2 y old, 3 1 kg). Each animal was initially injected intravenously with unlabeled antibody in a peripheral vessel in the right arm (10 mg/kg, providing therapeutic-level antibody concentrations), immediately followed by approximately 40 MBq of one of the Zr-89-labeled antibodies injected intravenously in a peripheral vessel in the left arm. All animals were imaged 6 times over a period of 30 d, with an initial 60-min dynamic scan on day 0 (day of injection) followed by static scans of 3045 min on approximately days 3, 7, 14, 21, and 30, with all acquired using a single bed position and images reconstructed using time-offlight list-mode ordered-subsets expectation maximization. Activity concentrations in various organs were extracted from the PET images using manually defined regions of interest. Results: Excellent image quality was obtained, capturing the initial distribution phase in the whole-body scan; later time points showed residual Zr-89 mainly in the liver. Even at 30 d after injection, representing approximately 9 half-lives of Zr-89 and with a total residual activity of only 20-40 kBq in the animal, the image quality was sufficient to readily identify activity in the liver, kidneys, and upper and lower limb joints. Significant differences were noted in late time point liver uptake, bone uptake, and whole-body clearance between chelator-linker types, whereas little variation (10%) was observed within each type. Conclusion: These studies demonstrate the ability to image Zr-89-radiolabeled antibodies up to 30 d after injection while maintaining satisfactory image quality, as provided by the primate mini EXPLORER with high sensitivity and long axial field of view. Quantification demonstrated potentially important differences in the behavior of the 4 chelators. This finding supports further investigation.