ORM-1153：一种新型CD123靶向降解剂抗体偶联物，携带专有GSPT1降解载荷，用于治疗急性髓系白血病

Acute myeloid leukemia (AML) is a devastating hematological malignancy, with limited treatment options and an overall poor prognosis. Due in part to the complex cytogenetics and clonal heterogeneity, targeted therapies have demonstrated some success in disease control, albeit with frequent relapse due to clonal selection. The only approved ADC for AML therapy is gemtuzumab ozogamicin (GO). However, its clinical utility is restricted by safety concerns. Therefore, there exists an unmet need for effective therapies for AML with superior safety and tolerability profiles as compared to standard of care treatment options. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease. In addition, recent studies have reported that small-molecule GSPT1 degraders, such as CC-90009, exhibit potent antileukemic cytotoxicity in AML and demonstrate activity against TP53-mutant disease, one of the highest unmet needs. However, their therapeutic window may be potentially narrow. Therefore, we have developed ORM-1153, a CD123 targeting Degrader Antibody Conjugate (DAC) generated by conjugating our proprietary GSPT1 degrading payload SMol006 to the OR000559 antibody, which is characterized by significantly enhanced cellular internalization, via clinically validated beta-glucuronide release linker. ORM-1153 showed robust in vitro activity in CD123+ AML cell line and AML blast. This in vitro activity is comparable to GO and ~3-log greater than venetoclax. Though the TP53 isogenic model study, TP53 null status did not affect MoA and potency of ORM-1153. Moreover, ORM-1153 showed lower cytotoxicity than Mylotarg in healthy hematopoietic progenitor lineages via colony formation assays. We evaluated ORM-1153 in vivo MV4-11 xenograft model, and treatment with ORM-1153 demonstrated superior activity than standard of care treatment option. Our results indicate that ORM-1153 may represent a viable therapeutic agent for the treatment of AML, including in patients with TP53-mutant status who face limited options and an overall poor prognosis, and warrants further investigation in clinical trials.