Research Center, Nihon Medi-Physics Co., Ltd., 299-0266 Sodegaura, Japan.
Business Development and Project Department, Nihon Medi-Physics Co., Ltd., 136-0075 Tokyo, Japan.
Nucl Med Biol. 2022 May-Jun;108-109:33-43. doi: 10.1016/j.nucmedbio.2022.02.003. Epub 2022 Feb 26.
Theranostic applications are currently difficult to achieve owing to the limited evaluation of suitable chelators for therapeutic nuclides, such as Ac and Th. With a focus on targeted α therapy and theranostics using human IgG as a drug-delivery system (i.e., combining highly cytotoxic α-particle emitter radiation with efficient tumor targeting), we developed a recombinant humanized Nd2 (hNd2) as an anti-MUC5AC antibody since MUC5AC is highly expressed in patients with pancreatic cancer. Therefore, we aimed to evaluate the performance of Zr- (for diagnosis) and Ac- (for therapy) labeling of these antibodies using well-controlled radioisotope (RI)-labeling technology in pancreatic cancer mouse models.
Zr-labeled hNd2 (NMK89) and Ac-labeled hNd2 (NMT25) were manufactured by chemical conjugation using affinity peptides. A binding assay and the evaluation of plasma stability were performed in vitro to confirm the properties of NMK89 and NMT25. In vivo, we evaluated biodistribution, positron emission tomography (PET)/computed tomography (CT) imaging, antitumor effects, and toxicity. Moreover, the exposure dose in humans was estimated based on the biodistribution evaluation in normal mice.
NMK89 and NMT25 showed binding specificity to MUC5AC and stability with radiochemical purity ≥90% in mice and human plasma following incubation for 168 h. NMK89 showed high accumulation in tumors and low non-specific accumulation in normal tissues. The antitumor effect of NMT25 was dose-dependent and significantly suppressed tumor growth in the NMT25 treatment groups compared with the control group (p < 0.05). NMK89 and NMT25 showed similar pharmacokinetics and biodistribution characteristics. Additionally, the human estimated exposure dose of NMK89 and NMT25 was confirmed, and the effective dose of NMK89 and NMT25 was 0.33 mSv/MBq and 177.5 mSv/MBq, respectively.
NMK89 showed specific accumulation in the MUC5AC-expressing tumors, while NMT25 showed strong antitumor effects. These results suggest NMK89 and NMT25 as promising theranostic agents for pancreatic cancer.
由于治疗核素（如 Ac 和 Th）合适螯合剂的评估有限，治疗诊断应用目前难以实现。鉴于靶向α治疗和以人 IgG 作为药物输送系统的治疗诊断（即将高效的α粒子发射体辐射与高效的肿瘤靶向相结合）的重要性，我们开发了一种重组人源化 Nd2（hNd2）作为抗 MUC5AC 抗体，因为 MUC5AC 在胰腺癌患者中高度表达。因此，我们旨在使用经过良好控制的放射性同位素（RI）标记技术，在胰腺癌小鼠模型中评估这些抗体的 Zr-（用于诊断）和 Ac-（用于治疗）标记性能。
通过使用亲和肽的化学偶联法制造 Zr 标记的 hNd2（NMK89）和 Ac 标记的 hNd2（NMT25）。在体外进行结合测定和血浆稳定性评估，以确认 NMK89 和 NMT25 的特性。在体内，我们评估了生物分布、正电子发射断层扫描（PET）/计算机断层扫描（CT）成像、抗肿瘤作用和毒性。此外，根据正常小鼠的生物分布评估，估算了人体的暴露剂量。
NMK89 和 NMT25 对 MUC5AC 表现出特异性结合，并且在与小鼠和人血浆孵育 168 小时后，放射化学纯度≥90%。NMK89 在肿瘤中高度积累，在正常组织中低非特异性积累。NMT25 的抗肿瘤作用呈剂量依赖性，与对照组相比，NMT25 治疗组显著抑制肿瘤生长（p < 0.05）。NMK89 和 NMT25 表现出相似的药代动力学和生物分布特征。此外，还确认了 NMK89 和 NMT25 的人体估计暴露剂量，NMK89 和 NMT25 的有效剂量分别为 0.33 mSv/MBq 和 177.5 mSv/MBq。
NMK89 显示在表达 MUC5AC 的肿瘤中有特异性积累，而 NMT25 显示出强烈的抗肿瘤作用。这些结果表明 NMK89 和 NMT25 是有前途的胰腺癌治疗诊断剂。
