The CD123 antibody–drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia

Abstract

Abstract Antibody–drug conjugates (ADCs) combining monoclonal antibodies with cytotoxic payloads are a rapidly emerging class of immune‐based therapeutics with the potential to improve the treatment of cancer, including children with relapse/refractory acute lymphoblastic leukemia (ALL). CD123, the α subunit of the interleukin‐3 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‐targeting antibody, G4723A, and the cytotoxic payload, DGN549, was highly effective in vivo against a large panel of pediatric ALL patient‐derived xenograft (PDX) models (n = 39). PVEK administered once weekly for 3 weeks resulted in a median event‐free survival (EFS) of 57.2 days across all PDXs. CD123 mRNA and protein expression was significantly higher in B‐lineage (n = 65) compared with T‐lineage (n = 25) ALL PDXs (p < 0.0001), and mice engrafted with B‐lineage PDXs achieved significantly longer EFS than those engrafted with T‐lineage PDXs (p < 0.0001). PVEK treatment also resulted in significant clearance of human leukemia cells in hematolymphoid organs in mice engrafted with B‐ALL 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‐ALL PDXs supporting its clinical translation for B‐lineage pediatric ALL.