Intrinsic/proximal cell surface marker logic-gated extracellular targeted protein degradation in specific cell...

Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more than 50 receptors with variable tissue distributions are screened for identification of those with substantial endocytic rates. We subsequently assemble the bispecific, "Selected endocytic carrier-targeting chimeras (SecTAC)," and validate their efficacies to program the target cells to internalize membrane/extracellular protein cargos (or nucleic acids). Moreover, administration of a SecTAC for removal of excessive immunoglobulin G via a currently validated, emerging degrader (CD71) leads to evident therapeutic effect in a mouse lupus model. To further enhance cell-targeting specificity, we next develop logic-gated eTPD (LOG-eTPD) based on a combination of chimeras that indirectly couple cargo and degrader via another cell surface gating marker. Particularly, we find that a selective surface marker from the neighboring cells also may be exploited as input for LOG-eTPD in a therapeutically relevant context. Taken together, the present work has laid a strong foundation for developing eTPD agents that combine high potency with precision and safety.