New Bifunctional Ligands for Radioimmunotherapy

用于放射免疫治疗的新型双功能配体

基本信息

批准号：
8784193
负责人：
HYUN-SOON CHONG
金额：
$ 31.77万
依托单位：
ILLINOIS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8784193
关键词：
90Y Affect Antibodies Antineoplastic Agents Beta Particle Binding Biodistribution Blood Bone Marrow Cancer Patient Charge Chelating Agents Chemistry Chimera organism Clinical Clinical Research Clinical Trials Colon Carcinoma Comparative Study Complex Cytotoxic agent Data Development Drug Kinetics ERBB2 gene Enzyme-Linked Immunosorbent Assay Epidermal Growth Factor Receptor Evaluation FDA approved Health High Pressure Liquid Chromatography Human In Vitro Investigation Kidney Kinetics LS174 Label Lead Ligands Liver MS4A1 gene Malignant Neoplasms Metals Mus Non-Hodgkin&apos s Lymphoma Nude Mice Organ Pentetic Acid Pharmaceutical Preparations Preparation Property Radiation therapy Radioactivity Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiolabeled Reaction Recombinants Research Roche brand of trastuzumab Roentgen Rays Series Serum Serum Albumin Temperature Therapeutic Thermodynamics Toxic effect Treatment Efficacy Xenograft procedure Y 90 Ibritumomab Tiuxetan antibody conjugate base cancer radioimmunotherapy chelation chemical synthesis cytotoxic design dosimetry immunoreactivity in vivo leukemia/lymphoma metal complex neoplastic cell novel overexpression panitumumab preclinical study radiotracer response rituximab stereochemistry tositumomab tumor uptake

项目摘要

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.

描述（由申请人提供）：大量临床和临床前研究证明，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前景。第一个 FDA 批准的 RIT 药物 Zevalin(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），显着提高了治疗的总体缓解率与单独的抗CD20治疗相比，非霍奇金淋巴瘤(NHL)的治疗效果更好。 α 或 β 发射放射性核素 Y-90、Lu-177、Bi-213、Pb-212 和 Ac-225 是有效的细胞毒剂，并已针对包括白血病、淋巴瘤和微转移肿瘤在内的癌症的 RIT 进行了研究。为了最大限度地减少放射性毒性并增强 RIT 的效力，必须使用能够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 积极临床探索的一个限制。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型双峰双功能配体将与 Y-90、Lu-177、Bi-213、Pb-212 和 Ac-225 快速形成高度稳定的复合物。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) 将配体与肿瘤靶向抗体、赫赛汀或帕尼单抗缀合，并用 Y-90、Lu-177、Bi-213、Pb-212 和评估相应配体-抗体缀合物的放射性标记动力学和血清稳定性Ac-225； iii) Y-90、Lu-177、Bi-213、Pb-212 和 Ac-225 放射性标记抗体缀合物在结肠癌小鼠中的生物分布、药代动力学和剂量测定研究； iv) 放射性标记抗体缀合物的治疗和毒性研究。拟议的研究将促进高级螯合化学的发展，从而可以实际制备毒性更小、更有效的 RIT 癌症药物。