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  • A humanized biparatopic nanobody composed of two blocking domains for the Wnt ligand co-receptors lipoprotein receptor-related proteins (LRP) 5 and 6, with potential antineoplastic and immunomodulating activities. Upon administration, BI 905677 targets and binds to LRP5 and LRP6, thereby blocking the binding of Wnt ligands to LRP5/6. This prevents the activation of the Frizzled (FZD)-Wnt-LRP5/6 trimeric complex and prevents the inactivation of the beta-catenin degradation complex, which leads to beta-catenin degradation. This inhibits the Wnt/beta-catenin signaling pathway, prevents the beta-catenin-mediated activation of Wnt target genes, and inhibits the proliferation and survival of Wnt-driven tumor cells. In addition, inhibition of Wnt signaling by BI 905677 prevents Wnt-mediated immune escape, thereby re-activating the immune system, specifically inducing the activation of dendritic cells (DCs) and activation as well as infiltration of cytotoxic T-cells into the tumor tissue. The FZD-Wnt-LRP5/6 trimeric complex induces phosphorylation of LRP5 or LRP6 intracellular domains leading to inactivation of the beta-catenin degradation complex, allowing beta-catenin accumulation; stabilized beta-catenin enters the nucleus and acts as a transcriptional activator of Wnt target genes. Wnt/beta-catenin signaling plays a key role in tumorigenesis and resistance to immunotherapy.
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