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Updated: May 30, 2025

Chemical Conjugation of a Purified DEC-205-Directed Antibody with Full-Length Protein for Targeting Mouse Dendritic Cells In Vitro and In Vivo
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Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody

Bin Xie1, Shipeng Xu2, Sanjeevi Sivasankar3,4

  • 1Biophysics Graduate Group, University of California, Davis, CA, USA.

Nature Communications
|January 29, 2025
PubMed

Insights

Antibodies targeting P-cadherin can trigger its internalization by trapping it in an X-dimer conformation. This mechanism, involving p120-catenin phosphorylation, enables targeted intracellular drug delivery for cancer therapy.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biophysics

Background:

  • P-cadherin is a key cell-cell adhesion protein overexpressed in many cancers.
  • Antibodies targeting P-cadherin are explored for cancer drug delivery.
  • Molecular mechanisms for P-cadherin-mediated antibody internalization are not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which antibodies binding to P-cadherin trigger its internalization.
  • To identify strategies for engineering antibodies for effective intracellular drug delivery targeting P-cadherin.

Main Methods:

  • Biophysical, biochemical, and cell biological assays were employed.
  • Analysis of P-cadherin conformation and its interaction with p120-catenin.
  • Investigated the role of p120-catenin phosphorylation in cadherin endocytosis.

Main Results:

  • Trapping P-cadherin in an X-dimer conformation induces endocytosis via outside-in signaling.
  • The monoclonal antibody CQY684 induces stable P-cadherin X-dimers.
  • X-dimer formation leads to p120-catenin phosphorylation, dissociation, and lysosomal targeting of the antibody-cadherin complex.

Conclusions:

  • An outside-in signaling pathway regulates P-cadherin endocytosis.
  • This mechanism can be leveraged by anti-P-cadherin antibodies for targeted intracellular drug delivery.
  • Provides fundamental insights into cell adhesion regulation.

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