Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot

摘要 项目概述：急性髓性白血病（AML）和骨髓增生异常综合征（MDS）目前杀死 大多数患者尽管接受了联合化疗和造血细胞治疗， 移植（HCT）。HCT作为急性白血病潜在治疗的选择必须进一步扩展到 没有现成的HLA匹配供体的患者，如少数民族患者。 放射性标记的抗CD 45单克隆抗体（Ab）已显示可改善AML和MDS的结局 在HCT的情况下，但毒性仍然很高，治愈率也不理想。本研究的目的 一项建议是制定一项战略，以提高AML和MDS的治愈率，使用放射免疫治疗（RIT） 预靶向CD 45细胞抗原。在目标1中，我们将优化药物的治疗效果和毒性。 通过比较90 Y-和177 Lu-标记的生物素在比较中的相对优点， 生物分布、剂量测定和治疗实验，以确定177 Lu的较短路径长度B发射 提供比90 Y更有利的肿瘤与正常器官比率。在目标2中，我们将评估 采用MHC半相合干细胞的HCT的相对优点是利用清髓性预靶向RIT， 抗CD 45 Ab（30 F11）-链霉亲和素（SA）偶联物，随后是90 Y-或177 Lu-标记的DOTA-生物素（作为 与直接使用放射性核素的常规RIT相比， 放射性标记的抗CD 45 Ab（30 F11）在临床相关的播散性AML小鼠白血病模型中， 白血病细胞和正常造血细胞都表达CD 45。我们预计，这一目标的结果 将证明预先靶向的RIT上级传统的RIT，并将使我们能够改善 单倍相合骨髓移植的疗效，毒性可耐受。在目标3中，我们将描述并最大化 淋巴造血组织辐射的骨髓抑制和免疫抑制作用 通过90 Y-或177 Lu-标记的生物素（根据目的1确定）与优化的补充剂组合， 在临床前鼠单倍体相合HCT模型中全身照射（TBI）和氟达拉滨（FLU）的剂量 采用环磷酰胺（CY）预防移植后移植物抗宿主病。减少TBI， FLU剂量，同时给予高剂量的预靶向90 Y-或177 Lu-生物素作为准备方案的一部分 对于骨髓HCT，将取决于这种方法的能力的证明：1）消融 骨髓空间，和2）产生足够的免疫抑制。因此，在目标3中，我们还将评估动力学 和使用抗mCD 45 Ab-SA缀合物（30 F11）的造血和免疫细胞重建的持久性 Ab-SA）和放射性生物素，随后是减少剂量的TBI和/或FLU和输注MHC-半相合BM 和移植后CY。我们假设预先设定的RIT策略 在这个提议中定义的将放大传递到白血病细胞的辐射量， 递送到肝脏、肺和其他正常器官，提高缓解率和治愈率，延长生存期， 与常规RIT结合标准调节试剂相比，显著减弱毒性。 因此，我们预期将优化的有希望的预靶向RIT快速转化为我们的临床RIT HCT AML和MDS的治疗方案。

ABSTRACT Project summary: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) currently kill the majority of afflicted patients despite treatment with combination chemotherapy and hematopoietic cell transplantation (HCT). The option of HCT for potential therapy of acute leukemias must be further extended to patients who do not have a readily available HLA-matched donor, such as patients in ethnic minority groups. Radiolabeled anti-CD45 monoclonal antibodies (Ab) have been shown to improve outcomes for AML and MDS in the setting of HCT, but toxicity remains high and cure rates are suboptimal. The objective of this research proposal is to develop a strategy to improve the cure rate of AML and MDS using radioimmunotherapy (RIT) pretargeted to the CD45 cell antigen. In Aim 1 we will optimize the therapeutic efficacy and toxicities of the pretargeted RIT approach by comparing the relative merits of 90Y- and 177Lu-labeled biotin in comparative biodistribution, dosimetry and therapy experiments to determine if the shorter path length b emissions of 177Lu afford more favorable tumor-to-normal organ ratios than those achievable with 90Y. In Aim 2 we will assess the relative merits of HCT employing MHC-haploidentical stem cells utilizing myeloablative pretargeted RIT with an anti-CD45 Ab (30F11)-streptavidin (SA) conjugate followed by either 90Y- or 177Lu-labeled DOTA-biotin (as determined from aim 1 the best radionuclide will be used), compared to conventional RIT using a directly radiolabeled anti-CD45 Ab (30F11) in clinically relevant disseminated AML murine leukemia model in which both leukemic cells and normal hematopoietic cells express CD45. We anticipate that the results from this aim will demonstrate that pretargeted RIT is superior to conventional RIT and will allow us to improve the therapeutic efficacy of haploidentical BMT, with tolerable toxicity. In Aim 3 we will characterize and maximize the myelosuppressive and immunosuppressive effects of radiation delivered to lymphohematopoietic tissues via either 90Y- or 177Lu-labeled biotin (as determined from aim 1) in combination with optimized supplemental doses of total body irradiation (TBI) and Fludarabine (FLU) in a preclinical murine haploidentical HCT model employing cyclophosphamide (CY) post-transplant graft-vs-host disease prophylaxis. Reducing the TBI and FLU doses, while administering high doses of pretargeted 90Y- or 177Lu-biotin as part of a preparative regimen for marrow HCT, would depend upon the demonstration of the ability of such an approach to: 1) ablate the marrow space, and 2) produce adequate immunosuppression. Thus, in aim 3 we will also evaluate the kinetics and durability of hematopoietic and immune cell reconstitution using an anti-mCD45 Ab-SA conjugate (30F11 Ab-SA) and radiobiotin, followed by reduced doses of TBI and/or FLU and infusion of MHC-haploidentical BM and post-transplantation CY in a murine leukemia model. We hypothesize that the pretargeted RIT strategy defined in this proposal will amplify the amount of radiation delivered to leukemia cells, decrease the radiation delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and markedly attenuate toxicities compared to conventional RIT combined with standard conditioning reagents. We therefore anticipate rapid translation of the optimized promising pretargeted RIT into our clinical RIT HCT program for AML and MDS.