ORM-1153：一种新一代CD123靶向降解剂抗体偶联物（DAC）

ORM-1153 is a next-generation CD123-targeting Degrader Antibody Conjugate (DAC) designed to improve safety and therapeutic index through advanced antibody and linker engineering. DACs combine the tissue selectivity of antibody-mediated delivery with the well-validated catalytic mechanism of targeted protein degradation, offering opportunities to expand beyond conventional cytotoxic ADC payloads. ORM-1153 is comprised of a proprietary GSPT1-degrading payload (SMol006) conjugated to a high-affinity anti-CD123 antibody via a novel beta-glucuronide cleavable linker. The antibody was engineered to minimize Fc gamma receptor interactions, reducing off-target and immune cell engagement, while the linker was optimized for enhanced plasma stability. Together, these modifications combined to produce a molecule with a robust preclinical therapeutic index (TI), suggesting the potential for ORM-1153 in the clinic. ORM-1153 was determined to have a minimal efficacious dose (MED) of 0.1 mg/kg in a disseminated AML model. Efficacy was superior to standard of care (SoC) and to a competitor ADC: anti-CD123/TOP1i. Improved efficacy correlated with a better PK profile consisting of a longer plasma half-life and minimal or undetectable free payload at most timepoints with a LLOQ of 1 ng/ml. Because SMol006 is a CRBN-based molecular glue degrader; rodent species have amino acid differences in CRBN that renders their cells insensitive to the MoA. Therefore, the relevant species for assessing tolerability is non-human primates (NHP). ORM-1153 had a favorable safety profile in repeat-dose monkey studies with clinical pathology findings limited to transient, reversible reductions in platelets and transient, reversible increases in clotting times, fibrinogen and C-reactive protein. Of note, hepatic biomarkers remained within the normal range. Consistent with a common ADC toxicity of thrombocytopenia and prior findings with our DACs, we observed transient and reversible decreases in platelet levels. These results highlight how molecular engineering of both the antibody and linker can dramatically shift the balance between efficacy and tolerability for complex bioconjugates. Collectively, ORM-1153 exemplifies a rationally engineered DAC with superior pharmacologic properties, including robust potency and a broad therapeutic window, supporting advancement toward clinical introduction