Radioimmunotherapy of CD20+ Lymphomas & CD45+Leukemias

CD20淋巴瘤的放射免疫治疗

基本信息

批准号：
7285620
负责人：
JOHN M PAGEL
金额：
$ 13.37万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-10 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7285620
关键词：
90Y 90Y-DOTA-Biotin Acetylgalactosamine Acute Myelocytic Leukemia Adult Lymphoma Affinity Agranulocytosis Allogenic Antibodies Antigen Targeting Autologous Stem Cell Transplantation Avidity B-Cell NonHodgkins Lymphoma Binding Biodistribution Biological Assay Biotin Blood Circulation Body Weight decreased CD20 Antigens CD45 Antigens Cells Chimeric Proteins Clinical Research Clinical Trials DOTA-biotin Disease Disease remission Dissociation Dose Drug Kinetics Elements Engineering Exhibits Grant Half-Life Hematopoietic Hematopoietic Stem Cell Transplantation Hepatic Hour Human I131 isotope Indolent Intervention K-Series Research Career Programs Label Leukemic Cell Liver Localized Lung Lymphoma MS4A1 gene Malignant Neoplasms Marrow Measurement Methods Modality Modeling Monoclonal Antibodies Monoclonal Antibody CD20 Mus Myeloid Leukemia Newly Diagnosed Non-Hodgkin&apos s Lymphoma Normal tissue morphology One-Step dentin bonding system Organ PTPRC gene Patients Phase Phase I Clinical Trials Pilot Projects Radiation Radioactivity Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiolabeled Rate Recombinants Recurrence Relapse Relative (related person)Research Safety Site Solid Neoplasm Standards of Weights and Measures Stem cell transplant Streptavidin Surface Survival Rate System T-Lymphocyte Testing Therapeutic Therapeutic Index Thrombocytopenia Time Toxic effect Transaminases Translating Transplantation Treatment Efficacy Treatment Protocols Xenograft Model Xenograft procedure antigen binding cancer cell career chemical conjugate clinical efficacy cytotoxic dosimetry hematopoietic tissue human study immunogenic improved innovation leukemia leukemia/lymphoma neoplastic cell new technology outcome forecast pre-clinical radiotracer response tumor

项目摘要

Radioimmunotherapy (RIT) using radiolabeled anti-CD20 monoclonal antibodies (Ab) induces remissions in 50-90% of relapsed lymphoma (NHL) patients; however, most patients eventually succumb to recurrent lymphoma. Our group has documented the promise of radiolabeled anti-CD45 monoclonal Abs administered in the setting of allogeneic stem cell transplantation (SCT) for acute myeloid leukemia (AML), but toxicity remains high and cure rates are still only 60-65% for patients with newly diagnosed AML transplanted in first complete remission (CR) and 20-30% for relapsed AML using directly radiolabeled anti-CD45 Ab and SCT. The efficacy of RIT is currently limited by non-specific delivery of radiation to normal tissues, as a result of the long circulating half-life of radiolabeled antibodies in the bloodstream. The primary objective of this proposal is to launch an academic research career developing innovative approaches to optimize the efficacy of RIT using a two-step streptavidin(SA)-biotin pretargeting strategy to target the anti-CD20 and anti-CD45 antigens on the surface of NHL and AML tumor cells, respectively. In Aim 1, we will compare and contrast the pharmacokinetics, tumor localization, and therapeutic efficacies obtained with directly radiolabeled anti-CD20 Ab (1F5) and pretargeted RIT using an anti-CD20 tetravalent single chain (scFv)4SA fusion protein followed by escalating doses of radiolabeled DOTA-biotin in murine lymphoma xenograft and disseminated lymphoma transplant models. In dim 2, we will compare the pharmacokinetics, tumor localization, and therapeutic efficacies of leukemia bearing mice treated with radiolabeled anti-human (h)CD45 Ab using conventional RIT, and optimized two-step pretargeting KIT utilizing non-radiolabeled anti-hCD45 (scFv)4SA followed by 90y-DOTA-biotin. In Aim 3, we will assess the toxicities of anti-CD45 pretargeting in a murine syngeneic leukemia model in which the target antigen is present on both leukemia cells as well as normal hematopoietic tissues. In Aim 4, we will conduct a phase I clinical study to investigate the feasibility, tolerability, and potential efficacy of pretargeted KIT for patients with relapsed indolent NHL or mantle cell NHL. We hypothesize that targeting radiation specifically to malignant cells using anti-CD20 (scFv)4SA and anti-CD45 (scFv)4SA fusion proteins will augment the efficacy and decrease the toxicity of therapy compared with conventional RIT regimens employing directly radiolabeled Abs. We anticipate that these interventions will ultimately enhance the prognosis for patients with relapsed lymphomas and advanced AML by increasing the response and survival rates, while simultaneously minimizing toxicities.

使用放射性标记的抗CD20单克隆抗体（AB）的放射免疫疗法（RIT）可导致50-90％的复发淋巴瘤（NHL）患者的减免；但是，大多数患者最终屈服于复发性淋巴瘤。我们的小组已经记录了在同种异体干细胞移植（SCT）中给予放射性标记的抗CD45单克隆ABS的承诺，用于急性骨髓性白血病（AML），但毒性仍然很高，但对于新诊断的AML的毒性仍然只有60-65％的治疗率，直接诊断为60-65％，并直接诊断出AML的AML和20％（CR）和20％的毒性（CR）（CR）和20％的毒性（CR）（CR）。抗CD45 AB和SCT。由于血液中放射性标记的抗体的长期循环半衰期，RIT的功效目前受到非特异性辐射向正常组织的递送的限制。该建议的主要目的是启动学术研究职业，开发创新方法使用两步链霉亲素（SA） - 生物素预先定位策略来优化RIT的功效，以分别在NHL和AML肿瘤细胞表面靶向抗CD20和抗CD45抗原。 In Aim 1, we will compare and contrast the pharmacokinetics, tumor localization, and therapeutic efficacies obtained with directly radiolabeled anti-CD20 Ab (1F5) and pretargeted RIT using an anti-CD20 tetravalent single chain (scFv)4SA fusion protein followed by escalating doses of radiolabeled DOTA-biotin in murine lymphoma xenograft and传播淋巴瘤移植模型。在DIM 2中，我们将使用常规RIT使用放射性标记的抗人类（H）CD45 AB处理的白血病的药代动力学，肿瘤定位和治疗功效，并使用常规RIT进行了优化，并优化了使用非红外线抗抗抗HCD45（scfa）的两步性预处理（SCFA）4s fy-nin fiby taim fy 90y，biot fy-biout fy-biout fy-nin-niny taka。在AIM 3中，我们将评估在鼠类合成性白血病模型中抗CD45的毒性，其中靶抗原存在于白血病细胞以及正常的造血组织。在AIM 4中，我们将进行一项I期临床研究，以研究有预定剂试剂盒对复发性NHL或地幔细胞NHL患者的可行性，耐受性和潜在功效。我们假设使用抗CD20（SCFV）4SA和抗CD45（SCFV）4SA融合蛋白专门针对恶性细胞靶向辐射，将增强治疗的功效并降低治疗的毒性，与采用直接放射线腹部的常规RIT方案相比。我们预计，这些干预措施最终将通过提高反应和存活率，同时最大程度地减少毒性，最终增强淋巴瘤和晚期AML患者的预后。