title: Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth.
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.
  
  
  
  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.
authors.affiliation: Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Heather
authors.initials: H
authors.lastname: Jackson
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Granger
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Jones
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Louisa
authors.initials: L
authors.lastname: Anderson
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Friel
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rycroft
authors.affiliation: Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: William
authors.initials: W
authors.lastname: Fieles
authors.affiliation: Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: James
authors.initials: J
authors.lastname: Tunstead
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Steward
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Wattam
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Walker
authors.affiliation: Biopharmaceuticals R&D, GlaxoSmithKline, Medicines Research Centre, Cambridge, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Griggs
authors.affiliation: Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Al-Hajj
authors.affiliation: Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania. Christopher.A.Shelton@gsk.com.
authors.forename: Christopher
authors.initials: C
authors.lastname: Shelton
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D019699:Thrombospondins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; C555475:LRP6 protein, human; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D019699:Thrombospondins; D051153:Wnt Proteins