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Development of [211At]astatine-based anti-CD123 radioimmunotherapy for acute leukemias and other CD123+ malignancies

Leukemia volume 36, pages 1485–1491 (2022)Cite this article

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Abstract

Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia and higher-risk myelodysplastic syndrome (MDS). Of increasing interest are alpha-particle-emitting radionuclides such as astatine-211 (211At) as they deliver large amounts of radiation over just a few cell diameters, enabling efficient and selective target cell kill. Here, we developed 211At-based RIT targeting CD123, an antigen widely displayed on acute leukemia and MDS cells including underlying neoplastic stem cells. We generated and characterized new murine monoclonal antibodies (mAbs) specific for human CD123 and selected four, all of which were internalized by CD123+ target cells, for further characterization. All mAbs could be conjugated to a boron cage, isothiocyanatophenethyl-ureido-closo-decaborate(2-) (B10), and labeled with 211At. CD123+ cell targeting studies in immunodeficient mice demonstrated specific uptake of 211At-labeled anti-CD123 mAbs in human CD123+ MOLM-13 cell tumors in the flank. In mice injected intravenously with MOLM-13 cells or a CD123NULL MOLM-13 subline, a single dose of up to 40 µCi of 211At delivered via anti-CD123 mAb decreased tumor burdens and substantially prolonged survival dose dependently in mice bearing CD123+ but not CD123– leukemia xenografts, demonstrating potent and target-specific in vivo anti-leukemia efficacy. These data support the further development of 211At-CD123 RIT toward clinical application.

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Fig. 1: Binding characteristics of new anti-CD123 mAbs.
Fig. 2: Internalization of anti-CD123 mAbs.
Fig. 3: In vitro cytotoxic properties of 10C4 and 10C4-B10.
Fig. 4: In vivo CD123+ cell targeting with 211At-CD123 RIT.
Fig. 5: In vivo anti-AML efficacy of 211At-CD123 RIT.
Fig. 6: Target antigen specificity of 211At-CD123 RIT in vivo.

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Acknowledgements

We would like to thank Dr Colin E. Correnti, Dr Christopher Mehlin, Dr James M. Olson, Jane Carter, and other members of the Molecular Design and Therapeutics (MDT) core facility as well as Benjamin G. Hoffstrom of the Antibody Technology Resource at Fred Hutchinson Cancer Research Center for help with the generation of anti-CD123 mAbs. Research reported in this publication was supported by the Leukemia & Lymphoma Society (Translational Research Program, grant 6489-16), the American Society of Hematology (Bridge Grant), the St. Baldrick Foundation (Emily Beazley Kures for Kids Research Grant), and the National Institutes of Health/National Cancer Institute (NIH/NCI; P30-CA015704). The Fred Hutchinson Cancer Research Center Antibody Technology Resource received support from the M.J. Murdock Charitable Trust.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    George S. Laszlo, Johnnie J. Orozco, Allie R. Kehret, Margaret C. Lunn, Jenny Huo, Shannon L. Dexter, Melissa L. Comstock, Shyril O’Steen, Brenda M. Sandmaier, Damian J. Green & Roland B. Walter

  2. Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA

    Johnnie J. Orozco, Brenda M. Sandmaier & Damian J. Green

  3. Department of Radiation Oncology, University of Washington, Seattle, WA, USA

    Donald K. Hamlin & D. Scott Wilbur

  4. Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

    Roland B. Walter

  5. Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA

    Roland B. Walter

  6. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Roland B. Walter

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  1. George S. Laszlo
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Contributions

GSL and JJO designed and performed research and analyzed and interpreted data. ARK, MCL, JH, DKH, SLD, and MLC performed research and analyzed and interpreted data. DSW, SO, BMS, and DJG analyzed and interpreted data. RBW conceptualized and designed this study and participated in data analysis and interpretation and drafting of the manuscript. All authors revised the manuscript critically and gave final approval to submit for publication.

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Correspondence to Roland B. Walter.

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Competing interests

GSL, JJO, and RBW have filed a provisional patent application related to 211At-CD123 RIT. All other authors declare no competing conflict of interest.

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Laszlo, G.S., Orozco, J.J., Kehret, A.R. et al. Development of [211At]astatine-based anti-CD123 radioimmunotherapy for acute leukemias and other CD123+ malignancies. Leukemia 36, 1485–1491 (2022). https://doi.org/10.1038/s41375-022-01580-7

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