CD45 Pretargeted Radioimmunotherapy for AML

CD45 预靶向放射免疫疗法治疗 AML

• 批准号: 7783781
• 负责人: Oliver W. Press
• 金额: $ 30.33万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783781
• 关键词: 90Y; Acetylgalactosamine; Acute Myelocytic Leukemia; Affect; Allogenic; American; Antibodies; Antigens; Attenuated; Biodistribution; Biotin; CD45 Antigens; Cells; Chimeric Proteins; Clinical; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Cytotoxic Chemotherapy; DOTA-biotin; Disease; Disease model; Disease remission; Dysmyelopoietic Syndromes; Effectiveness; Elements; Engineering; Funding; Grant; Granulocyte Colony-Stimulating Factor; Guidelines; Hematopoietic; Human; Injection of therapeutic agent; Isotopes; Label; Leukemic Cell; Liver; Lung; Macaca; Malignant Neoplasms; Methods; Modeling; Modification; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Normal Cell; One-Step dentin bonding system; Organ; Outcome; PTPRC gene; Palpable; Patients; Pilot Projects; Process; Production; Radiation; Radioactivity; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radiometry; Recombinants; Relapse; Relative (related person); Research Proposals; Residual Neoplasm; SCID Mice; SJL/J Mouse; Safety; Splenectomy; Stem cell transplant; Streptavidin; Testing; Therapeutic; Toxic effect; Translations; Transplantation; Treatment Efficacy; United States National Institutes of Health; Xenograft Model; Xenograft procedure; abstracting; advanced disease; biotin 2; cell bank; chemotherapy; clinically relevant; dosimetry; high risk; improved; in vivo; keratinocyte growth factor; killings; leukemia; mouse model; pre-clinical; programs; public health relevance; radiotracer; research study

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) currently kills the majority of afflicted patients despite treatment with combination chemotherapy and allogeneic stem cell transplantation (SCT). Radiolabeled anti- CD45 monoclonal antibodies (Ab) have been shown to improve outcomes for AML in the setting of SCT, but toxicity remains high and cure rates are suboptimal. The objective of this research proposal is to improve the cure rate of AML using radioimmunotherapy (RIT) targeting the CD45 cell antigen. In Aim 1, we will compare the merits of conventional RIT using a directly radiolabeled anti-mCD45 Ab (30F11) with pretargeted RIT using a 30F11-streptavidin (SA) conjugate, followed by 131I, 177Lu or 90Y-labeled DOTA-biotin. Studies will be done in a syngeneic murine leukemia model (SJL/J) in which both AML cells and normal hematopoietic cells express mCD45. In Aim 2, we will compare the in vivo biodistribution and radiation dosimetry of pretargeted ?-emitters (213Bi, 211At, 225Ac) with 2-emitting radionuclides in 4 different AML models. Two models target hCD45 on human AML cells (HEL) with a genetically engineered BC8 scFv4SA anti-hCD45 fusion protein that we eventually hope to use in clinical trials of pretargeted RIT. The other 2 models target mCD45 on murine AML cells in SJL/J mice with either minimal disease (2 days after injection of AML) or advanced disease (23 days after injection of AML) using an anti-mCD45 antibody-SA conjugate. In Aim 3 we will compare the therapeutic efficacy of pretargeted ??emitting radionuclides with pretargeted ? emitting radioisotopes (213Bi 211At, 225Ac) in the 4 mouse models described in Aim 2. In Aim 4 we will investigate combination therapy using cytotoxic chemotherapy with either pretargeted ?- or ?-emitting radionuclides, or both, in a disseminated model of AML. We hypothesize that the "pretargeted" RIT strategies defined in this proposal will amplify the amount of radiation delivered to AML cells, decrease the radiation delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and markedly attenuate toxicities compared to conventional RIT. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for AML. PUBLIC HEALTH RELEVANCE: Acute myelogenous leukemia (AML) develops in 13,290 Americans and kills 8,820 of them each year despite treatment with chemotherapy and stem cell transplantation. In this project, we plan to improve the cure rate of AML by targeting radionuclides to the CD45 antigen expressed on AML. Although this grant is specifically focused on AML, the treatment being developed can also be applied to other CD45-expressing malignancies, including other types of leukemia, myelodysplasia, and non-Hodgkin's lymphoma, that affect a total of more than 120,000 Americans each year.

描述（由申请人提供）：尽管采用联合化疗和同种异体干细胞移植（SCT）治疗，但目前大多数患者仍死于急性髓性白血病（AML）。放射性标记的抗 CD45 单克隆抗体 (Ab) 已被证明可以改善 SCT 中 AML 的治疗结果，但毒性仍然很高，治愈率也不佳。本研究提案的目的是利用针对 CD45 细胞抗原的放射免疫疗法 (RIT) 提高 AML 的治愈率。在目标 1 中，我们将比较使用直接放射性标记的抗 mCD45 Ab (30F11) 的传统 RIT 与使用 30F11-链霉亲和素 (SA) 缀合物，然后使用 131I、177Lu 或 90Y 标记的 DOTA-生物素的预靶向 RIT 的优点。研究将在同基因小鼠白血病模型（SJL/J）中进行，其中 AML 细胞和正常造血细胞均表达 mCD45。在目标 2 中，我们将在 4 个不同的 AML 模型中比较预靶向 β 发射体（213Bi、211At、225Ac）与 2 发射放射性核素的体内生物分布和辐射剂量测定。两个模型使用基因工程 BC8 scFv4SA 抗 hCD45 融合蛋白靶向人类 AML 细胞 (HEL) 上的 hCD45，我们最终希望将其用于预靶向 RIT 的临床试验。另外 2 个模型使用抗 mCD45 抗体-SA 缀合物，将 mCD45 靶向患有轻度疾病（注射 AML 后 2 天）或晚期疾病（注射 AML 后 23 天）的 SJL/J 小鼠的小鼠 AML 细胞上的 mCD45。在目标 3 中，我们将比较预靶向发射放射性核素与预靶向发射放射性核素的治疗效果。在目标 2 中描述的 4 种小鼠模型中发射放射性同位素（213Bi、211At、225Ac）。在目标 4 中，我们将在 AML 播散性模型中研究使用细胞毒性化疗与预靶向 β 或 β 发射放射性核素或两者的联合治疗。我们假设，该提案中定义的“预先靶向”RIT策略将放大输送到AML细胞的辐射量，减少输送到肝脏、肺和其他正常器官的辐射，提高缓解和治愈率，延长生存期，并显着提高患者的生存率。与传统 RIT 相比，可减轻毒性。我们预计这些临床前实验的结果将快速转化为我们的 AML 临床 RIT 计划。 公共卫生相关性：尽管接受化疗和干细胞移植治疗，但每年仍有 13,290 名美国人患上急性髓性白血病 (AML)，并导致 8,820 人死亡。在这个项目中，我们计划通过将放射性核素靶向AML表达的CD45抗原来提高AML的治愈率。尽管这笔拨款专门针对 AML，但正在开发的治疗方法也可应用于其他表达 CD45 的恶性肿瘤，包括其他类型的白血病、骨髓增生异常和非霍奇金淋巴瘤，这些疾病每年影响超过 120,000 名美国人。