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）：尽管结合化疗和同种异体干细胞移植（SCT），尽管急性髓性白血病（AML）目前杀死了大多数患者。放射标记的抗CD45单克隆抗体（AB）已证明可以改善SCT环境中AML的预后，但是毒性保持较高，治愈率均优于优势。该研究建议的目的是使用针对CD45细胞抗原的放射免疫疗法（RIT）提高AML的治愈率。在AIM 1中，我们将使用直接标记的抗MCD45 AB（30F11）与预先靶向的RIT进行比较常规RIT的优点，并使用30F11-链霉亲素（SA）结合物进行了预先定位的RIT，然后是131i，177lu或90y标记的Dota-biotin。研究将在合成鼠白血病模型（SJL/J）中进行，其中AML细胞和正常造血细胞表达MCD45。在AIM 2中，我们将在4种不同的AML模型中比较有效的？发射器（213BI，211AT，225AC）的体内生物分布和辐射剂量法（213BI，211AT，225AC）。两种模型靶向HCD45在人类AML细胞（HEL）上，具有基因工程的BC8 SCFV4SA抗HCD45融合蛋白，我们最终希望将其用于预先构成RIT的临床试验中。其他两种模型使用抗MCD45抗体-SA结合物靶向具有最小疾病（注射AML后2天）或晚期疾病（注射AML后2天）的SJL/J小鼠的鼠AML细胞。在AIM 3中，我们将比较有能力发射放射性核素的治疗功效和预定的？在AIM 2中描述的4个小鼠模型中，发射放射性同位素（213Bi 211at，225AC）。在AIM 4中，我们将使用预先定位的细胞毒性化学疗法研究组合疗法？ - 或？在AML的传播模型中使用？或？发射放射性核素，或两者兼而有之。我们假设该提案中定义的“有能力”的RIT策略将扩大输送到AML细胞的辐射量，减少传递给肝脏，肺部和其他正常器官的辐射，改善缓解和治愈速率，延长的生存率，并显着减轻与传统RIT相比的毒性。我们预计，这些临床前实验的结果可以快速地转换为我们针对AML的临床RIT计划。 公共卫生相关性：急性骨髓性白血病（AML）在13,290名美国人中发展，尽管接受化学疗法和干细胞移植治疗，但每年杀死其中8,820人。在这个项目中，我们计划通过将放射性核素靶向在AML上表达的CD45抗原来提高AML的治疗速率。尽管该赠款专门针对AML，但正在开发的治疗也可以应用于其他表达CD45的恶性肿瘤，包括其他类型的白血病，脊髓增生性倍增加性和非霍奇金淋巴瘤，每年影响超过12万美国人。