Festival of Biologics Day 1 @ 17:10
ORM-5029: A First-in-Class, Tumor-Targeted, Targeted Protein Degradation Therapy for HER2-Positive Breast Cancer
Targeted protein degradation (TPD) molecules, including IMiD-based molecular glues and heterobifunctional degraders have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. Here, we describe the development of ORM-5029, comprised of a highly potent and selective GSPT1 degrader targeted to HER2-expressing tumor cells. An unbiased global proteomics evaluation of changes in abundance identified SMol006 as a specific GSPT1 degrader, with no significant depletion of over 6500 other proteins detected. To evaluate whether antibody delivery could provide a potency increase of Smol006 and other GSTP1 degrader payloads, we conjugated these payloads to the HER2-targeting antibodies, trastuzumab and pertuzumab. Further medicinal chemistry optimization and evaluation of many linker-payloads led to the identification of our first preclinical AnDC candidate ORM-5029, which is composed of SMol006, a highly potent GSPT1 degrader conjugated to pertuzumab via a clinically validated Val-Cit PABc linker. ORM-5029 treatment in the HER2-expressing cell lines showed 10-1000-fold superiority in potency compared to SMol006, T-DM1 and/or T-DXd treatment. We evaluated ORM-5029 in several in vivo xenograft models and observed robust efficacy, following a single-dose treatment as low as 3 mg/kg.