Combining Targeted RIT and Synergistic Novel Agents to Eradicate AML

项目摘要/摘要 急性髓系白血病(AML)的潜在治疗方法仅限于全身强化治疗 化疗加或不加异基因骨髓移植(BMT)。然而，并不是每个病人都是 健康到足以耐受强化治疗，并不是每个患者都有合适的人类白细胞抗原匹配的干细胞 细胞捐献者，特别是少数民族患者。目标特工最近已被批准 治疗AML，但这些通常需要密集的全身化疗来优化疗效。此外，AML 在基因上是异质性的，具有明显的基因突变和染色体变化，这使得靶向- 单一药物疗法不太可能治愈。像大多数血液系统恶性肿瘤一样，急性髓细胞白血病对 放射治疗，但即使是涉及的现场辐射也可能毒性太大，对全身播散性辐射无效 疾病。然而，放射免疫疗法(RIT)通过使用单抗来减轻靶外毒性。 与放射性同位素结合，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，使用90Y和131I标记的抗CD45抗体靶点的RIT 对白血病部位的辐射，同时将对未受影响的器官的辐射降至最低。我们已经改进了我们的 通过瞄准更高能量的阿尔法发射的放射性核素而不增加毒性的方法(Atatine-211； 211At)，并通过使用双特异性抗体开发预靶向RIT(PRIT)方法 目标是CD45和90Y-DOTA。 利用临床前小鼠模型，我们现在建议确定211At-和90Y-抗-TdR的协同组合 CD45RIT与干扰DNA修复或促进细胞凋亡的新型靶向治疗。我们将在以下时间完成这项工作 首次评估用于反辐射的α或β放射性核素(~(211)At和~(90)Y)之间的协同作用 CD45与新近批准的靶向药物(PARP和BCL2抑制剂)在两者中直接标记RIT 播散性同基因和异种移植白血病小鼠模型。二是提高疗效。 以CD45和90Y-DOTA为靶点的双特异性抗体构建及其协同作用的研究 靶向治疗(PARP和BCL2抑制剂)在白血病小鼠模型中的应用。我们将描述其程度 用这两种方法获得的DNA损伤作为阐明疗效机制的一种手段。 最后，我们将比较这两种方法作为异基因骨髓移植前条件处理的一部分。 半相合或部分匹配的捐献者，因为所有患者都应该有半相合的捐赠者。 考虑到我们为NIH资助的基础设施和 药物赞助的临床试验，在骨髓移植前使用抗CD45RIT治疗 侵袭性血液系统恶性肿瘤。这些研究将增加有效的、耐受性良好的治疗方案 通过确定靶向药物与抗CD45 RIT方法的协同组合治疗AML患者 并通过在半相合BMT之前识别最佳RIT方法。

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.