Project 2: Minimal-Intensity Conditioning with Antibody-Targeted Alpha Radiation

项目 2：使用抗体靶向阿尔法辐射进行最低强度调节

• 批准号: 9105438
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 49.25万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9105438
• 关键词: Allogenic; Alpha Particles; Antibodies; Aplastic Anemia; Astatine; B-Lymphocytes; Bystander Effect; CD34 gene; Canis familiaris; Cell Therapy; Cells; Child; Clinical; Clinical Trials; Development; Disease; Dose; Energy Transfer; Engraftment; Erythrocytes; Failure; Functional disorder; Gastrointestinal tract structure; Goals; Graft Rejection; Graft-Versus-Tumor Induction; Growth; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Hemoglobinopathies; High Dose Chemotherapy; Immune Targeting; Immunologic Deficiency Syndromes; Infertility; Label; Late Effects; Lead; Length; Linear Energy Transfer; Malignant - descriptor; Malignant Neoplasms; Marrow; Minor Histocompatibility Antigens; Minority Groups; Modeling; Monoclonal Antibodies; Non-Malignant; Organ; Outcome; PTPRC gene; Patients; Pyruvate Kinase; Radiation; Radioimmunotherapy; Radioisotopes; Regimen; Resistance; Risk; Second Primary Cancers; Severe Combined Immunodeficiency; Sickle Cell Anemia; Staging; Stem cells; T-Lymphocyte; Thalassemia; Time; Toxic effect; Transfusion; Translations; Whole-Body Irradiation; Work; X-Linked Severe Combined Immunodeficiency; base; body system; cell killing; chemotherapy; clinically relevant; conditioning; cytokine; disorder control; ethnic minority population; experience; gene therapy; graft vs host disease; hematopoietic cell transplantation; high risk; in vivo; irradiation; mortality; pediatric patients; pre-clinical; prevent; public health relevance; systemic toxicity

ABSTRACT – PROJECT 2 This preclinical project uses canine models of nonmalignant blood disorders to develop conditioning regimens for allogeneic hematopoietic cell transplantation (HCT; Project 1) and gene therapy (Project 3) that have minimal toxicity, are safe, avert the short- and long-term toxicities such as growth failure, infertility, and late cancers, while at the same time achieving high-level donor multi-lineage engraftment. We seek to accomplish these goals with monoclonal antibody (MAb) targeted radioimmunotherapy (RIT) using a powerful alpha- emitting radionuclide, astatine-211 (211At). Alpha-emitters are characterized by efficient cell killing due to their very short path length (40-70 μm) and high linear energy transfer. Targeted irradiation will avoid the short- and long-term toxicities of systemic conditioning regimens used up to now. Specific Aim 1: Develop conditioning regimens for DLA-identical and DLA-haploidentical HCT using 211At-labeled anti-CD45 MAb in a dog model of red blood cell disorders. Here we intend to overcome engraftment problems and toxicities of conventional conditioning by using targeted irradiation with an 211At-labeled panhematopoietic anti-CD45 MAb. Pyruvate kinase (PK) deficient dogs serve as a model of hemoglobinopathy. We will optimize 211At dosing for both DLA-identical and DLA-haploidentical HCT. Specific Aim 2: Develop conditioning regimens for DLA-haploidentical HCT using 211At-labeled anti- CD45 MAb in a dog model of X-linked severe combined immunodeficiency (SCID-X1). HCT with minimal or no conditioning often results in deficient B-cell engraftment and function in patients with SCID-X1. A modest degree of stable donor marrow engraftment is also required for long-term cure. We propose that a regimen incorporating 211At-labeled anti-CD45 MAb will achieve multi-lineage engraftment, with minimal toxicity in patients with SCID-X1. Specific Aim 3: Evaluate the use of 211At-labeled anti-CD45 MAb to overcome transfusion-induced sensitization and subsequent graft rejection in a well-established DLA-identical HCT model. Studies will be conducted to determine the optimal doses of 211At-labeled anti-CD45 MAb that are needed to target the immune cells responsible for graft rejection and consistently establish engraftment of donor hematopoietic cells with minimal toxicity. Specific Aim 4: Ex vivo expanded DLA-identical hematopoietic stem cells to facilitate engraftment after nonmyeloablative conditioning with 211At. There is no benefit in the development of graft versus host disease in patients with nonmalignant disorders. This aim will explore the ability to use RIT to engraft very high numbers of expanded stem cells (developed in Project 3) as a model of T-cell-depleted allogeneic HCT.

摘要-项目2 该临床前项目使用犬的非恶性血液疾病模型来开发预处理方案 异基因造血细胞移植（HCT;项目1）和基因治疗（项目3）， 最小的毒性，是安全的，避免短期和长期毒性，如生长失败，不育，和晚期 癌症，同时实现高水平供体多谱系移植。我们力求实现 这些目标与单克隆抗体（MAb）靶向放射免疫治疗（RIT）使用强大的α- 放射性核素：211 At。α-发射体的特征在于由于它们的 非常短的路径长度（40-70 μm）和高线性能量传递。有针对性的照射将避免短-和 目前使用的全身预处理方案的长期毒性。 具体目标1：使用以下方法开发用于DLA一致和DLA半相合HCT的预处理方案： 211 At标记的抗CD 45单克隆抗体在犬红细胞疾病模型中的应用在这里我们打算克服 植入问题和毒性的常规调理通过使用靶向照射与 211 At标记的泛造血抗CD 45单克隆抗体。丙酮酸激酶（PK）缺陷的狗作为模型， 血红蛋白病我们将优化211 At给药用于DLA-相同和DLA-半倍体相同的HCT。 具体目标2：使用211 At标记的抗-HCV抗体开发DLA-半相合HCT的预处理方案。 X连锁重度联合免疫缺陷（SCID-X1）犬模型中的CD 45 MAb。HCT极轻微或无 预处理通常导致SCID-X1患者的B细胞移植和功能缺陷。适度 长期治愈还需要一定程度的稳定供体骨髓移植。我们建议一种养生法 掺入211 At标记的抗CD 45单克隆抗体将实现多谱系植入， SCID-X1患者。 具体目的3：评价211 At标记的抗CD 45单克隆抗体用于克服输血诱导的 致敏和随后的移植物排斥反应在一个良好建立的DLA-相同的HCT模型。研究将 以确定211 At标记的抗CD 45单抗的最佳剂量， 免疫细胞负责移植物排斥反应，并始终建立供体造血细胞的植入 毒性最小。 具体目的4：离体扩增的DLA-相同的造血干细胞以促进移植后的植入 211 At非清髓性预处理。在移植物抗宿主病的发展中， 非恶性疾病患者。这个目标将探索使用RIT移植非常高的数字的能力 扩增的干细胞（在项目3中开发）作为T细胞耗尽的同种异体HCT的模型。