ORM-1153: A CD123-targeting degrader antibody conjugate with GSPT1-degrading payload exhibits potent preclinical antitumor activity in Acute Myeloid Leukemia

Abstract

Abstract Background: Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited treatment options and an overall poor prognosis. Due to the complex cytogenetics and mutationalheterogeneity, targeted therapies have demonstrated some success in disease control in patients with relevant mutations, albeit with relapse due to clonal selection driving resistance. Treatment options for unfit patients without actionable mutations are more limited following first-line treatment with the venetoclax / HMA standard-of-care. Notably, patients with TP53 mutations are largely unresponsive to chemotherapy, representing a significant unmet medical need. Currently, there is only one approved ADC for AML therapy: gemtuzumab ozogamicin (GO). However, there continues to be an unmet need for an effective therapeutic capable of treating a broad spectrum of AML patients and having a favorable tolerability profile. Because of its high expression on leukemic blast and stem cells as compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a desirable candidate for targeted therapeutic approaches in AML. We developed ORM-1153, a CD123-targeting Degrader Antibody Conjugate (DAC) with a novel GSPT1-degrading payload, with the aim of achieving selective delivery to AML blasts and inducing cytotoxicity via GSPT1 degradation. Methods: The payload was screened for cytotoxicity across a panel of hematologic tumor cell lines. In vitro cytotoxicity of ORM-1153 was assessed in multiple AML cell lines and patient derived AML blasts, with comparison to healthy bone marrow progenitors. In vivo efficacy was evaluated in mice engrafted with luciferase-expressing MV4-11 cells, analyzing tumor burden following a single IV dose. Results: ORM-1153 exhibited robust in vitro cytotoxicity via GSPT1 degradation, independent of TP53 status, across diverse AML cell lines and primary AML blasts, while showing minimal toxicity to hematopoietic progenitors or PBMC from healthy donors, suggesting an acceptable level of tolerability and differential sensitivity in diseased versus healthy tissues. Importantly, ORM-1153 maintained potency in TP53-mutant AML isogenic cell lines, highlighting its potential utility in genetically high-risk disease. This in vitro potency translates in vivo where a single intravenous dose of ORM-1153 significantly reduced systemic AML tumor burden in a dose-dependent manner in the MV4-11 tumor model. Conclusions: ORM-1153 combines CD123 target specificity with GSPT1 degradation to deliver potent anti-AML activity and a favorable safety profile in preclinical models. These data indicate that ORM-1153 may represent a viable therapeutic agent for the treatment of AML, including TP53-mutant and CD123-positive subtypes, and warrants further investigation in clinical trials.