title: Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer.
abstract: Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. polson@gene.com junttila.melissa@gene.com.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Mao
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Bu-Er
authors.initials: BE
authors.lastname: Wang
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Thinh
authors.initials: T
authors.lastname: Pham
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: John
authors.initials: J
authors.lastname: Flygare
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Yee
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldenberg
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Carter
authors.initials: C
authors.lastname: Fields
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Singh
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Vij
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Hongo
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Schutten
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Flagella
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.affiliation: Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. polson@gene.com junttila.melissa@gene.com.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D000922:Immunotoxins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000922:Immunotoxins; C116884:LGR5 protein, human; C493597:Lgr5 protein, mouse; C576179:Lgr5 protein, rat; D043562:Receptors, G-Protein-Coupled