Astatine-211 Conditioning for Nonmyeloablative Hematopoietic Stem Cell Allografts

Astatine-211 用于非清髓性造血干细胞同种异体移植物的调理

• 批准号: 7153524
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 27.34万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-06 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7153524
• 关键词: Allogenic; Allografting; Animals; Astatine; Binding; Biodistribution; Biological; Blood; Borates; Breeding; Canis familiaris; Cell Survival; Cell Transplantation; Cells; Chemicals; Clinical; Clinical Research; Comparative Study; Complex; Condition; Count; Cultured Cells; Data; Dose; Drug Kinetics; Engraftment; Ensure; Esters; Evaluation; HLA Antigens; Half-Life; Hematopoietic; Hematopoietic stem cells; Hepatic; Histocompatibility Antigens; Host vs Graft Reaction; Human; Image; Immune Targeting; In Vitro; Isotopes; Label; Logistics; Malignant - descriptor; Methods; Modality; Modeling; Monitor; Monoclonal Antibodies; Mus; Myelosuppression; Natural Killer Cells; Non-Neoplastic Hematologic and Lymphocytic Disorder; Numbers; Oxidants; PTPRC gene; Pain; Patients; Pre-Clinical Model; Process; Radiation; Radioactive; Radioisotopes; Radiolabeled; Reagent; Relative (related person); Renal function; Research; Research Personnel; Time; Tissues; Toxic effect; Transplantation; Treatment Efficacy; Treatment Protocols; Weight; Whole-Body Irradiation; base; cell killing; chloramine-T; conditioning; cost; in vivo; killings; mouse model; particle; physical property; programs; radiochemical; radiotracer; scale up; success

DESCRIPTION (provided by applicant): 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 alpha-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 random bred 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 involving DLA- haploidentical littermates.

描述（由申请人提供）：同种异体造血细胞移植（HCT）是恶性和非恶性血液疾病患者的重要治疗方式。然而，由于与所用预处理方案的毒性相关的并发症，这种治疗的应用仅限于相对年轻的患者。为了减少毒性，已经开发了非清髓性治疗方案。虽然这些在主要组织相容性抗原复合物 (MHC) 一致移植中相当成功，其中 200 cGy 全身照射 (TBI) 足以进行植入，但在更复杂的 MHC 半相合环境中，需要更高且有毒的 TBI 剂量才能确保植入。我们建议研究一种系统靶向放射形式，以替代 MHC 一致和 MHC 单倍体 HCT 中的 TBI，这将为没有 MHC 匹配供体的患者提供治疗选择。具体来说，该研究工作将确定α发射放射性核素211砹（211At）与泛造血抗CD45单克隆抗体（MAb）缀合时是否可以替代TBI来为受者提供同种异体HCT条件。我们将利用我们完善的随机饲养狗的临床前模型，该模型可以预测人类的同种异体 HCT。在具体目标 1 中，我们将评估和优化一种用 211At 标记 MAb 的新方法。目前使用 211At 标记 MAb 的最有效方法涉及两步过程，其中苯甲锡烷基酯被砹化，然后与 MAb 缀合。待研究的方法将涉及将含有砹反应性硼酸盐 (2-) 部分的分子与 MAb 缀合，然后进行砹化。新标记方法的潜在优势包括减少放射性材料的处理，以及更高且更一致的标记产量。在具体目标 2 中，将在 CD45 表达细胞和小鼠模型中比较 211At 标记的抗 CD45 MAb 与另一种发射放射性核素 213Bismuth (213Bi) 标记的 MAb 的功效和毒性。比较研究将允许使用先前 213Bi 标记单克隆抗体研究中获得的信息来帮助确定 211At 研究的初始条件和数量。在具体目标 3 中，将对 211At 标记的 MAb 在狗身上进行评估，以找到狗白细胞抗原 (DLA) 相同和 DLA 单倍体 HCT 的有效剂量。最初，将进行剂量探索研究以确定对骨髓抑制有效的最小剂量。随后，将确定在涉及 DLA 相同同窝仔鼠的 HCT 中获得稳定植入所需的 211At 标记的抗 CD45 MAb 的数量。最后也是最重要的研究将涉及确定在涉及 DLA 单倍体同窝仔鼠的 HCT 中获得稳定植入所需的 211At 标记 MAb 的数量。