Project 2: Alpha-Emitter Radioimmunotherapy-Based Allografting to Cure Acute Leukemia and Myelodysplastic Syndrome

项目2：基于α发射体放射免疫疗法的同种异体移植治疗急性白血病和骨髓增生异常综合征

• 批准号: 10442610
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 33.78万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-12 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442610
• 关键词: 90Y; Acute leukemia; Address; Adult; Allogenic; Allografting; Alpha Particles; Antibodies; Antineoplastic Agents; Astatine; Behavior Therapy; Biodistribution; CD45 Antigens; Caliber; Cells; Characteristics; Chimerism; Clinical; Clinical Trials; Coupled; Disease remission; Dose; Dysmyelopoietic Syndromes; Engineering; Fc Receptor; Funding; Generations; Goals; HLA Antigens; Half-Life; Hematopoiesis; Hematopoietic; Human; Human Anti-Mouse Antibody; I131 isotope; IgG1; IgG2; IgG4; Immunization; Infusion procedures; Label; Late Effects; Lead; Length; Liver; Malignant Neoplasms; Marrow; Maximum Tolerated Dose; Measurable; Monoclonal Antibodies; Morphology; Mus; Normal Cell; PTPRC gene; Patient Isolation; Patient-Focused Outcomes; Patients; Property; Radiation; Radiation Dose Unit; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Reaction; Reagent; Regimen; Relapse; Residual Tumors; Safety; Second Primary Cancers; Series; Spleen; Stem cell transplant; Testing; Therapeutic; Toxic effect; Translating; Transplantation; Transplantation Conditioning; Treatment-related toxicity; Variant; Whole-Body Irradiation; Xenograft procedure; base; cancer cell; cell killing; cell type; cohort; conditioning; early phase clinical trial; ethnic minority population; experience; first-in-human; fludarabine; hematopoietic cell transplantation; hematopoietic tissue; high risk; human model; immune reconstitution; improved; in vivo; liver injury; mortality; mouse model; murine monoclonal antibody; particle; patient subsets; pre-clinical; preclinical study; prevent; radiation delivery; randomized trial; relapse risk; response; success; targeted delivery; therapeutic candidate; tumor

PROJECT SUMMARY / ABSTRACT – Project 2 Allogeneic hematopoietic cell transplantation (HCT) cures some patients with acute leukemia and myelodysplastic syndrome (MDS). Still, relapse rates remain high, and treatment-related toxicities further limit the success with this strategy. Randomized trials showing that reduced relapse risks with higher doses of total body irradiation (TBI) are offset by increased non-relapse mortality provided the impetus to employ radiolabeled monoclonal antibodies (MAbs) to target radiation to hematopoietic tissues to improve the efficacy of allogeneic HCT. Our early approaches used ?-emitters, iodine-131 (131I) and yttrium-90, conjugated to our murine anti- CD45 MAb BC8 to deliver targeted radiation in the HCT setting. However, the long path-length, long half-life, and low energy of ?-emitters limits the amount and precision of the delivered radiation, and ??emissions of 131I require patient isolation. The ?-emitter astatine-211 (211At) is ideally suited to overcome these limitations as it delivers a very high amount of radiation over a few cell diameters, thus minimizing toxicity to non-targeted cells. The potent anti-tumor efficacy of ?-particles and their target precision when conjugated to MAbs may avoid early and late adverse effects, including secondary cancers, associated with other HCT conditioning agents. During the current funding cycle, we successfully translated our preclinical findings with 211At-based radioimmuno- therapy to 2 clinical trials with first-in-human infusions of BC8 coupled to 211At (211At-BC8-B10) to augment minimal-intensity conditioning with fludarabine/low-dose TBI in adults with acute leukemia/MDS. To further develop and refine this approach, we propose in Specific Aim 1 use of 211At-BC8-B10 as part of a minimal- intensity conditioning for adults with advanced acute leukemia and high-risk MDS undergoing HLA-matched or -haploidentical HCT to determine the maximal tolerated dose (MTD) and safety, and estimate its anti-tumor efficacy. A subsequent trial will test 211At-BC8-B10 (at the MTD) in high-risk patients in morphologic remission. A limitation of the use of a murine MAb such as BC8 is the significant infusion toxicities, along with potential to cause a human anti-mouse antibody (HAMA) reaction, which limit its clinical use. Moreover, non-marrow toxicity with 211At is primarily limited to hepatic injury which may, in part, be due to cells in the liver avidly taking up conjugated MAbs via Fc receptors, resulting in liver-dominant off-target delivery of radiation. Therefore, in Specific Aim 2, we propose to use humanized (“Trianni”) mice to develop fully human anti-human CD45 MAbs and then preclinically characterize an improved 211At-labeled anti-CD45 MAb using Fc engineering to minimize/abolish Fc receptor interactions, thus minimizing non-specific toxicities associated with the current MAb form. Together, the overarching goal of Project 2 is to improve HCT outcomes for patients with advanced acute leukemia and high-risk MDS by further advancing the use of the first-generation 211At-CD45 RIT in early phase clinical trials while, in parallel, preclinically developing an optimized second-generation RIT reagent targeting CD45 to limit off-target delivery and non-specific toxicities.

项目摘要 /摘要 - 项目2 同种异体造血细胞移植（HCT）治愈一些急性白血病患者 骨髓增生综合征（MDS）。尽管如此，继电器率仍然很高，并且与治疗相关的毒性进一步限制 这种策略的成功。随机试验表明，总剂量降低了总剂量 人体辐照（TBI）被非释放死亡率的增加所抵消 单克隆抗体（mAb）靶向造血组织，以提高同种异体的效率 HCT。我们使用的早期方法是iodine-131（131i）和Yttrium-90，与我们的鼠抗 - CD45 MAB BC8在HCT设置中提供靶向辐射。但是，长的长度长度，长半衰期， - 发射器的低能量限制了辐射的数量和精度，并且排放为131i 需要患者隔离。 ？ - emitter astatine-211（211AT）非常适合克服这些局限性 在几个细胞直径上提供了很高的辐射，从而最大程度地减少了对非靶向细胞的毒性。 结合与mAb时，粒子及其目标精度的潜在抗肿瘤效率可能会避免早期 与其他HCT调节剂有关的晚期不良反应，包括次要癌症。期间 当前的融资周期，我们通过基于211AT的放射膜 - 成功地翻译了我们的临床前发现。 对2次临床试验进行治疗，该试验的首先是人类输注的BC8耦合到211AT（211AT-BC8-B10）以增强 急性白血病/MD的成年人使用氟达拉滨/低剂量TBI的最小强度调节。进一步 开发和完善这种方法，我们在特定的目的1中提出了使用211AT-BC8-B10作为最小的一部分 患有高级急性白血病和高风险MD的成年人的强度调节 或-Haploidential HCT确定最大耐受剂量（MTD）和安全性，并估计其抗肿瘤 随后的试验将在形态缓解中测试高危患者的211AT-BC8-B10（MTD）。 使用鼠（BC8）的使用局限性的局限性是重要的输液策略，并有潜力 引起人类抗小鼠抗体（HAMA）反应，从而限制其临床用途。此外，非果毒性 211AT主要仅限于肝炎损伤，这可能部分是由于肝脏中的细胞狂热地造成 通过FC受体共轭mAb，导致辐射的实现脱靶传递。因此，在 具体目的2，我们建议使用人源化（“ Trianni”）小鼠发展完全人类的抗人CD45 mAb 然后临床上描述使用FC工程的改进的211AT标记的抗CD45 MAB 最小化/废除FC受体相互作用，从而最大程度地减少与当前MAB相关的非特异性毒性 形式。总之，项目2的总体目标是改善高级急性患者的HCT结果 通过进一步推进第一代211AT-CD45 RIT的使用，白血病和高风险MDS早期使用 临床试验并行，临床上开发了优化的第二代RIT试剂靶向 CD45限制了脱离目标的交付和非特异性战术。