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TitleStructural basis of nectin-4 recognition by the antibody-drug conjugate 9MW2821.
Journal, issue, pagesJ Biol Chem, Vol. 301, Issue 12, Page 110816, Year 2025
Publish dateOct 14, 2025
AuthorsPeng Fang / Meng You / Haiying Wen / Yuxia Cao / Wei Zhou / Xiaohong Zhu / Lei Shi / Xiaowei Sun / Kaiying Li / Wendi Li / Jin Wang / Hai Wu / Xiaoding Tan /
PubMed AbstractNectin-4, a membrane protein highly expressed in multiple solid tumors, has become an attractive target for antibody-drug conjugate development. We designed and developed 9MW2821, an anti-nectin-4 ...Nectin-4, a membrane protein highly expressed in multiple solid tumors, has become an attractive target for antibody-drug conjugate development. We designed and developed 9MW2821, an anti-nectin-4 antibody-drug conjugate with an enzymatically cleavable valine-citrulline linker and monomethyl auristatin E as the payload. Although 9MW2821 has shown good efficacy and safety in multiple solid tumors in clinical trials, the interaction between 9MW2821 and nectin-4 at the molecular level remains unclear. In this study, we solved the structure of the antigen-binding fragment of 9MW2821 in complex with nectin-4 at a resolution of 3.26 Å using single-particle cryo-EM. The structure shows that 9MW2821 binds the front β-sheet of nectin-4 D1 through three complementarity-determining region loops from the heavy chain and two complementarity-determining region loops from the light chain. The binding involves extensive hydrogen bonds and hydrophobic interactions. The buried surface area is more than 1600 Å. Mutagenesis studies revealed that four residues (Q77, E78, H83, and E95) of nectin-4 contributed significantly to the binding of 9MW2821 monoclonal antibody (mAb). The structure also shows that 9MW2821 mAb blocks nectin-4 homodimer formation by competing with the nectin-4 partner D1 domain for part of the nectin-4 surface area. Furthermore, 9MW2821 mAb prevents nectin-4 from interacting with nectin-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, enhancing the activation of NK cells. Based on the structure of the nectin-4 D1-9MW2821 antigen-binding fragment complex resolved in this study, we have elucidated the molecular mechanism of 9MW2821 in cancer therapy. The findings provide a basis for optimizing future mAbs targeting nectin-4.
External linksJ Biol Chem / PubMed:41101504 / PubMed Central
MethodsEM (single particle)
Resolution3.26 Å
Structure data

62389

9kkj

EMDB-62389, PDB-9kkj:
Structure of Nectin-4 D1 domain in complex with the Fab fragment of 9MW2821 mAb
Method: EM (single particle) / Resolution: 3.26 Å

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / antibody-antigen complex

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