Antibody drug conjugates (ADCs) have come of age as a clinically validated and successful modality with 14 approved by FDA. HER2-targeted ADCs, Kadcyla and Enhertu, have improved survival rates for patients with metastatic breast cancer, but additional therapies are needed due to dose-limiting toxicities and ultimate drug resistance. Targeted protein degraders (TPD) offer a catalytic MOA and ability to degrade previously “undruggable” proteins, but low oral bioavailability and off-target degradation are limitations. Our Dual-precision Targeted Protein Degradation (TPD²) approach combines the cell-targeting precision of therapeutic antibodies with TPDs to catalytically degrade proteins of interest. We describe the discovery of ORM-5029, a potent and selective GSPT1 molecular glue degrader targeting HER2-expressing tumors.

Medicinal chemistry payload optimization was guided by physics-based modeling and CRISPR-HiBit screening for protein degradation. From ~70 synthesized degraders, we selected SMol006 and close analogues for further screening as HER2-targeting TPD², given their water solubility and compatibility with our linker library. We tested 46 huMab + linker-degrader combinations and selected 12 leads for in vivo efficacy screening based on conjugatability and plasma stability. We evaluated several linker classes and varied the cross-cell permeability of the GSPT1 degrader payload catabolite. The most active conjugates in BT474 tumor xenografts used cleavable linkers derivatized with less permeable SMol006 (-logPe = 8.7, PAMPA). We selected pertuzumab as our targeting antibody to allow for combination with trastuzumab-based therapies in clinic. As a result, we nominated ORM-5029, composed of SMol006 conjugated to pertuzumab via a Val-Cit PABc linker (average degrader-to-antibody ratio ~4).

ORM-5029 treatment in HER2-expressing cell lines showed 10 to 1000-fold greater potency compared to Enhertu and tumor growth delay at 3 mg/kg in the HER2-low, MDA-MB-453 triple negative breast cancer model (HER2 2+ by IHC). ORM-5029 is currently in clinical development (ClinicalTrials.gov Identifier: NCT05511844) as a potential first-in-class targeted protein degrader powered with ADC technology.

Yeonhee Yang

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