Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody

Area of Science:

• Molecular biology
• Cellular adhesion
• Cancer biology
• Immunology

Background:

• P-cadherin is a cell-cell adhesion protein frequently overexpressed in various malignant cancers.
• It is a promising target for antibody-based drug delivery systems.
• Mechanisms for engineering antibodies that induce P-cadherin internalization are not well understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying P-cadherin internalization upon antibody binding.
• To establish guidelines for engineering antibodies that facilitate intracellular drug delivery targeting P-cadherin.

Main Methods:

• Utilized a combination of biophysical, biochemical, and cell biological techniques.
• Investigated the conformational changes of P-cadherin induced by the monoclonal antibody CQY684.
• Analyzed the role of p120-catenin in P-cadherin endocytosis.

Main Results:

• The monoclonal antibody CQY684 traps P-cadherin in a specific X-dimer conformation, stabilizing the adhesive structure.
• This stable X-dimer formation leads to the dissociation of p120-catenin, a known suppressor of cadherin endocytosis.
• The dissociation of p120-catenin promotes P-cadherin turnover and directs the antibody-P-cadherin complex to the lysosome.

Conclusions:

• A novel outside-in signaling mechanism regulating P-cadherin endocytosis has been identified.
• This mechanism involves antibody-induced stabilization of P-cadherin X-dimers, p120-catenin dissociation, and lysosomal targeting.
• These findings provide a foundation for designing anti-P-cadherin antibodies for effective intracellular drug delivery in cancer therapy.