New Bifunctional Ligands for Radioimmunotherapy

描述（由申请人提供）：抗体靶向放射治疗（放射免疫治疗，RIT）在治疗各种癌症方面显示出巨大的前景，如许多临床和临床前研究所证明的。第一种FDA批准的RIT药物Zevalin（R）含有Y-90（β粒子发射放射性核素）、1B 4 M-DTPA（双功能配体）和利妥昔单抗（抗CD 20抗体），与单独的抗CD 20疗法相比，显著提高了治疗非霍奇金淋巴瘤（NHL）的总体反应率。发射α或β的放射性核素Y-90、Lu-177、Bi-213、Pb-212和Ac-225是有效的细胞毒性剂，并已被研究用于癌症的RIT，包括白血病和淋巴瘤以及微转移性肿瘤。为了最大限度地减少放射性毒性和提高RIT的效力，必须使用能够有效螯合放射性核素的双功能配体。缺乏有效的放射性核素双功能配体仍然是限制RIT积极的临床探索。本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的RIT配体。本研究的假设是，具有大环和无环结合部分的新的双峰双官能配体将与Y-90、Lu-177、Bi-213、Pb-212和Ac-225快速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）配体与肿瘤靶向抗体赫赛汀或帕尼单抗的缀合，以及用Y-90、Lu-177、Bi-213、Pb-212和Ac-225评价相应配体-抗体缀合物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-放射性标记的抗体缀合物在携带结肠癌的小鼠中的生物分布、药代动力学和剂量测定研究;拟议的研究将导致上级螯合化学的发展，允许实际制备毒性更小和更有效的RIT药物治疗癌症。

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.