PRETARGETED ANTI-CD45 RADIOIMMUNOTHERAPY STUDIES IN MACAQUES

猕猴中的预先靶向抗 CD45 放射免疫治疗研究

• 批准号: 8172763
• 负责人: Oliver W. Press
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172763
• 关键词: Affinity; Antibodies; Antigen Targeting; Binding; Biotin; Blood; Blood Circulation; Bone Marrow Stem Cell Transplantation; Cells; Chimeric Proteins; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Dose; Effectiveness; Funding; Goals; Grant; Institution; Investigation; Low Dose Radiation; Lymphoma; Macaca; Methods; Mus; Organ; Outcome; Patients; Phase; Process; Radiation; Radioactive; Radioactivity; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Reagent; Relative (related person); Research; Research Personnel; Resources; Safety; Site; Solid Neoplasm; Source; Streptavidin; System; Techniques; Therapeutic; Tissues; Toxic effect; United States National Institutes of Health; Urine; blood forming organ; improved; leukemia; nonhuman primate; pre-clinical; protein complex; time interval

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our main goal is to improve the outcome of bone marrow (stem cell) transplantation for patients with leukemia or lymphoma by delivering supplemental radiation to target tissues using radiolabeled antibodies. The improvement of targeting methods may allow the delivery of larger doses of radioactivity from antibody to diseased cells and blood-forming organs, while delivering lower radiation doses to non-target organs, this may result in higher cure rates and fewer treatment-related toxicities. We are investigating a new technique called pretargeting which consists of a multi-step process to separate the slow distribution phase of the antibody molecule from the administration of the therapeutic radiation (radionuclide). First, a non-radioactive streptavidin (SA)-antibody or fusion protein (FP) complex capable of binding with the target antigen is administered. After maximal accumulation of the antibody/FP in the target organ, a biotin-containing clearing agent is injected. Biotin and SA have high affinity for each other, allowing the clearing agent to removes unbound antibody/FP from the bloodstream. Finally, a biotin-containing radioactive moiety with high affinity for the SA-antibody/FP complex is administered. Because of their small size, unbound molecules of radioactive reagent are rapidly cleared from the blood and excreted in the urine. This system has resulted in superior delivery of radiation to target versus nontarget organs in preclinical and clinical studies of radioimmunotherapy for solid tumors. Mouse studies using this technique with anti-CD45 antibodies also support the efficacy of this approach. Studies performed on macaques have demonstrated the safety of infusing each reagent in the three-step pretargeting process into nonhuman primates. Additional studies have documented the effectiveness of the pretargeting approach in improving the ratio of radiation delivered to target sites relative to non-target normal organs. Further investigations are ongoing to establish the optimal doses and time intervals for each step in the pretargeting process.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们的主要目的是通过使用放射性标记抗体向靶组织提供补充辐射，改善白血病或淋巴瘤患者的骨髓（干细胞）移植结果。靶向方法的改进可以允许从抗体到患病细胞和血液形成器官的较大剂量的放射性递送，同时将较低的放射剂量传递给非靶向器官，这可能会导致较高的治疗率和较少的治疗毒性。我们正在研究一种名为Prestargeting的新技术，该技术由一个多步骤过程组成，该过程将抗体分子的缓慢分布阶段与治疗辐射（放射性核素）的给药分开。首先，施用了与靶抗原结合的非放射性链霉亲和蛋白（SA） - 抗体或融合蛋白（FP）复合物。在目标器官中抗体/FP的最大积累后，注入了含生物素的清除剂。生物素和SA彼此具有高亲和力，使清除剂可以从血液中去除未结合的抗体/FP。最后，对具有高亲和力的含生物素的放射性部分对SA抗体/FP复合物进行了施用。 由于其尺寸很小，因此从血液中迅速清除了放射性试剂的未结合分子，并在尿液中排出。该系统在临床前和临床研究实体疗法的临床前和临床研究中，将辐射递送到靶标与非目标器官的递送较高。使用该技术使用抗CD45抗体的小鼠研究也支持这种方法的功效。 对猕猴进行的研究表明，将每种试剂在三步有限的过程中注入到非人类灵长类动物中的安全性。其他研究已经记录了有限方法在改善相对于非目标正常器官的辐射比的有效性。正在进行进一步的研究，以在有限的过程中为每个步骤建立最佳剂量和时间间隔。