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CD123, the \u03b1 subunit of the interleukin\u20103 receptor, is overexpressed in ALL and is a potential therapeutic target. Here, we show that pivekimab sunirine (PVEK), a recently developed ADC comprising the CD123\u2010targeting antibody, G4723A, and the cytotoxic payload, DGN549, was highly effective in vivo against a large panel of pediatric ALL patient\u2010derived xenograft (PDX) models (<jats:italic>n<\/jats:italic>\u2009=\u200939). PVEK administered once weekly for 3 weeks resulted in a median event\u2010free survival (EFS) of 57.2 days across all PDXs. CD123 mRNA and protein expression was significantly higher in B\u2010lineage (<jats:italic>n<\/jats:italic>\u2009=\u200965) compared with T\u2010lineage (<jats:italic>n<\/jats:italic>\u2009=\u200925) ALL PDXs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), and mice engrafted with B\u2010lineage PDXs achieved significantly longer EFS than those engrafted with T\u2010lineage PDXs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). PVEK treatment also resulted in significant clearance of human leukemia cells in hematolymphoid organs in mice engrafted with B\u2010ALL PDXs. Notably, our results showed no direct correlation between CD123 expression and mouse EFS, indicating that CD123 is necessary but not sufficient for in vivo PVEK activity. Importantly, a PDX with very high CD123 cell surface expression but resistant to in vivo PVEK treatment, failed to internalize the G4723A antibody while remaining sensitive to the PVEK payload, DGN549, suggesting a novel mechanism of resistance. In conclusion, PVEK was highly effective against a large panel of B\u2010ALL PDXs supporting its clinical translation for B\u2010lineage pediatric ALL.<\/jats:p>","DOI":"10.1002\/hem3.70063","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T10:58:02Z","timestamp":1737111482000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The CD123 antibody\u2013drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia"],"prefix":"10.1002","volume":"9","author":[{"given":"Ben","family":"Watts","sequence":"first","affiliation":[{"name":"Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, UNSW Centre for Childhood Cancer Research UNSW Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, UNSW Centre for Childhood Cancer Research UNSW Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Evans","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, UNSW Centre for Childhood Cancer Research UNSW Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Gifford","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, UNSW Centre for Childhood Cancer Research UNSW Sydney Sydney New South Wales Australia"},{"name":"Anatomical Pathology, NSW Health Pathology Prince of Wales Hospital Randwick New South Wales Australia"},{"name":"School of Clinical Medicine, UNSW Medicine &amp; Health UNSW Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M. A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine &amp; Health, UNSW Centre for Childhood Cancer Research UNSW Sydney Sydney New South Wales Australia"},{"name":"Department of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy, Ain Shams University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W.","family":"Erickson","sequence":"additional","affiliation":[{"name":"RTI International Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Earley","sequence":"additional","affiliation":[{"name":"RTI International Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Neuhauser","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Stearns","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek M.","family":"Philip","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Chuang","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick A.","family":"Zweidler\u2010McKay","sequence":"additional","affiliation":[{"name":"ImmunoGen, Inc. 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