Combining Targeted RIT and Synergistic Novel Agents to Eradicate AML

项目总结/摘要 急性髓性白血病（AML）的潜在治愈性治疗仅限于强化全身化疗， 化疗与或不与异基因骨髓移植（BMT）。但并不是每个病人都 健康到足以承受强化治疗，并不是每个患者都有合适的HLA匹配干细胞 特别是来自少数民族的患者。目标代理最近已被批准， 治疗AML，但这些通常需要强化全身化疗以优化疗效。此外，AML 是遗传异质性与不同的基因突变和染色体改变，使目标- 单药治疗不太可能治愈。AML与大多数血液恶性肿瘤一样，对 放射治疗，但即使涉及场辐射可能太毒和无效的弥散性全身 疾病然而，放射免疫治疗（RIT）通过使用单克隆抗体减轻脱靶毒性 与放射性同位素共轭，以通过放射性同位素将放射有效载荷直接递送到疾病部位。 抗体特异性我们已经证明，使用90 Y和131 I放射性标记的抗CD45抗体的RIT靶向 对白血病部位的辐射，同时尽量减少对未受累器官的辐射。我们已经改进了我们的 通过靶向高能α发射放射性核素（<$-211; 211At）至疾病部位，并通过开发使用双特异性抗体的预靶向RIT（PRIT）方法， 靶向CD45和90Y-DOTA。 使用临床前小鼠模型，我们现在提出鉴定211At-和90Y-抗肿瘤药物的协同组合。 CD45 RIT与干扰DNA修复或促进细胞凋亡的新型靶向疗法。我们将通过 第一次评估α或β发射放射性核素（211 At-和90 Y-）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BCL 2抑制剂）， 播散性同基因和异种移植白血病小鼠模型。二是提高疗效 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的抗CD45 PRIT的 靶向治疗（PARP和BCL 2抑制剂）。我们将描述 的DNA损伤实现了这两种方法作为一种手段来阐明疗效的机制。 最后，我们将比较这两种方法，作为同种异体骨髓移植前条件作用的一部分， 单倍相合或部分匹配的供体，因为所有患者都应该有单倍相合的供体。 这些临床前研究应该很容易转化为临床试验， 药物申办的临床试验，在骨髓移植前使用抗CD45 RIT， 侵袭性恶性血液病这些研究将增加有效的，耐受性良好的治疗选择， 通过鉴定靶向药物与抗CD45 RIT方法的协同组合治疗AML患者 并通过在单倍相合BMT之前确定最佳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.