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

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).