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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的主要目标是通过使用放射性标记抗体向靶组织提供补充辐射来改善白血病或淋巴瘤患者的骨髓(干细胞)移植的结果。靶向方法的改进可能允许将较大剂量的放射性从抗体输送到病变细胞和造血器官，而将较低剂量的辐射输送到非靶器官，这可能会导致更高的治愈率和更少的治疗相关毒性。我们正在研究一种名为前靶向的新技术，它包括一个多步骤的过程，将抗体分子的缓慢分布阶段与治疗性辐射(放射性核素)的管理分开。首先，给予能够与靶抗原结合的非放射性链霉亲和素(SA)抗体或融合蛋白(FP)复合体。在抗体/FP在靶器官中最大限度积聚后，注射含有生物素的清除剂。生物素和SA具有很高的亲和力，允许清除剂从血液中去除未结合的抗体/FP。最后，给予SA-抗体/FP复合体具有高亲和力的含有生物素的放射性部分。由于其体积较小，放射性试剂的游离分子可以迅速从血液中清除并从尿液中排出。在实体肿瘤放射免疫治疗的临床前和临床研究中，该系统已导致向目标器官提供比非目标器官更好的辐射。将这项技术与抗CD45抗体一起使用的小鼠研究也支持了这种方法的有效性。在猕猴身上进行的研究已经证明，在三步预靶向过程中将每种试剂注入非人类灵长类动物是安全的。更多的研究证明了预靶向方法在改善相对于非靶点正常器官向目标部位提供的辐射比率方面的有效性。目前正在进行进一步的调查，以确定预先确定目标进程中每一步骤的最佳剂量和时间间隔。