CD117-Targeted Radioimmunotherapy with Astatine-211 for Acute Myeloid Leukemia and Myelodysplastic Syndrome

CD117 靶向放射免疫治疗砹 211 治疗急性髓系白血病和骨髓增生异常综合征

• 批准号: 10670383
• 负责人: Roland Bruno Walter
• 金额: $ 23.69万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670383
• 关键词: AML/MDS; Acute Myelocytic Leukemia; Address; Allogenic; Alpha Particles; Animal Model; Animals; Antibodies; Antibody Therapy; Antigens; Astatine; Biodistribution; Biological Models; Blood Cells; Bone Marrow; Cell surface; Cells; Clinical; Coupled; Development; Diagnosis; Diameter; Disease; Dose; Dysmyelopoietic Syndromes; Engraftment; Ensure; Half-Life; Hematological Disease; Hematopoietic System; Hematopoietic stem cells; Hour; Human; Immune; Immunocompetent; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunotherapeutic agent; In Vitro; Ionizing radiation; Knowledge; Label; Learning; Leukemic Cell; Measurable; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Normal Cell; Organ; PTPRC gene; Patient-Focused Outcomes; Patients; Production; Proliferating; Property; Proteins; Proto-Oncogene Protein c-kit; Radiation; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reagent; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Residual Neoplasm; Safety; Stem cell transplant; Testing; Therapeutic; Toxic effect; Transplantation Conditioning; Xenograft procedure; acute myeloid leukemia cell; antileukemic activity; burden of illness; cancer cell; cancer risk; cell killing; cell type; chemotherapy; clinical application; conditioning; curative treatments; expectation; experimental study; hematopoietic cell transplantation; hematopoietic differentiation; improved outcome; in vivo; insight; interest; irradiation; mouse model; multidisciplinary; neoplastic; neoplastic cell; novel; novel therapeutics; pre-clinical; side effect; stem cell engraftment; tumor

ABSTRACT Radiolabeled monoclonal antibodies (mAbs) have long been pursued to improve outcomes for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) because neoplastic myeloid cells are exquisitely sensitive to ionizing radiation. Of particular interest are alpha-particle emitting radionuclides such as astatine-211 (211At) as they deliver a very high amount of radiation over just a few cell diameters. With this, they enable highly potent, precise, and efficient target cell kill with minimal off-target toxicity. Given its half-life of 7.2 hours, 211At is ideal for patient application. So far, alpha-emitters have been primarily used with mAbs against CD45 or CD33 for AML/MDS. However, broad display of these antigens on normal cells, including cells residing outside the bone marrow space, curtails the anti-tumor efficacy of this approach as it limits how much radiation can be safely delivered. Moreover, when used to augment HCT, CD45- and CD33-directed radioimmunotherapies (RITs) need to be given in conjunction with conditioning therapeutics, which by themselves may have little additional anti-leukemia activity but are necessary to ensure allogeneic hematopoietic stem cell (HSC) engraftment. Relative to RIT targeting CD45 or CD33, we hypothesize that 211At-based RIT targeting KIT (CD117), a receptor tyrosine kinase that is crucial for proliferation, survival, and differentiation of hematopoietic cells, will be a more precise approach to effectively treat AML/MDS that entails greatly reduced risks off-cancer cell toxicities and increased safety when used in the context of allogeneic HCT. Supporting this notion, 60-90% of patients with AML, and most patients with MDS, express CD117 on their neoplastic cells. Compared to CD45 or CD33, however, CD117 is expressed on a much more discrete set of normal cells, rendering it a highly suitable immunotherapeutic target to treat AML/MDS. What makes targeting CD117 particularly attractive for patients with AML or MDS – both disorders for which curative therapeutic strategies routinely include allogeneic HCT – is that anti-CD117 mAbs efficiently deplete endogenous HSCs and allow engraftment of allogeneic HSCs in immunodeficient mice. Combined with low-dose irradiation, anti-CD117 mAbs also provide effective conditioning and durable donor-derived HSC engraftment in immunocompetent animals. Thus, we envision 211At-CD117 RIT could be used with minimized or no need for additional conditioning therapeutics to enable allogeneic HCT. Here, we propose to conduct proof-of-principle studies to test the 2 core components of our hypothesis, namely effective leukemia cell eradiation and facilitation of allogeneic HSC engraftment, with 211At-CD117 RIT, using suitable immunodeficient and immunocompetent mouse models. Upon completion of the proposed research, it is our expectation that we will have gained critical insight into how 211At- labeled anti-CD117 mAbs can be best utilized to treat AML/MDS. This knowledge will guide further development of this approach for clinical application.

抽象的 长期以来，人们一直在寻求放射性标记的单克隆抗体（mAb）来改善患有以下疾病的患者的预后： 急性髓系白血病 (AML) 和骨髓增生异常综合征 (MDS)，因为肿瘤性髓系细胞 对电离辐射极其敏感。特别感兴趣的是发射α粒子的放射性核素，例如 astatine-211 (211At)，因为它们仅在几个细胞直径范围内传递非常大量的辐射。以此，他们 能够高效、精确、高效地杀死靶细胞，同时将脱靶毒性降至最低。鉴于其半衰期为 7.2 小时，211At 非常适合患者应用。到目前为止，α发射体主要与单克隆抗体一起使用 CD45 或 CD33 用于 AML/MDS。然而，这些抗原在正常细胞（包括驻留细胞）上广泛展示 在骨髓空间之外，限制了这种方法的抗肿瘤功效，因为它限制了辐射量 可以安全送达。此外，当用于增强 HCT 时，CD45 和 CD33 定向 放射免疫疗法（RIT）需要与调理疗法结合使用， 它们本身可能几乎没有额外的抗白血病活性，但对于确保同种异体造血是必要的 干细胞（HSC）植入。相对于针对 CD45 或 CD33 的 RIT，我们假设基于 211At 的 RIT 靶向 KIT (CD117)，一种受体酪氨酸激酶，对于细胞增殖、存活和分化至关重要 造血细胞，将是有效治疗 AML/MDS 的更精确方法，需要大大减少 在同种异体 HCT 中使用时，存在非癌细胞毒性的风险并增加了安全性。支持这个 概念上，60-90% 的 AML 患者和大多数 MDS 患者的肿瘤细胞上表达 CD117。 然而，与 CD45 或 CD33 相比，CD117 在一组更加离散的正常细胞上表达， 使其成为治疗 AML/MDS 的非常合适的免疫治疗靶点。是什么使得靶向 CD117 对于 AML 或 MDS 患者尤其有吸引力——这两种疾病都有治疗策略 常规包括同种异体 HCT – 抗 CD117 mAb 可有效耗尽内源性 HSC，并允许 将同种异体 HSC 植入免疫缺陷小鼠体内。结合低剂量照射，抗CD117单克隆抗体 还可以在免疫功能正常的动物中提供有效的调理和持久的供体来源的 HSC 移植。 因此，我们设想 211At-CD117 RIT 可以在最少或不需要额外调节的情况下使用 能够进行同种异体 HCT 的疗法。在这里，我们建议进行原理验证研究来测试 2 个核心 我们的假设的组成部分，即有效的白血病细胞根除和同种异体 HSC 的促进 使用合适的免疫缺陷和免疫功能正常的小鼠模型，用 211At-CD117 RIT 进行移植。之上 完成拟议的研究后，我们期望我们能够对 211At- 标记的抗 CD117 mAb 最适合用于治疗 AML/MDS。这些知识将指导进一步的发展 将此方法应用于临床。