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ACUTE MYELOID LEUKEMIA

Preclinical characterization of the anti-leukemia activity of the CD123 antibody-drug conjugate, pivekimab sunirine (IMGN632)

Leukemia volume 39, pages 1243–1246 (2025)Cite this article

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Acute myeloid leukemia (AML) remains difficult to cure [1, 2]. Antibody-based drugs have long been pursued to improve these outcomes. While early efforts focused on CD33, there is increasing interest in CD123 as a drug target [3]. Expressed on only a relatively small subset of normal hematopoietic cells, CD123 is displayed on blast cells of 45–95% of AML patients. What makes CD123 particularly attractive is its overexpression on leukemic stem/progenitor cells relative to normal hematopoietic stem/progenitor cells [3].

One CD123-targeted drug under development is pivekimab sunirine (PVEK; formerly IMGN632), an antibody-drug conjugate consisting of a humanized CD123 antibody with engineered cysteines in the CH3 domain to enable site-specific attachment of an alkylating monoamine indolinobenzodiazepine pseudodimer (IGN) via protease cleavable peptide linker [4]. After demonstration of potent preclinical anti-leukemia activity, PVEK entered early phase testing as monotherapy and in combination with azacitidine and venetoclax, with emerging data indicating significant activity in adults with AML [5,6,7]. So far, critical characteristics for PVEK’s anti-leukemia activity have not been explored in detail. Herein, we therefore examined potential variables that might modulate the in vitro cytotoxic effects of PVEK and sFGN849, the catabolite of PVEK’s payload (both provided by ImmunoGen; Waltham, MA, USA), against human AML cells, using genetically and functionally well-defined cell line models (see Supplementary Data for detailed Materials and Methods).

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Fig. 1: Impact of CD123 expression levels and TP53 function on PVEK and sFGN849-induced cytotoxicity.
Fig. 2: Effect of PVEK or sFGN849 on primary human AML cells and human cell lines engineered to overexpress ABC transporter proteins or anti-apoptotic BCL-2 family member proteins.

Data availability

For original data and reagents, please contact the corresponding author (rwalter@fredhutch.org).

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Acknowledgements

Research reported in this publication was supported by a sponsored research agreement with ImmunoGen (to RBW). RBW also acknowledges support from the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research. This work was supported by the Fred Hutch/UW Hematopoietic Diseases Repository, and the Cell Manipulation Tools Core-Vector Production of Fred Hutch, which is funded by NIDDK Cooperative Center of Excellence in Hematology (U54-DK106829).

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Authors and Affiliations

  1. Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Frances M. Cole, George S. Laszlo, Margaret C. Lunn-Halbert, Allie R. Kehret, Eduardo Rodríguez-Arbolí, Kyle Nyberg, Junyang Li, Sheryl Y. T. Lim, Camryn M. Pettenger-Willey & Roland B. Walter

  2. ImmunoGen Inc, Waltham, MA, USA

    Patrick A. Zweidler-McKay & Sribalaji Lakshmikanthan

  3. Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), University of Seville, Seville, Spain

    Eduardo Rodríguez-Arbolí

  4. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    David Wu & Roland B. Walter

  5. Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA

    Roland B. Walter

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  1. Frances M. Cole
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  2. George S. Laszlo
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Contributions

FMC and GSL performed research, analyzed and interpreted data, and wrote the manuscript. MCL-H, ARK, ER-A, DW, KN, JL, SYTL, and CMP-W performed research and analyzed and interpreted data. PAZ-M and SL provided vital reagents and analyzed and interpreted data. RBW conceptualized and designed this study, participated in data analysis and interpretation, and wrote the manuscript. All authors revised the manuscript critically and gave final approval to submit for publication.

Corresponding author

Correspondence to Roland B. Walter.

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Competing interests

PAZ-M reports previous employment with ImmunoGen (now AbbVie). SL reports employment with AbbVie. RBW received laboratory research grants and/or clinical trial support from Celgene/Bristol Myers Squibb, ImmunoGen/AbbVie, Janssen, Jazz, Kite, Kura, Pfizer, and Vor Biopharma, and has been a consultant to Wugen. The other authors declare no competing financial interests.

Ethics approval and consent to participate

All laboratory research described in this article was conducted under a broad research protocol approved by the Fred Hutchinson Cancer Center Institutional Review Board (Fred Hutch IRB; protocol #9045). Biospecimens from adults with AML were obtained from an institutional repository under protocol #1690 approved by the Fred Hutch IRB; all patients provided written informed consent for sample collection and use for research. All methods were performed in accordance with the relevant guidelines and regulations.

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Cole, F.M., Laszlo, G.S., Lunn-Halbert, M.C. et al. Preclinical characterization of the anti-leukemia activity of the CD123 antibody-drug conjugate, pivekimab sunirine (IMGN632). Leukemia 39, 1243–1246 (2025). https://doi.org/10.1038/s41375-025-02571-0

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