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.

摘要 长期以来，放射性标记的单抗(MAbbs)一直被用来改善慢性粒细胞白血病患者的预后。 急性髓系白血病(AML)和骨髓增生异常综合征(MDS)，因为肿瘤髓系细胞是 对电离辐射极其敏感。特别令人感兴趣的是发射放射性核素的阿尔法粒子，如 At-211(211At)，因为它们只在几个细胞直径上提供非常高的辐射量。有了这个，他们 以最小的脱靶毒性实现高效、精确和高效的靶细胞杀伤。考虑到它的半衰期为7.2 小时，211At是患者应用的理想选择。到目前为止，阿尔法发射体主要与单抗一起使用。 CD45或CD33适用于AML/MDS。然而，这些抗原广泛地显示在正常细胞上，包括驻留的细胞 在骨髓外，这种方法的抗肿瘤效果受到限制，因为它限制了多少辐射。 可以安全地运送。此外，当用于增强红细胞压积时，CD45和CD33导向 放射免疫疗法(RITs)需要与条件疗法一起给予，这通过 它们本身可能没有多少额外的抗白血病活性，但却是确保异基因造血所必需的 干细胞(HSC)植入。相对于以CD45或CD33为目标的RIT，我们假设基于211At的RIT 靶向试剂盒(CD117)，一种受体酪氨酸激酶，对细胞的增殖、存活和分化至关重要 造血细胞，将是有效治疗AML/MDS的更精确的方法，所需的费用大大减少 在异体血细胞移植的背景下使用时，存在非癌细胞毒性的风险和更高的安全性。支持这一点 据认为，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在一组更离散的正常细胞上表达， 使其成为治疗AML/MDS的高度合适的免疫治疗靶点。是什么让CD117成为靶子 对AML或MDS患者特别有吸引力-这两种疾病都是根治性治疗策略 常规包括同种异体HCT-抗CD117单抗是否有效地耗尽内源性HSCs并允许 异基因造血干细胞在免疫缺陷小鼠体内的植入。联合低剂量照射，抗CD117单抗 还提供有效的调节和持久的供体来源的HSC在免疫活性动物中的植入。 因此，我们设想211At-CD117RIT可以最大限度地减少或不需要额外的条件作用 治疗使异基因血细胞移植成为可能。在这里，我们建议进行原则证明研究，以测试2个核心 我们假设的组成部分，即白血病细胞的有效辐射和同种异体HSC的易化 用211At-CD117RIT植入，使用合适的免疫缺陷和免疫活性小鼠模型。vt.在.的基础上 随着拟议研究的完成，我们预计我们将对211如何- 标记的抗CD117单抗最适合用于治疗AML/MDS。这一知识将指导进一步的发展 这一方法的临床应用。