# Project 2: Alpha-Emitter Radioimmunotherapy-Based Allografting to Cure Acute Leukemia and Myelodysplastic Syndrome > **NIH NIH P01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $515,540 ## Abstract 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 adv... ## Key facts - **NIH application ID:** 10266074 - **Project number:** 5P01CA078902-23 - **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER - **Principal Investigator:** BRENDA MARIE SANDMAIER - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $515,540 - **Award type:** 5 - **Project period:** 1999-04-12 → 2022-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10266074 ## Citation > US National Institutes of Health, RePORTER application 10266074, Project 2: Alpha-Emitter Radioimmunotherapy-Based Allografting to Cure Acute Leukemia and Myelodysplastic Syndrome (5P01CA078902-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10266074. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*