PDF(Pubmed)
Abstract：
BACKGROUND: A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach for cancer treatment tackling disseminated cancer. As tumor size decreases, alpha-particles gain prominence due to their high Linear Energy Transfer (LET) and short path length. Among alpha-particle emitters, 211At stands out with its 7.2 hour half-life and 100% alpha emission decay. However, optimizing the pharmacokinetics of radiopharmaceuticals with short lived radionuclides such as 211At is pivotal, and in this regard, pretargeting is a valuable tool. This method involves priming the tumor with a modified monoclonal antibody capable of binding both the tumor antigen and the radiolabeled carrier, termed the \"effector molecule. This smaller, faster-clearing molecule improves efficacy. Utilizing the Diels Alder click reaction between Tetrazine (Tz) and Trans-cyclooctene (TCO), the Tz-substituted effector molecule combines seamlessly with the TCO-modified antibody. This study aims to evaluate the in vivo biodistribution of two Poly-L-Lysine-based effector molecule sizes (10 and 21 kDa), labelled with 211At, and the in vitro binding of the most favorable polymer size, in order to optimize the pretargeted radioimmunotherapy with 211At.
RESULTS: In vivo results favor the smaller polymer\'s biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group.
CONCLUSIONS: Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model.
RESULTS: In vivo results favor the smaller polymer\'s biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group.
CONCLUSIONS: Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model.
摘要：
背景：癌症治疗的一个重大挑战在于根除隐藏的播散性肿瘤细胞。在核医学中，靶向α治疗是解决播散性癌症的癌症治疗的一种有前途的方法。随着肿瘤大小的减小,α粒子由于其高线性能量转移（LET）和短路径长度而获得突出。在阿尔法粒子发射器中，211At以其7.2小时的半衰期和100％的α发射衰减而脱颖而出。然而,用短寿命放射性核素如211At优化放射性药物的药代动力学至关重要，在这方面，预定位是一个有价值的工具。该方法涉及用能够结合肿瘤抗原和放射性标记的载体的修饰的单克隆抗体引发肿瘤。称为“效应分子”。这个更小的，更快的清除分子提高疗效。利用四嗪（Tz）和反式环辛烯（TCO）之间的DielsAlder点击反应，Tz取代的效应分子与TCO修饰的抗体无缝结合。本研究旨在评估两种基于聚-L-赖氨酸的效应分子大小（10和21kDa）的体内生物分布，标有211At，和最有利的聚合物大小的体外结合，以优化211At的预靶向放射免疫治疗。
结果：体内结果有利于较小的聚合物的生物分布模式，积聚在肝脏和脾脏等器官中。当比较较小聚合物与直接标记的单克隆抗体的生物分布时,这尤其明显。较小的变体还显示在体外与预先装载TCO修饰的曲妥珠单抗的SKOV-3细胞快速有效地结合，强调其潜力。与用相同的辅基标记的单克隆抗体相比，两种聚合物的大小均显示出相等或更好的statine-碳键的体内稳定性。
结论：总体而言，基于聚-L-赖氨酸的小效应分子（10kDa）对未来的研究最有希望，与较大的效应物（21kDa）相比，在肾脏和脾脏中表现出明显较低的摄取，同时保持了与完整抗体相当或更好的β-碳键的体内稳定性。体外细胞研究的概念证明证明了小的效应子和TCO标记的抗体之间的快速反应，表明这种新型的基于聚-L-赖氨酸的预靶向系统在体内肿瘤模型中进一步研究的潜力。
结果：体内结果有利于较小的聚合物的生物分布模式，积聚在肝脏和脾脏等器官中。当比较较小聚合物与直接标记的单克隆抗体的生物分布时,这尤其明显。较小的变体还显示在体外与预先装载TCO修饰的曲妥珠单抗的SKOV-3细胞快速有效地结合，强调其潜力。与用相同的辅基标记的单克隆抗体相比，两种聚合物的大小均显示出相等或更好的statine-碳键的体内稳定性。
结论：总体而言，基于聚-L-赖氨酸的小效应分子（10kDa）对未来的研究最有希望，与较大的效应物（21kDa）相比，在肾脏和脾脏中表现出明显较低的摄取，同时保持了与完整抗体相当或更好的β-碳键的体内稳定性。体外细胞研究的概念证明证明了小的效应子和TCO标记的抗体之间的快速反应，表明这种新型的基于聚-L-赖氨酸的预靶向系统在体内肿瘤模型中进一步研究的潜力。
