A modular platform for Sterically Masked Activated Cytokines (SMACks)

Cytokines are critical signaling molecules, but their therapeutic potential remains unrealized due to pleiotropic effects across cell types. Current strategies to develop conditionally active cytokines involve complex engineering and production, limiting their application to a select few cytokines and receptors. Here, we describe a simple, highly modular format called Sterically Masked Activated Cytokine (SMACk) via facile assembly of a targeting Fab/VHH, cytokine, and Fc. We first develop an interleukin-22 (IL-22) SMACk selective for intestinal epithelial cells, wherein the Fab/VHH serves a dual masking and targeting role. Detailed analysis revealed a <i>cis</i> signaling mechanism via a reduced on-rate and identified tunable format parameters. In mice, the IL-22-SMACk showed selective activity in the colon and efficacy in a colitis model. Finally, we highlight the versatility of SMACks by selectively directing interferon-α, IL-2, IL-4, or IL-7 to CD8⁺ T cells, underscoring the potential of this platform to advance cytokine research and therapies.