New Bifunctional Ligands for Radioimmunotherapy

描述（由申请人提供）：大量的临床和临床前研究表明，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希望。fda批准的首个RIT药物泽伐林（Zevalin）含有Y-90 （β粒子发射放射性核素）、1b4 - dtpa（双功能配体）和利妥昔单抗（抗cd20抗体），与单独抗cd20治疗相比，显著提高了非霍奇金淋巴瘤（NHL）治疗的总有效率。发射α或β的放射性核素Y-90、Lu-177、Bi-213、Pb-212和Ac-225是有效的细胞毒性药物，已被研究用于白血病、淋巴瘤和微转移性肿瘤等癌症的RIT。为了减少放射性毒性和提高RIT的效力，必须使用一种能有效隔离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RIT临床探索的一个限制。本研究的目的是发展高效的双功能

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.