Chelator for a Therapeutic Ra-223 Radiopharmaceutical

描述（由申请人提供）：放射免疫疗法（RIT）是一个极有前途的癌症治疗领域，它将单克隆抗体的靶向能力与局部辐射相结合，以破坏肿瘤细胞。目前，由于最近癌症靶向抗体的生产取得进展，以及FDA批准了第一个RIT药物泽伐林，RIT引起了人们的极大兴趣。高线性能量传递（LET）和相对较短的穿透范围（几个细胞直径）使α粒子对微肿瘤的治疗特别有吸引力。在所有被评估用于RIT的α -发射体（Bi-213、Bi-212、Ra-223和At-211）中，Ra-223 （Tl/2 = 11.4天）非常有吸引力，因为它可以从发生器中获得，而且半衰期更长。然而，这种同位素的研究和临床应用受到体内稳定螯合剂的有限可用性的阻碍。为了克服这一限制，Lynntech提议评估三种不同环尺寸（24、26和28元）的六aza大环螯合剂，作为基于Ra-223的RIT的双功能螯合剂。基于理论计算的初步结果表明，这些大环具有适合于结合Ra的空腔尺寸。在第一阶段，化合物将在初步的体外实验中合成，表征和评估其动力学稳定性。Lynntech还将优化螯合剂与抗体结合的条件以及螯合剂-抗体结合物的Ba-133 （Ra-223的替代品）标记。最后，对Ba-133螯合剂-抗体偶联物的体外稳定性进行评价。该项目的最终目标是使这些大环螯合剂商业化，用于标记RIT应用中的各种癌症靶向抗体。

DESCRIPTION (provided by applicant): Radioimmunotherapy (RIT) is an extremely promising area of cancer treatment that combines the targeting power of monoclonal antibodies with localized radiation in order to damage tumor cells. Currently, there is great interest in RIT due to the recent progress in production of cancer targeting antibodies and the FDA approval of the first RIT agent, Zevalin. The high linear energy transfer (LET) and relatively short penetration range (a few cell diameters) makes alpha particles particularly attractive for the treatment of micro tumors. Of all alpha-emitters (Bi-213, Bi-212, Ra-223 and At-211) that are being evaluated for the RIT, Ra-223 (Tl/2 = 11.4 days) is very attractive because of its availability from a generator and longer half-life. However, the research and clinical application of this isotope are hindered by the limited availability of an in vivo stable chelator. To overcome this limitation, Lynntech is proposing to evaluate three hexaaza macrocyclic chelators of different ring sizes (24, 26 and 28-membered) for use as bifunctional chelating agents for Ra-223 based RIT. The preliminary results based on theoretical calculations have demonstrated that these macrocycles will have cavity size suitable for binding Ra. During Phase I, the compounds will be synthesized, characterized and evaluated for their kinetic stability in preliminary in vitro experiments. The conditions for the conjugation of the chelators to the antibodies and Ba-133 (a surrogate for Ra-223) labeling for the chelator-antibody conjugate will also be optimized at Lynntech. Finally, the in vitro stability of the Ba-133 chelator-antibody conjugate will be evaluated. The ultimate goal of this project is to make these macrocyclic chelators commercially available for labeling a variety of cancer targeting antibodies for the RIT applications.