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

摘要 放射性标记的单克隆抗体（mAb）长期以来一直被用于改善患有以下疾病的患者的结果： 急性骨髓性白血病（AML）和骨髓增生异常综合征（MDS），因为肿瘤性骨髓细胞是 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， 他们提供了一个非常高的辐射量在几个细胞直径。有了这个，他们 能够以最小的脱靶毒性高效、精确和有效地杀死靶细胞。鉴于其半衰期为7.2 小时，211 At是患者应用的理想选择。到目前为止，α-发射体主要与单克隆抗体一起使用， CD 45或CD 33用于AML/MDS。然而，这些抗原在正常细胞上的广泛展示，包括细胞驻留， 在骨髓空间之外，由于它限制了辐射量， 可以安全交付。此外，当用于增加HCT时，CD 45-和CD 33-定向的 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细胞的生长是必需的。 干细胞（HSC）移植。相对于靶向CD 45或CD 33的RIT，我们假设基于211 At的RIT 靶向KIT（CD 117），一种对细胞增殖、存活和分化至关重要的受体酪氨酸激酶， 造血细胞，将是一种更精确的方法，有效地治疗AML/MDS，需要大大减少 当用于同种异体HCT时，具有脱癌细胞毒性的风险和增加的安全性。支持这一 根据这一概念，60-90%的AML患者和大多数MDS患者在其肿瘤细胞上表达CD 117。 然而，与CD 45或CD 33相比，CD 117在一组更加离散的正常细胞上表达， 使其成为治疗AML/MDS的高度合适的免疫靶点。是什么让靶向CD 117 对AML或MDS患者特别有吸引力-这两种疾病的治愈性治疗策略 通常包括同种异体HCT -抗CD 117 mAb有效地耗尽内源性HSC并允许 在免疫缺陷小鼠中移植同种异体HSC。结合低剂量照射，抗CD 117单克隆抗体 还在免疫活性动物中提供有效的调节和持久的供体来源的HSC植入。 因此，我们设想211 At-CD 117 RIT可以在最小化或不需要额外调节的情况下使用 治疗剂以实现同种异体HCT。在这里，我们建议进行原理验证研究，以测试2个核心 我们的假设的组成部分，即有效的白血病细胞辐射和促进同种异体HSC 移植，使用合适的免疫缺陷和免疫活性小鼠模型，用211 At-CD 117 RIT。后 完成拟议的研究，这是我们的期望，我们将获得关键的洞察如何211 At- 标记的抗CD 117单克隆抗体可最好地用于治疗AML/MDS。这些知识将指导进一步的发展 这种方法的临床应用。

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.