Radioimmunotherapy of CD20+ Lymphomas & CD45+Leukemias

CD20淋巴瘤的放射免疫治疗

基本信息

批准号：
7488312
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/7488312
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) 进行放射免疫疗法 (RIT) 可诱导 50-90% 的复发性淋巴瘤 (NHL) 患者缓解；然而，大多数患者最终死于复发性淋巴瘤。我们的小组已经记录了在急性髓性白血病 (AML) 的同种异体干细胞移植 (SCT) 中施用放射性标记的抗 CD45 单克隆抗体的前景，但毒性仍然很高，并且对于患有以下疾病的患者来说，治愈率仍然仅为 60-65%使用直接放射性标记的抗 CD45 Ab 和 SCT，新诊断的 AML 在第一次完全缓解 (CR) 时进行移植，20-30% 的复发 AML 进行移植。由于血液中放射性标记抗体的循环半衰期较长，RIT 的功效目前受到正常组织非特异性辐射的限制。该提案的主要目标是开展学术研究生涯，开发创新方法使用两步链霉亲和素 (SA)-生物素预靶向策略优化 RIT 的功效，分别靶向 NHL 和 AML 肿瘤细胞表面的抗 CD20 和抗 CD45 抗原。在目标 1 中，我们将比较和对比直接放射性标记的抗 CD20 Ab (1F5) 和使用抗 CD20 四价单链 (scFv)4SA 融合蛋白随后递增剂量的预靶向 RIT 获得的药代动力学、肿瘤定位和治疗效果放射性标记的 DOTA-生物素在小鼠淋巴瘤异种移植和播散性淋巴瘤移植模型中的应用。在 Dim 2 中，我们将比较使用常规 RIT 进行放射性标记抗人 (h)CD45 Ab 治疗的白血病小鼠的药代动力学、肿瘤定位和治疗效果，以及使用非放射性标记抗 hCD45 优化的两步预靶向 KIT（ scFv)4SA 随后是 90y-DOTA-生物素。在目标 3 中，我们将在小鼠同基因白血病模型中评估抗 CD45 预靶向的毒性，其中靶抗原同时存在于白血病细胞和正常造血组织上。在目标 4 中，我们将进行一项 I 期临床研究，以调查预靶向 KIT 对于复发性惰性 NHL 或套细胞 NHL 患者的可行性、耐受性和潜在疗效。我们假设，与使用直接放射性标记抗体的传统 RIT 方案相比，使用抗 CD20 (scFv)4SA 和抗 CD45 (scFv)4SA 融合蛋白特异性针对恶性细胞进行放射靶向治疗将增强疗效并降低治疗毒性。我们预计这些干预措施最终将通过提高缓解率和生存率来改善复发性淋巴瘤和晚期 AML 患者的预后，同时最大限度地减少毒性。