The Agonist redirected checkpoint platform (ARC)
Design and Structure
About the ARC
Shattuck was founded to solve the challenge of consolidating checkpoint blockade and Tumor Necrosis Factor Receptor Superfamily (TNFRSF) agonism into single therapeutics. The Agonist Redirected Checkpoint (ARC) platform has emerged as the first therapeutic modality to achieve this goal. Using the modularity of the ARC platform, Shattuck has created over 300 unique therapeutic candidates for the treatment of cancer and autoimmune disease.
An ARC molecule combines an immune checkpoint receptor (such as PD-1, SIRPα, or TIGIT) with a TNF ligand (such as OX40L, 41BBL, CD40L, or LIGHT), and achieves a hexameric structure. The unique structure of ARC therapeutics has two distinct advantages when compared to antibody-based therapeutics, namely: 1) activation of TNFRSF in the absence of Fc-receptor mediated cross-linking and 2) co-localization of checkpoint blockade and immune co-stimulation within a single compound.
These advantages have translated to superior tumor rejection when compared to traditional antibody therapeutics in multiple published pre-clinical studies.
Key Attributes of the ARC Platform
- ARCs combine Checkpoint blockade + TNFRSF activation, endowing one molecule with multiple functions
- ARC compounds combine a Type I transmembrane and Type II transmembrane protein through an IgG Fc protein
- The unique structural characteristics of these transmembrane proteins allow the creation of a functionally active fusion
- ARCs link a potent co-stimulator of immune cells with immune checkpoint blockade in the disease microenvironment, thus disrupting two synergistic pathways
- Each Type I and Type II protein in the ARC can be substituted, enabling a plug and play approach to producing thousands of potential therapeutic combinations