Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth

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 bispecific antibody (GSK3178022) to LRP6 was identified that is capable of blocking stimulation in the presence of a range of 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 models, and delays tumor growth in a patient-derived RSPO fusion model of colorectal Cancer.

Implications: This article demonstrates the inhibition of a key oncogenic receptor, intractable to mAb inhibition due to multiple independent ligand interaction sites, using an innovative dAb approach. Mol Cancer Res; 14(9); 859-68. ©2016 AACR.