Combining Targeted RIT and Synergistic Novel Agents to Eradicate AML

结合靶向 RIT 和协同新型药物来根除 AML

• 批准号: 10601287
• 负责人: Johnnie Jose Orozco
• 金额: $ 69.67万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601287
• 关键词: Combining; Targeted; RIT; Synergistic; Novel

PROJECT SUMMARY/ABSTRACT Potentially curative treatments for acute myeloid leukemia (AML) are limited to intensive systemic chemotherapy with or without allogeneic bone marrow transplantation (BMT). However, not every patient is healthy enough to tolerate intensive treatments, and not every patient may have a suitably HLA-matched stem cell donor, especially patients from ethnic minority groups. Targeted agents have recently been approved to treat AML, but these usually require intensive systemic chemotherapy to optimize efficacy. Furthermore, AML is genetically heterogeneous with distinct genetic mutations and chromosomal alterations that makes targeted- agent monotherapy unlikely to be curative. AML, like most hematologic malignancies, is very sensitive to radiation therapy but even involved field radiation may be too toxic and ineffective for disseminated systemic disease. However, radioimmunotherapy (RIT) mitigates the off-target toxicity by using monoclonal antibodies conjugated to radioactive isotopes to deliver radiation payloads directly to sites of disease by virtue of the antibody specificity. We have shown that RIT using 90Y- and 131I-radiolabeled anti-CD45 antibody targets radiation to sites of leukemia while minimizing radiation to uninvolved organs. We have improved upon our approach without increasing toxicity by targeting higher energy alpha-emitting radionuclides (astatine-211; 211At) to sites of disease and by developing a pre-targeted RIT (PRIT) approach using bispecific antibodies targeting CD45 and 90Y-DOTA. Using preclinical murine models, we now propose to identify synergistic combinations of 211At- and 90Y-anti- CD45 RIT with novel targeted therapies that interfere with DNA repair or promote apoptosis. We will do this by first assessing for synergy between alpha- or beta-emitting radionuclides (211At- and 90Y-) employed in anti- CD45 directly labeled RIT with recently approved targeted agents (PARP and BCL2 inhibitors) in both disseminated syngeneic and xenograft leukemia murine models. Second, we will improve therapeutic efficacy of anti-CD45 PRIT via bispecific antibody constructs targeting CD45 and 90Y-DOTA by assessing for synergy with targeted therapies (PARP and BCL2 inhibitors) in leukemia murine models. We will characterize the extent of DNA damage achieved with these two approaches as a means to elucidate the mechanism of efficacy. Finally, we will compare these two approaches as part of conditioning prior to allogeneic BMT using haploidentical, or partially matched donors, as all patients should have haploidentical donors. These preclinical studies should readily translate into clinical trials given our infrastructure for NIH funded and pharmaceutical-sponsored clinical trials, using anti-CD45 RIT prior to bone marrow transplantation for aggressive hematologic malignancies. These studies will add effective, well-tolerated treatment options for patients with AML by identifying synergistic combinations of targeted agents with anti-CD45 RIT approaches and by identifying the optimal RIT approach prior to haploidentical BMT.

项目概要/摘要 急性髓系白血病 (AML) 的潜在治愈方法仅限于强化全身治疗 化疗联合或不联合同种异体骨髓移植（BMT）。然而，并不是每个患者都 健康状况足以耐受强化治疗，并且并非每个患者都可能拥有适当的 HLA 匹配干细胞 细胞捐赠者，尤其是来自少数族裔的患者。靶向药物最近已被批准用于 治疗 AML，但通常需要强化全身化疗才能优化疗效。此外，反洗钱 具有遗传异质性，具有独特的基因突变和染色体改变，使得靶向 单一药物治疗不太可能治愈。与大多数血液系统恶性肿瘤一样，AML 对以下因素非常敏感： 放射治疗，但即使涉及现场放射也可能毒性太大且对播散性全身无效 疾病。然而，放射免疫疗法（RIT）通过使用单克隆抗体减轻脱靶毒性 与放射性同位素结合，通过以下方式将辐射有效载荷直接传递到疾病部位： 抗体特异性。我们已经证明，RIT 使用 90Y 和 131I 放射性标记的抗 CD45 抗体靶标 对白血病部位进行辐射，同时最大限度地减少对未受累器官的辐射。我们已经改进了我们的 通过瞄准更高能量的α发射放射性核素（砹-211； 211At) 到疾病部位，并使用双特异性抗体开发预靶向 RIT (PRIT) 方法 针对 CD45 和 90Y-DOTA。 使用临床前小鼠模型，我们现在建议确定 211At- 和 90Y-anti-的协同组合 CD45 RIT 具有干扰 DNA 修复或促进细胞凋亡的新型靶向疗法。我们将通过以下方式做到这一点 首先评估用于抗-治疗的α或β发射放射性核素（211At-和90Y-）之间的协同作用 CD45 直接标记 RIT 与最近批准的靶向药物（PARP 和 BCL2 抑制剂） 播散性同基因和异种移植白血病小鼠模型。二、提高治疗效果 通过评估协同作用，通过靶向 CD45 和 90Y-DOTA 的双特异性抗体构建体来制备抗 CD45 PRIT 在白血病小鼠模型中使用靶向治疗（PARP 和 BCL2 抑制剂）。我们将描述程度 通过这两种方法造成的 DNA 损伤，作为阐明功效机制的一种手段。 最后，我们将比较这两种方法，作为同种异体 BMT 之前调理的一部分，使用 单倍体相合或部分匹配的供体，因为所有患者都应有单倍体相合的供体。 考虑到我们的 NIH 资助和基础设施，这些临床前研究应该很容易转化为临床试验。 药物赞助的临床试验，在骨髓移植前使用抗 CD45 RIT 侵袭性血液恶性肿瘤。这些研究将为以下疾病增加有效、耐受性良好的治疗选择： 通过确定靶向药物与抗 CD45 RIT 方法的协同组合来治疗 AML 患者 并在半相合 BMT 之前确定最佳 RIT 方法。