Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth.
2016
Aberrant WNT signaling is associated with the formation and growth of numerous human cancer types. The low-density lipoprotein receptor-related protein 6 (LRP6) is the least redundant component of the WNT receptor complex with two independent WNT ligand binding sites. Using domain antibody (dAb) technology, a bi-specific antibody (GSK3178022) to LRP6 was identified that is capable of blocking stimulation in the presence of a range of Wnt (WNT) and R-spondin (RSPO) ligands in vitro. GSK3178022 was also efficacious in reducing WNT target gene expression in vivo, in both cancer cell line and patient-derived xenograft (PDX) models, and delays tumor growth in a patient-derived RSPO fusion model of colorectal cancer. Implications: This study demonstrates the inhibition of a key oncogenic receptor, intractable to monoclonal antibody inhibition due to multiple independent ligand interaction sites, using an innovative domain antibody approach.
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