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.

抽象的 长期以来，人们一直在寻求针对 CD33 的疗法来改善急性髓系白血病 (AML) 的预后。 CD33 单克隆抗体 (mAb)-药物偶联物吉妥珠单抗奥佐米星 (GO) 可延长生存期 然而，CD33 是一个具有挑战性的目标：几种药物在临床上失败了，但也受益了。 GO 仅限于 AML 患者亚群，这是一个可能的缺点，几乎所有针对 CD33 的药物， 包括 GO 在内的实验室识别出 CD33 的膜远端 V 型结构域作为新疗法的基础。 该部门主任（Roland B. Walter，医学博士、博士、硕士）提出了新的全人单克隆抗体，不仅针对 V- set 结构域以及 CD33 的近膜 C2-set 结构域，后者显示出增强的效应细胞； 功能并针对所有天然存在的 CD33 变体（即“CD33PAN”mAb）。 沃尔特实验室将进行良好控制的体外和体内机制研究，以优化 CD33靶向治疗的有效性和安全性，以及患者应用的明确目标。 我们在使用发射α粒子的放射性同位素砹211 (211At) 的放射免疫治疗 (RIT) 方面所做的努力， 利用 AML 细胞精致的放射敏感性、211At 的高效力和靶细胞选择性，以及我们的 将基于 211At 的 RIT 从实验室带到临床的机构基础设施和专业知识，因为 CD33。 也显示在正常血细胞上，CD33 靶向药物会引起显着的“靶向、脱靶 AML 细胞”毒性， 因此，在我们努力最大化骨髓抑制的同时，最显着的是长期、深度的骨髓抑制。 为了提高CD33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细胞 来自这些药物的造血干细胞和祖细胞，以扩大其治疗窗口并利用它们 研究专家 George S. Laszlo 博士自 Walter 实验室成立以来一直是该实验室的成员。 2010年，他负责所有技术人员的培训、指导和监督以及 开发和验证所有实验方法、途径、测定以及所有的生成 工具/试剂共同为 NCI 支持的优化 CD33-研究项目奠定了基础 定向治疗以及沃尔特实验室参与的其他几个由 NIH 支持的研究项目。 Laszlo 博士和 Walter 博士共发表了 22 篇经过同行评审的联合出版物（其中 9 篇以 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，Laszlo 博士对于我们的开展至关重要。 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疗法的表征、基因工程细胞的开发 用于药物测试的基于线路的工具，以及针对人类 AML 细胞的药物功效的体内评估。 Laszlo 博士的技能和专业知识对于我们开发新的、有效的 CD33 靶向药物的努力是不可或缺的 简化药物流程，造福 AML 和其他 CD33+ 疾病患者，目前对他们而言 治疗常常无效。