Recent research has opened new avenues in cancer treatment by exploring the mechanisms of P-cadherin endocytosis, particularly through the engineering of antibodies. P-cadherin, known for its overexpression in various cancers, presents substantial opportunities for targeted drug delivery. A study published on January 30, 2025, outlines how CQY684, a monoclonal antibody, can effectively strengthen P-cadherin’s adhesive structure, triggering its endocytosis via what researchers describe as an outside-in signaling mechanism.
P-cadherin, or placental cadherin, plays significant roles as part of the cadherin family, facilitating cell adhesion. Malignant cancers often see elevated levels of P-cadherin, leading to its identification as a prime target for antibody-drug conjugates. Despite the therapeutic potential, the molecular mechanisms enabling the effective internalization of antibody-P-cadherin complexes remained poorly understood—until now.
The researchers employed various biophysical, biochemical, and computational methods to demonstrate how CQY684 stabilizes P-cadherin by trapping its extracellular region, setting it up as an X-dimer. This newly understood conformation of cadherin reportedly enhances its interaction with p120-catenin, which acts as both stabilizer and endocytosis inhibitor. When p120-catenin is phosphorylated, it is prompted to dissociate, thereby increasing P-cadherin turnover and directing the P-cadherin-CQY684 complex to lysosomes for degradation.
The findings are particularly relevant for the design of antibody-drug conjugates like PCA062, which had entered first-in-human phase I trials. "Our results establish an outside-in signaling mechanism..." assert the authors. The antibody CQY684 effectively modifies the cadherin signaling pathway, potentially enhancing the efficacy of treatments aimed at P-cadherin overexpressing cancers.
Nonetheless, the research brings to light some unintended consequences of antibody treatment. The same CQY684 antibody, which strengthens cell adhesion at a molecular level, appears to disrupt P-cadherin-mediated cell-cell adhesion under various experimental conditions. Observations from cell adhesion assays revealed significant fragmentation of cell monolayers treated with CQY684, contrary to the initial expectation of strengthened adhesion. Evidence suggests CQY684 enhances the dynamic turnover of cadherins—a finding of noteworthy importance when considering the consequences for cancer progression.
This outside-in engineering of cadherin endocytosis may provide insights for more precise drug delivery mechanisms. The study posits, "...the stabilization of X-dimers triggers the phosphorylation of p120..." underscoring the antibody's functional role within the signaling cascade initiated by cadherins. This novel mechanism indicates potential pathways for developing customized treatments for P-cadherin positive tumors, possibly sidestepping problematic stages of cancer metastasis.
Nevertheless, the findings introduce caution, highlighting the need for thorough investigations to identify how these effects may vary depending on the cellular contexts and cadherin types involved. The hope is for continued multifaceted research focused on antibody manipulation of cadherin dynamics, potentially leading to groundbreaking therapeutic strategies for addressing aggressive cancers. Future studies should also investigate alternative pathways or cancer cell lines where P-cadherin is not the predominant cadherin to avoid disruptions typical of CQY684 treatment.