Efficient 1-Step Radiolabeling of Monoclonal Antibodies to High Specific Activity with 225Ac for α-Particle Radioimmunotherapy of Cancer
Efficient 1-Step Radiolabeling of Monoclonal Antibodies to High Specific Activity with 225Ac for α-Particle Radioimmunotherapy of Cancer
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DOI：
10.2967/jnumed.114.138347
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发表时间：
2014-09-01
影响因子：
9.3
通讯作者：
Scheinberg, David A.
中科院分区：
文献类型：
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作者：
Maguire, William F.;McDevitt, Michael R.;Scheinberg, David A.
使用放射性同位素Ac-225的靶向α粒子辐射是治疗各种类型癌症的有希望的形式。使用Ac-225的历史障碍是难以找到合适的螯合剂以将其稳定地连接到靶向载体如肽和单克隆抗体，产物的低比活性，以及缺乏成本有效的放射性标记程序。我们最初解决了第一个问题，涉及2个化学步骤，已被用作临床前和临床研究的标准。然而，该过程涉及90%的输入Ac-225的损失。需要一种更有效、更经济的方法来促进Ac-225的更广泛使用。方法：我们将代表性抗体与2种形式的DOTA以及其他螯合剂缀合作为对照。我们开发了条件，放射性标记这些结构在1个化学步骤，并表征其稳定性，免疫反应性，生物分布，在健康和荷瘤小鼠的治疗效果。结果：DOTA抗体构建体在37 ℃下在1个化学步骤中被标记为宽范围的比活性。放射化学产率约高出10倍，比活性比以前的方法高出30倍。产物保留免疫反应性，并且在体外和小鼠中对血清挑战稳定。通过异硫氰酸苄酯键连接的DOTA抗体构建体的标记动力学比通过N-羟基琥珀酰亚胺键连接的那些更有利。结构之间的组织分布相似但不完全相同。该构建体在急性髓性白血病小鼠模型中产生特异性治疗反应。结论：我们已经表征了一种有效的一步放射性标记方法，该方法产生稳定的具有治疗活性的抗体与高比活性的Ac-225的缀合物。我们认为，该技术大大扩展了Ac-225单克隆抗体的临床应用。
Targeted alpha-particle radiation using the radioisotope Ac-225 is a promising form of therapy for various types of cancer. Historic obstacles to the use of Ac-225 nave been the difficulty in finding suitable chelators to stably attach it to targeting vehicles such as peptides and monoclonal antibodies, the low specific activities of the products, and the lack of cost-effective radiolabeling procedures. We initially solved the first problem with a procedure involving 2 chemical steps that has been used as a standard in preclinical and clinical studies. However, this procedure involves the loss of 90% of the input Ac-225. A more efficient, economical process is needed to facilitate the more widespread use of Ac-225. Methods: We conjugated representative antibodies with 2 forms of DOTA as well as other chelators as controls. We developed conditions to radiolabel these constructs in 1 chemical step and characterized their stability, immunoreactivity, biodistribution, and therapeutic efficacy in healthy and tumor-bearing mice. Results: DOTA antibody constructs were labeled to a wide range of specific activities in 1 chemical step at 37 degrees C. Radiochemical yields were approximately 10-fold higher, and specific activities were up to 30-fold higher than with the previous approach. The products retained immunoreactivity and were stable to serum challenge in vitro and in mice. Labeling kinetics of DOTA antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through an N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs produced specific therapeutic responses in a mouse model of acute myeloid leukemia. Conclusion:. We have characterized an efficient, 1-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with Ac-225 at, high specific activity. We propose that this technology greatly expands the possible clinical applications of Ac-225 monoclonal antibodies.