Astatine-211 Conditioning for Nonmyeloablative Hematopoietic Stem Cell Allografts

异基因造血细胞移植(HCT)是治疗慢性粒细胞白血病的重要手段。 恶性和非恶性血液病。然而，这种治疗的应用已经 由于与调理疗法的毒性有关的并发症，仅限于相对年轻的患者 使用。为了减少毒性，已经开发了非清髓性方案。虽然这些都是相当 成功进行了主要组织相容性抗原复合体(MHC)相合的移植，总计200cGy. 在更复杂的MHC-半相合环境中，身体照射(TBI)足以植入 为了确保植入，需要更高和毒性更高的TBI剂量。我们建议系统地调查一起 靶向形式的辐射，以取代MHC相合和MHC半相合HCT中的TBI，这将 为没有MHC匹配供者的患者提供治疗选择。具体地说，研究工作将 确定a发射放射性核素211他汀类(211At)在与全造血抗-药结合时是否 CD45单抗(MAb)可替代TBI用于异基因造血干细胞移植受者的治疗。我们将利用 我们建立的随机繁殖的狗的临床前模型已经预测了同种异体血细胞移植 人类。 在具体目标1中，我们将评估和优化一种用~(211)At标记单抗的新方法。最多的 目前使用的标记单抗的有效方法包括两步过程，其中 将苯甲酸锡酯固定，然后与抗体偶联，将研究的方法 包括将含有反式反应性的硼酸盐(2-)部分的分子偶联到单抗上，然后 大吃一惊。新标记方法的潜在优势包括更少地处理放射性材料， 以及更高和更一致的标记率。在特定目标2中，~(211)At-T的疗效和毒性。 标记的抗CD45单抗将与用另一发射放射性核素标记的单抗进行比较， ~(213)铋(~(213)Bi)对CD45表达细胞和小鼠模型的影响。比较研究将允许使用 用~(213)Bi标记的单抗在先前研究中获得的信息，以帮助确定初始条件和 11At研究的数量。在具体目标3中，将在狗身上进行211At标记单抗的评估 寻找狗白细胞抗原(DLA)相合和DLA半相合HCT的有效剂量。最初， 将进行剂量发现研究，以确定对骨髓抑制有效的最小剂量。 随后，需要大量的211At标记的抗CD45单抗才能在HCT中获得稳定的植入 将确定是否涉及DLA完全相同的窝产仔。最后，也是最重要的一项研究将涉及 确定获得稳定植入Hct所需的~(211)At标记单抗的量，涉及DLA- 单倍体相同的产仔。

Allogeneic hematopoietic cell transplantation (HCT) is an important treatment modality for patients with both malignant and nonmalignant hematologic disorders. However, the application of this treatment has been limited to relatively young patients by complications related to the toxicity of the conditioning regimens used. To decrease toxicities, nonmyeloablative regimens have been developed. While these have been quite successful in major histocompatibility antigen complex (MHC)-identical transplants, where 200 cGy total body irradiation (TBI)is adequate for engraftment, in the more complex MHC-haploidentical setting much higher and toxic TBI doses are required to ensure engraftment. We propose to investigate a systemically targeted form of radiation to replace TBI in both MHC-identical and MHC-haploidentical HCT which would provide a treatment option for patients without MHC-matched donors. Specifically, the research efforts will determine if the a-emitting radionuclide 211 Astatine (211At), when conjugated to a panhematopoietic anti- CD45 monoclonal antibody (MAb), can replace TBI to condition recipients for allogeneic HCT. We will utilize our well-established preclinical model of randombred dogs which has been predictive of allogeneic HCT in humans. In specific aim 1, we will evaluate and optimize a new method for labeling MAbs with 211At. The most effective method for labeling MAbs with 211At used currently involves a two-step process where a stannylbenzoate ester is astatinated, then conjugated with the MAb.The method to be investigated will involve conjugation of a molecule containing an astatine-reactive borate(2-) moiety to the MAb, followed by astatination. Potential advantages of the new labeling method include less handling of radioactive materials, as well as higher and more consistent labeling yields. In specific aim 2, the efficacy and toxicity of 211At- labeled anti-CD45 MAbs will be compared with MAbs labeled with another a-emitting radionuclide, 213Bismuth (213Bi) on CD45-expressing cells and in a mouse model. The comparative studies will allow use of information obtained in prior studies with 213Bi-labeled MAbs to help determine initial conditions and quantities for the 211At studies. In specific aim 3, evaluations of 211At-labeled MAbs will be conducted in dogs to find effective doses for both dog leukocyte antigen (DLA)-identical and DLA-haploidentical HCT.Initially, dose-finding studies will be conducted to determine the minimal dose that is effective for myelosuppression. Following that, quantity of 211At-labeled anti-CD45 MAb required to obtain stable engraftment in HCT involving DLA-identical littermates will be determined. The final, and most important, studies will involve determining the quantity of 211At-labeled MAb required to obtain stable engraftment in HCT involvingDLA- haploidentical littermates.