PRETARGETED ANTI-CD45 RADIOIMMUNOTHEARPY STUDIES IN MACAQUES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们的目标是改善急性白血病干细胞移植的结果，并使用放射性标记抗体对靶组织进行补充放射治疗。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递送更大剂量的放射性，同时向非靶器官递送更低的辐射剂量，这可能导致更高的治愈率和更少的治疗相关毒性。本研究采用预靶向，其由多步骤过程组成，以从治疗性放射性同位素的施用中解离抗体分子的缓慢分布相。首先，施用与靶抗原结合的非放射性链霉亲和素（SA）-抗体复合物。抗体在靶器官中积累后，注射含维生素（生物素）的清除剂。最后，施用对SA-抗体复合物具有高亲和力的含生物素的放射性构建体。由于它们的小尺寸，未结合的放射性试剂分子迅速从血液中清除并随尿排出。在实体瘤放射免疫治疗的临床前和临床研究中，该系统导致了对靶器官的放射优于对非靶器官的放射的上级递送。使用抗CD 45抗体进行的小鼠研究似乎也很有希望。在非人灵长类动物中进行这些研究的具体目的是：评价放射性碘标记的抗CD 45融合蛋白BC 8（scFv）4SA对非人灵长类动物给药的可行性、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CD 45（BC 8）抗体的药代动力学和组织渗透性。 比较使用抗CD 45 BC 8（scFv）4SA融合蛋白预靶向的放射性生物素在猕猴中的生物分布和剂量测定与直接放射性标记的抗CD 45 BC 8 Ab的生物分布和剂量测定。 在本报告所述期间，我们进行了一项研究，涉及两个M。fascicularis动物进行该研究以确定BC 8（scFv）4SA的药代动力学性质。使用了比我们先前实验中更高的剂量以优化向靶位点的递送。动物耐受输注，无毒性证据。目前正在分析收集的数据。

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.