Abstract
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.
©2016 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Bispecific / immunology*
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Antibodies, Bispecific / pharmacokinetics
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Antibodies, Bispecific / pharmacology*
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Cell Line, Tumor
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Female
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Fibrosarcoma / immunology
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Fibrosarcoma / metabolism
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Fibrosarcoma / pathology
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Fibrosarcoma / therapy
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HEK293 Cells
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Humans
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Ligands
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Low Density Lipoprotein Receptor-Related Protein-6 / antagonists & inhibitors
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Low Density Lipoprotein Receptor-Related Protein-6 / immunology*
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Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Thrombospondins / antagonists & inhibitors
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Thrombospondins / immunology
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Thrombospondins / metabolism
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Wnt Proteins / antagonists & inhibitors
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Wnt Proteins / immunology
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / drug effects*
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Wnt Signaling Pathway / immunology
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Bispecific
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LRP6 protein, human
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Ligands
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Low Density Lipoprotein Receptor-Related Protein-6
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Thrombospondins
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Wnt Proteins