Trogocytosis targeting chimeras (TrogoTACs) for targeted protein transfer

Cell surface proteins contribute to cellular identity and mediate a myriad of pathological and normal physiological processes. Multiple induced proximity strategies have emerged to manipulate the cell surface proteome, wherein a protein of interest can be depleted in a targeted manner. These strategies can be applied to diseases marked by the presence of a pathogenic protein. However, many pathologies result from the absence of critical cell surface proteins.1–4 Restoring deficient cell-surface proteins without genetic intervention remains a formidable challenge. We sought to address this problem by exploiting a natural process for cell-to-cell transfer of membrane proteins known as trogocytosis. Here we report the development of Trogocytosis-TArgeting Chimeras (TrogoTACs), bispecific molecules capable of inducing protein transfer between distinct cells. We designed TrogoTACs that bind the B cell receptor CD22 through a synthetic small molecule ligand chemically linked to an antibody that recognizes a cell surface molecule expressed on a target cell. These CD22-targeted TrogoTACs induce cell surface protein transfer from the target cell to B cells by redirecting trogocytosis in a targeted fashion. We show that the process depends on cell-cell contact, expression of CD22, and requires high-affinity CD22 binding. We demonstrate the utility of TrogoTACs across several cell models, achieving efficient transfer of therapeutically relevant proteins such as PD-1, CD25, EGFR, and HER2. Finally, we show that trogocytosed MHC class I can elicit T cell activation and cell killing. This technology offers a new avenue for non-genetic cell surface modification, therapeutic interventions, and a platform for targeted modulation of the cell surface proteome.