Loss of E-cadherin expression often occurs in tumors, but many metastases retain E-cadherin. Regulation of the adhesive activity of E-cadherin at the cell surface is important for metastasis of mammary tumor cells, and cancer-associated missense mutations in E-cadherin selectively affect the mechanism of cell surface regulation.
The activity state of E-cadherin is controlled by conformational epitopes at interfaces between different EC domains, which are coupled to p120-catenin phosphorylation. Dephosphorylation activates adhesion, whereas phosphorylation inhibits activation. p120-dependent changes in the physical state of E-cadherin regulate epithelial cell morphogenesis.
Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor-specific antibody-dependent cellular cytotoxicity. Here we report a symbiotic approach that is highly selective and superior compared with investigational clinical antibodies. This bispecific-anchored cytotoxicity activator antibody is rationally designed to instigate "cis" and "trans" cytotoxicity by combining specificities against folate receptor alpha-1 (FOLR1) and death receptor 5 (DR5). Whereas the in vivo agonist DR5 signaling requires FcγRIIB interaction, the FOLR1 anchor functions as a primary clustering point to retain and maintain a high level of tumor-specific apoptosis. The presented proof of concept study strategically makes use of a tumor cell-enriched anchor receptor for agonist death receptor targeting to potentially generate a clinically viable strategy for OvCa.
Highlights d Structure-based design of SARS-CoV-2 spike ectodomain and subdomain probes d On-column biotinylation and purification is enabled by affinity tag and HRV3C cleavage d Development of diverse molecular probes by ''cut-andpaste'' strategy d Application of probes to SARS-CoV-2 antibody discovery and immune evaluation
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