Optimizing the Efficacy and Safety of CD33-Targeted Immunotherapy for Acute Myeloid Leukemia and Other CD33+ Disorders

优化 CD33 靶向免疫疗法治疗急性髓系白血病和其他 CD33 疾病的疗效和安全性

基本信息

批准号：
10733379
负责人：
GEORGE S LASZLO
金额：
$ 16.19万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733379
关键词：
Acute Myelocytic Leukemia Alpha Particles Antibodies Antibody-drug conjugates Astatine Binding Biological Assay Blood Cells Cell Line Cell physiology Cells Clinical Development Disease Distal Doctor of Philosophy Drug Targeting Effector Cell Foundations Gemtuzumab Ozogamicin Generations Genes Goals Hematopoietic Neoplasms Hematopoietic stem cells Human Immunotherapy In Vitro Infrastructure Institution Joints Laboratories Lead Membrane Methodology Monoclonal Antibodies Myelosuppression Patients Peer Review Pharmaceutical Preparations Process Production Publications Radiation Tolerance Radioimmunotherapy Radioisotopes Reagent Recombinants Research Research Project Grants Research Support SET Domain Safety Specialist Supervision Therapeutic Therapeutic Monoclonal Antibodies Toxic effect Training United States National Institutes of Health Validation Variant Work acute myeloid leukemia cell bench to bedside drug efficacy drug testing genetically modified cells human monoclonal antibodies improved outcome in vivo interest member novel novel therapeutics patient subsets programs skills targeted treatment therapeutic target tool

项目摘要

ABSTRACT Therapies targeting CD33 have long been pursued to improve outcomes in acute myeloid leukemia (AML). Longer survival with the CD33 monoclonal antibody (mAb)-drug conjugate gemtuzumab ozogamicin (GO) validates this approach. However, CD33 is a challenging target: several drugs have failed clinically, and benefit with GO is restricted to AML patient subsets. As one possible shortcoming, almost all CD33-directed drugs, including GO, recognize the membrane-distal V-set domain of CD33. As a basis for new therapies, the laboratory of the Unit Director (Roland B. Walter, MD PhD MS) has raised new, fully human mAbs not only against the V- set domain but also the membrane-proximal C2-set domain of CD33; the latter show enhanced effector cell functions and target all naturally occurring CD33 variants (i.e., are “CD33PAN” mAbs). With these mAbs now available, the Walter Lab will conduct well-controlled mechanistic in vitro and in vivo studies to optimize the efficacy and safety of CD33-targeted therapy, with the explicit goal of patient application. We will primarily focus our efforts on radioimmunotherapy (RIT) with the alpha particle emitting radioisotope astatine-211 (211At), leveraging the exquisite radiosensitivity of AML cells, the high potency and target cell selectivity of 211At, and our institutional infrastructure and expertise in bringing 211At-based RIT from the bench to the clinic. Because CD33 is also displayed on normal blood cells, CD33-targeted drugs cause significant “on-target, off-AML cell” toxicity, most notably prolonged, profound myelosuppression. Therefore, in parallel to our work on maximizing the efficacy of CD33-targeted therapy, we are also developing novel gene editing approaches to protect normal hematopoietic stem and progenitor cells from these drugs to widen their therapeutic window and make their use safer. The Research Specialist, George S. Laszlo, PhD, has been a member of the Walter Lab since its inception in 2010. He has been responsible for the training, guidance, and supervision of all technicians as well as the development and validation of all experimental methodologies, approaches, assays, and generation of all tools/reagents that, together, built the foundation for the NCI-supported research program on optimizing CD33- directed therapy as well as several other NIH-supported research projects that the Walter Lab is involved in. A total of 22 peer-reviewed joint publications between Drs. Laszlo and Walter (9 with Dr. Laszlo as first author) document their fruitful work relationship. Over the next 5 years, Dr. Laszlo will be essential for the conduct of our studies described in this application, with key roles in the generation, production, purification, and characterization of recombinant mAbs and derived therapeutics, the development of genetically engineered cell line-based tools for drug testing, and the in vivo assessment of drug efficacies against human AML cells. With his skills and expertise, Dr. Laszlo will be indispensable for our efforts to develop new, efficacious CD33-targeted drugs in a stream-lined process for the benefit of patients with AML and other CD33+ disorders, for whom current therapies are often ineffective.

抽象的长期以来一直在追求针对CD33的疗法以改善急性髓样白血病（AML）的预后。 CD33单克隆抗体（MAB） - 药物缀合物gemtuzumab ozogamicin（GO）的生存更长验证这种方法。但是，CD33是一个挑战目标：几种药物在临床上失败并受益使用GO仅限于AML患者子集。作为一个可能的缺点，几乎所有CD33定向药物，包括GO，识别CD33的膜距离V-SET域。作为新疗法的基础，实验室单位主任（Roland B. Walter，MD博士MS）的培训不仅为V-提出了新的，完全的mabs 设定域，也是CD33的膜膜C2-set域；后者显示出增强的效应细胞函数和目标所有天然存在的CD33变体（即“ CD33PAN” mAb）。现在使用这些mabs 沃尔特实验室（Walter Lab）可用，将在体外和体内进行良好控制的机械性研究，以优化 CD33靶向治疗的功效和安全性，具有患者应用的明确目标。我们将主要集中精力我们在放射性免疫疗法（RIT）方面的努力与Alpha粒子发射放射性同位素助理211（211AT），利用AML细胞的独家放射敏性，高效力和目标细胞的选择性211AT以及我们的机构基础设施和专业知识将基于211的RIT从板凳带到诊所。因为CD33 也显示在正常血细胞上，CD33靶向药物会引起明显的“靶向，非AML细胞”毒性，最值得注意的是延长，深刻的骨髓抑制。因此，与我们最大化的工作并行 CD33靶向治疗的有效性，我们还在开发新型的基因编辑方法来保护正常造血茎和祖细胞从这些药物扩大其治疗窗口并使用更安全。研究专家乔治·S·拉斯洛（George S. 在2010年。他负责所有技术人员的培训，指导和监督所有实验方法，方法，测定和生成的开发和验证工具/试剂共同为NCI支持的研究计划建立了基础，以优化CD33-- 沃尔特实验室参与的定向疗法以及其他几项由NIH支持的研究项目。 DR之间共有22个同行评审的联合出版物。 Laszlo和Walter（9与Laszlo博士为第一作者）记录他们富有成果的工作关系。在接下来的5年中，Laszlo博士对于我们的行为至关重要在本应用中描述的研究，在发电，生产，纯化和重组mAB和衍生疗法的表征，开发一般工程细胞的发展基于线的药物测试工具，以及对人AML细胞的药物效率的体内评估。和他的技能和专业知识，Laszlo博士对于我们开发新的，有效的CD33目标的努力将是必不可少的在溪流过程中的药物，以使AML和其他CD33+疾病患者受益，目前疗法通常无效。