PRETARGETED ANTI-CD45 RADIOIMMUNOTHEARPY STUDIES IN MACAQUES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们的目标是改善急性白血病干细胞移植的结果，使用放射标记抗体对靶组织进行补充辐射。靶向方法的改进可能允许从抗体向白血病细胞和造血器官提供更大剂量的放射性，同时向非靶向器官提供更低剂量的辐射，这可能导致更高的治愈率和更少的治疗相关毒性。本研究采用了由多步骤过程组成的预靶向，将抗体分子的缓慢分布阶段与治疗性放射性同位素的施用分离开来。首先，使用非放射性链亲和素(SA)-抗体复合物与目标抗原结合。抗体在靶器官积累后，注射含维生素（生物素）的清除剂。最后，对sa抗体复合物具有高亲和力的含有生物素的放射性构建物进行管理。由于体积小，未结合的放射性试剂分子会迅速从血液中清除并随尿液排出。在实体瘤放射免疫治疗的临床前和临床研究中，该系统在靶向器官和非靶向器官的放射治疗中取得了更好的效果。使用这种技术对抗cd45抗体进行的小鼠研究似乎也很有希望。这些研究在非人灵长类动物中的具体目的是：评估放射性碘标记的抗cd45融合蛋白BC8(scFv)4SA对非人灵长类动物的可行性、安全性和毒性，并比较和对比融合蛋白与直接放射性标记的抗cd45 （BC8）抗体的药代动力学和组织渗透。为了比较抗cd45 BC8(scFv)4SA融合蛋白预先靶向的放射性生物素在猕猴体内的生物分布和剂量学，与直接放射性标记的抗cd45 BC8抗体在猕猴体内的生物分布和剂量学。在当前阶段，我们进行了一项涉及两只束状支链猴的研究。本研究旨在确定BC8(scFv)4SA的药代动力学特性。使用比我们之前的实验更高的剂量来优化靶部位的递送。这些动物耐受注射，没有毒性的迹象。目前正在分析收集到的数据。

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 goal is to improve the outcome of stem cell transplantation for acute leukemia with 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 leukemia 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. This study employs pretargeting which consists of a multi-step process to dissociate the slow distribution phase of the antibody molecule from the administration of the therapeutic radioisotope. First, a non-radioactive streptavidin (SA)-antibody complex which binds to the target antigen is administered. After accumulation of the antibody in the target organ, a vitamin (biotin)-containing clearing agent is injected. Finally, a biotin-containing radioactive construct with high affinity for the SA-antibody 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 seem promising. The specific aims of these studies in non-human primates are: To evaluate the feasibility, safety, and toxicity of administering radioiodine-labeled anti-CD45 fusion proteins, BC8(scFv)4SA, to nonhuman primates and to compare and contrast the pharmacokinetics and tissue penetration of the fusion proteins with those of directly radiolabeled anti-CD45 (BC8) antibodies. To compare the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD45 BC8(scFv)4SA fusion proteins in macaques with the biodistributions and dosimetries of directly radiolabeled anti-CD45 BC8 Abs. During the current period we have conducted one study, involving two M. fascicularis animals. The study was performed to determine the pharmacokinetic properties of the BC8(scFv)4SA. A higher dose was used than in our prior experiments to optimize delivery to target sites. The animals tolerated the infusions without evidence of toxicity. Data collected are currently being analyzed.