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 异基因造血细胞移植（HCT）治愈了一些急性白血病患者 尽管如此，骨髓增生异常综合征（MDS）的复发率仍然很高，并且与治疗相关的毒性进一步限制。 该策略的成功表明，较高的总剂量可降低复发风险。 身体照射（TBI）被增加的非复发死亡率所抵消，前提是采用放射性标记 单克隆抗体 (MAb) 将放射靶向造血组织，以提高同种异体治疗的疗效 我们早期的方法使用 β-发射体、碘 131 (131I) 和钇 90，与我们的鼠抗 - CD45 MAb BC8 可在 HCT 环境中提供靶向辐射，但其路径长度长、半衰期长， γ-发射器的低能量限制了所发射辐射的数量和精度，以及 131I 的发射 β-发射体砹-211 (211At) 非常适合克服这些限制，因为它 在几个细胞直径范围内提供非常高的辐射量，从而最大限度地减少对非目标细胞的毒性。 α-颗粒的强大抗肿瘤功效及其与 MAb 结合时的靶点精度可能会避免早期 以及与其他 HCT 调理剂相关的晚期不良反应，包括继发性癌症。 在当前的资助周期中，我们成功地将我们的临床前发现转化为基于 211At 的放射免疫- 两项临床试验的首次人体输注 BC8 联合 211At (211At-BC8-B10) 以增强疗效 使用氟达拉滨/低剂量 TBI 治疗成人急性白血病/骨髓增生异常综合征 (MDS) 进行微强度调节 开发和完善这种方法，我们建议在具体目标 1 中使用 211At-BC8-B10 作为最小- 对接受 HLA 匹配的晚期急性白血病和高危 MDS 成人进行强度调节 或-半相合HCT以确定最大耐受剂量（MTD）和安全性，并估计其抗肿瘤作用 随后的试验将在形态学缓解的高风险患者中测试 211At-BC8-B10（在 MTD）。 使用鼠 MAb（例如 BC8）的一个限制是显着的输注毒性，以及潜在的 引起人抗小鼠抗体（HAMA）反应，限制了其临床应用，而且非骨髓毒性。 211At 主要限于肝损伤，部分原因可能是肝脏细胞贪婪地吸收 通过 Fc 受体结合单克隆抗体，导致以肝脏为主的脱靶放射传递。 具体目标2，我们建议使用人源化（“Trianni”）小鼠来开发全人抗人CD45 MAb 然后使用 Fc 工程对改进的 211At 标记的抗 CD45 MAb 进行临床前表征 最大限度地减少/消除 Fc 受体相互作用，从而最大限度地减少与当前 MAb 相关的非特异性毒性 总之，项目 2 的总体目标是改善晚期急性患者的 HCT 结局。 通过进一步推进第一代211At-CD45 RIT的早期使用来治疗白血病和高危MDS 临床试验的同时，临床前开发优化的第二代 RIT 试剂靶向 CD45 可限制脱靶递送和非特异性毒性。