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

被引：132

作者：

Junttila, Melissa R. ^{[1
]}

Mao, Weiguang ^{[1
]}

Wang, Xi ^{[1
]}

Wang, Bu-Er ^{[1
]}

Thinh Pham ^{[1
]}

Flygare, John ^{[1
]}

Yu, Shang-Fan ^{[1
]}

Yee, Sharon ^{[1
]}

Goldenberg, David ^{[1
]}

Fields, Carter ^{[1
]}

Eastham-Anderson, Jeffrey ^{[1
]}

Singh, Mallika ^{[1
]}

Vij, Rajesh ^{[1
]}

Hongo, Jo-Anne ^{[1
]}

Firestein, Ron ^{[1
]}

Schutten, Melissa ^{[1
]}

Flagella, Kelly ^{[1
]}

Polakis, Paul ^{[1
]}

Polson, Andrew G. ^{[1
]}

机构：

[1] Genentech Inc, Res & Early Dev, San Francisco, CA 94080 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2015年 / 7卷 / 314期

关键词：

STEM-CELLS; SMALL-INTESTINE; TUMOR; IDENTIFICATION; EXPRESSION; LYMPHOMA; TISSUE; RATS; MICE; DOGS;

D O I：

10.1126/scitranslmed.aac7433

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：11

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