Trogocytosis Targeting Chimeras (TrogoTACs) for Targeted Protein Transfer

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Authors

Nicholas A. Till1,2, Muthukumar Ramanathan2,3, Kang Yong Loh1,2, and Carolyn R. Bertozzi1,2,4

Organizations

  1. Department of Chemistry, Stanford University, Stanford, CA 94305
  2. Sarafan ChEM-H, Stanford University, Stanford, CA 94305
  3. Department of Pathology, Stanford University, Stanford, CA 94305
  4. HHMI, Stanford University, Stanford, CA 94305

Abstract

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. 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.

CovalX Technology Used

MALDI-ToF
HM5

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Categories : Publications, High-Mass MS