Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer

Melissa R Junttila; Weiguang Mao; Xi Wang; Bu-Er Wang; Thinh Pham; John Flygare; Shang-Fan Yu; Sharon Yee; David Goldenberg; Carter Fields; Jeffrey Eastham-Anderson; Mallika Singh; Rajesh Vij; Jo-Anne Hongo; Ron Firestein; Melissa Schutten; Kelly Flagella; Paul Polakis; Andrew G Polson

doi:10.1126/scitranslmed.aac7433

Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer

Sci Transl Med. 2015 Nov 18;7(314):314ra186. doi: 10.1126/scitranslmed.aac7433.

Authors

Melissa R Junttila¹, Weiguang Mao², Xi Wang², Bu-Er Wang², Thinh Pham², John Flygare², Shang-Fan Yu², Sharon Yee², David Goldenberg², Carter Fields², Jeffrey Eastham-Anderson², Mallika Singh², Rajesh Vij², Jo-Anne Hongo², Ron Firestein², Melissa Schutten², Kelly Flagella², Paul Polakis², Andrew G Polson¹

Affiliations

¹ Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. polson@gene.com junttila.melissa@gene.com.
² Research and Early Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

PMID: 26582901
DOI: 10.1126/scitranslmed.aac7433

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / immunology
Antineoplastic Agents / metabolism*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / genetics
Colonic Neoplasms / immunology
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Dose-Response Relationship, Drug
Feasibility Studies
Female
Gene Expression Regulation, Neoplastic
Genes, APC
Immunotoxins / immunology
Immunotoxins / metabolism
Immunotoxins / pharmacology*
Inhibitory Concentration 50
Male
Mice, Inbred C57BL
Mice, Nude
Mice, Transgenic
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / immunology
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / immunology*
Receptors, G-Protein-Coupled / metabolism
Time Factors
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Immunotoxins
LGR5 protein, human
Lgr5 protein, mouse
Lgr5 protein, rat
Receptors, G-Protein-Coupled