Cell-Selective Targeting Chimeras (SelecTACB) for Membrane Protein Degradation on B Cells

Membrane protein degradation chimeras (MPDs) have expanded the application space of current targeted protein degradation technologies (TPDs), yet cell-selective MPDs are still lacking, particularly for surface proteins on immune cells. Precise degradation of a target protein on a specific cell type is challenging when it is expressed across multiple immune cell types. Here, we introduce SelecTAC^B as a targeted membrane protein degradation chimera that is selective on B cells. By leveraging CD22 as the B cell specific lysosome-targeting receptor to induce endocytosis and lysosome degradation, SelecTAC^B allowed membrane protein degradation in a targeted and cell-selective manner. We show that SelecTAC^B can effectively degrade indicated proteins such as CD40 and ICOSL on B cells from human peripheral blood mononuclear cells (PBMCs) without affecting protein expression in other immune cell types. The degradation of key proteins involved in T cell stimulation pathways led to sustained inhibition of B cell functions. Together, our work established a cell-type selective degradation platform that offers a general strategy for targeted membrane protein degradation on immune cells.