New Bifunctional Ligands for Radioimmunotherapy

描述(申请人提供)：许多临床和临床前研究表明，抗体靶向放射治疗(RIT)在治疗各种癌症方面显示出巨大的前景。FDA批准的第一种RIT药物Zvalin(R)含有Y-90(β粒子发射放射性核素)、1B4M-DTPA(双功能配体)和Rituximab(抗CD20抗体)，与单独使用抗CD20治疗相比，显著提高了非霍奇金淋巴瘤(NHL)的总有效率。放射性核素Y-90、Lu-177、Bi-213、Pb-212和Ac-225是有效的细胞毒剂，已被用于白血病、淋巴瘤和微转移瘤等癌症的RIT研究。为了将放射性毒性降到最低并增强RIT的效力，必须使用能够有效地隔离放射性核素的双功能配体。放射性核素缺乏有效的双功能配体仍然是限制RIT积极临床探索的一个因素。这项研究的目的是开发高效的双功能 使用Y-90、Lu-177、Bi-213、Pb-212和Ac-225作为RIT的配体。本研究的假设是，具有大环和非环结合部分的新型双峰双功能配体将迅速与Y-90、Lu-177、Bi-213、Pb-212和Ac-225形成高度稳定的络合物。本研究的具体目的是：i)新型双峰双功能配体的合成和化学评价；ii)将配体连接到肿瘤靶向抗体Herceptin或Panitumab上，并评价相应的配体-抗体结合物对Y-90、Lu-177、Bi-213、Pb-212和Ac-225的放射性标记动力学和血清稳定性；iii)Y-90、Lu-177、Bi-213、Pb-212和Ac-225标记抗体结合物在结肠癌小鼠中的生物分布、药代动力学和剂量学研究；iv)放射性标记抗体结合物的治疗和毒性研究。这项拟议的研究将导致开发更好的螯合化学，从而允许实际制备毒性更低、更有效的抗癌RIT药物。

DESCRIPTION (provided by applicant): Antibody-targeted radiation therapy (Radioimmunotherapy, RIT) has shown great promise in the treatment of various cancers as demonstrated by numerous clinical and preclinical studies. The first FDA-approved RIT drug, Zevalin(R), containing Y-90 (beta particle-emitting radionuclide), 1B4M-DTPA (bifunctional ligand), and Rituximab (anti-CD20 antibody) significantly enhanced the overall response rate in the treatment of non- Hodgkin's lymphoma (NHL) as compared to anti-CD20 therapy alone. The alpha- or beta-emitting radionuclides, Y-90, Lu-177, Bi-213, Pb-212, and Ac-225 are effective cytotoxic agents and have been investigated for RIT of cancers including leukemia and lymphoma and micrometastatic tumors. To minimize radiotoxicity and enhance potency of RIT, a bifunctional ligand that can effectively sequester the radionuclide must be employed. Absence of effective bifunctional ligands for the radionuclides remains a limitation in active clinical exploration of RIT. The objective of this investigation is to develop highly effective bifunctional ligands for RIT using Y-90, Lu-177, Bi-213, Pb-212, and Ac-225. The hypothesis of this study is that the new bimodal bifunctional ligands with both macrocyclic and acyclic binding moieties will rapidly form highly stable complexes with Y-90, Lu-177, Bi-213, Pb-212, and Ac-225. The specific aims of this study are i) synthesis and chemical evaluation of the novel bimodal bifunctional ligands; ii) conjugation of the ligands to a tumor-targeting antibody, Herceptin or Panitumumab, and evaluation of the corresponding ligand-antibody conjugates for radiolabeling kinetics and serum stability with Y-90, Lu-177, Bi-213, Pb-212, and Ac-225; iii) biodistribution, pharmacokinetics and dosimetry studies of Y-90, Lu-177, Bi-213, Pb-212, and Ac-225-radiolabeled antibody conjugates in colon cancer-bearing mice; iv) therapy and toxicity studies of the radiolabeled antibody conjugates. The proposed research will lead to the development of superior chelation chemistry that allows for practical preparation of less toxic and more potent RIT drugs for cancer.