Structural insights into the and assembly of human trophoblast cell surface antigen 2.

Human trophoblast cell surface antigen 2 (TROP-2) is an important target of tumor therapy, and antibody-drug conjugates with sacituzumab targeting TROP-2 have been approved for the treatment of triple-negative breast cancer. Here, we report the crystal structures of TROP-2-ECD, which can be either or dimers depending on which distinct but overlapping interfaces is used to engage with monomers. The or -tetrameric forms of TROP-2 can also be assembled with a non-overlapping interface with either - or dimerization, suggesting that - and dimers cluster on the cell surface. The binding site of sacituzumab on TROP-2 is mapped to be located on a stretched polypeptide in CPD (Q237-Q252), which is not involved in either or interactions. The present findings will improve understanding of the molecular assembly of TROP-2 on tumor cells and shed light on future design of biologics for tumor therapy.