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

• 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
• 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

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.

摘要 长期以来，人们一直在寻求靶向CD 33的治疗以改善急性髓性白血病（AML）的结局。 使用CD 33单克隆抗体（mAb）-药物偶联物吉妥珠单抗（GO）的生存期更长 验证了这种方法。然而，CD 33是一个具有挑战性的目标：几种药物在临床上失败， G 0仅限于AML患者亚群。作为一个可能的缺点，几乎所有的CD 33导向药物， 包括GO，识别CD 33的膜远端V-set结构域。作为新疗法的基础，实验室 单位主任（罗兰B。Walter，MD PhD MS）已经提出了新的，完全人类的mAb，不仅针对V- 集结构域，但也近膜C2集结构域的CD 33;后者显示增强效应细胞 功能并靶向所有天然存在的CD 33变体（即，是“CD 33 PAN”mAb）。有了这些单克隆抗体 可用，沃尔特实验室将进行良好的控制机制，在体外和体内研究，以优化 CD 33靶向治疗的有效性和安全性，明确患者应用目标。我们将主要关注 我们在放射免疫疗法（RIT）上的努力是使用α粒子发射放射性同位素<$-211（211 At）， 利用AML细胞的灵敏放射敏感性，211 At的高效力和靶细胞选择性，以及我们的 将基于211 At的RIT从实验室带到临床的机构基础设施和专业知识。因为CD 33 也显示在正常血细胞上，CD 33靶向药物引起显著的“靶向，非AML细胞”毒性， 最明显的是长期的严重骨髓抑制因此，在我们努力最大限度地提高 为了提高CD 33靶向治疗的疗效，我们还在开发新的基因编辑方法来保护正常的 从这些药物中提取造血干细胞和祖细胞，以拓宽其治疗窗口， 更安全研究专家，乔治S。Laszlo博士自Walter实验室成立以来一直是其成员 2010年他一直负责培训，指导和监督所有技术人员以及 开发和验证所有实验方法、途径、测定，并生成所有 这些工具/试剂共同为NCI支持的优化CD 33的研究计划奠定了基础。 定向治疗以及沃尔特实验室参与的其他几个NIH支持的研究项目。一 Laszlo博士和Walter之间共有22篇同行评审的联合出版物（9篇Laszlo博士为第一作者） 记录他们富有成效的工作关系。在接下来的5年里，拉兹洛博士将对我们的行为至关重要。 本申请中描述的研究，在生成、生产、纯化和 重组单克隆抗体和衍生治疗剂的表征，基因工程细胞的开发 用于药物检测的线基工具，以及针对人AML细胞的药物效力的体内评估。与 他的技能和专业知识，Laszlo博士将是我们努力开发新的，有效的CD 33靶向治疗不可或缺的。 在一个流线型的过程中的药物的利益与AML和其他CD 33+疾病的患者，为他们目前 治疗通常是无效的。