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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们的主要目标是通过使用放射性标记抗体向目标组织提供补充放射，改善白血病或淋巴瘤患者的骨髓（干细胞）移植结果。靶向方法的改进可能允许抗体向患病细胞和造血器官输送更大剂量的放射性，同时向非靶器官输送较低剂量的辐射，这可能会导致更高的治愈率和更少的治疗相关毒性。我们正在研究一种称为预靶向的新技术，该技术由一个多步骤过程组成，将抗体分子的缓慢分布阶段与治疗辐射（放射性核素）的施用分开。首先，施用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）复合物。当抗体/FP在靶器官中达到最大积累后，注射含生物素的清除剂。生物素和 SA 彼此具有高亲和力，允许清除剂从血流中去除未结合的抗体/FP。最后，施用对SA-抗体/FP复合物具有高亲和力的含有生物素的放射性部分。 由于其尺寸小，未结合的放射性试剂分子会迅速从血液中清除并通过尿液排出。在实体瘤放射免疫治疗的临床前和临床研究中，该系统比非靶器官具有更好的放射治疗效果。使用这种技术和抗 CD45 抗体进行的小鼠研究也支持这种方法的功效。 对猕猴进行的研究证明了将三步预靶向过程中的每种试剂注入非人类灵长类动物的安全性。其他研究已经证明了预靶向方法在提高目标部位相对于非目标正常器官的辐射比率方面的有效性。进一步的研究正在进行中，以确定预靶向过程中每个步骤的最佳剂量和时间间隔。