A monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis

Han Sun, Liqun Luo, Bachchu Lal, Xinrong Ma, Lieping Chen, Christine L. Hann, Amy M. Fulton, Daniel J. Leahy, John Laterra () and Min Li ()
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Han Sun: Johns Hopkins University School of Medicine
Liqun Luo: Immunotherapy Institute, Fujian Medical University
Bachchu Lal: Hugo W. Moser Research Institute at Kennedy Krieger
Xinrong Ma: University of Maryland
Lieping Chen: Yale University School of Medicine
Christine L. Hann: Johns Hopkins University School of Medicine
Amy M. Fulton: University of Maryland
Daniel J. Leahy: Johns Hopkins University School of Medicine
John Laterra: Johns Hopkins University School of Medicine
Min Li: Johns Hopkins University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Two-pore domain potassium (K2P) channels act to maintain cell resting membrane potential—a prerequisite for many biological processes. KCNK9, a member of K2P family, is implicated in cancer, owing to its overexpression in human tumours and its ability to promote neoplastic cell survival and growth. However, KCNK9’s underlying contributions to malignancy remain elusive due to the absence of specific modulators. Here we describe the development of monoclonal antibodies against the KCNK9 extracellular domain and their functional effects. We show that one antibody (Y4) with the highest affinity binding induces channel internalization. The addition of Y4 to KCNK9-expressing carcinoma cells reduces cell viability and increases cell death. Systemic administration of Y4 effectively inhibits growth of human lung cancer xenografts and murine breast cancer metastasis in mice. Evidence for Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity is presented. Our study reveals that antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies.

Date: 2016
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DOI: 10.1038/ncomms10339

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