Novel monoclonal antibody inhibitors targeting potassium channel KCNK9

Unmet Need:
KCNK9 is one of 15 mammalian subtypes in the highly conserved family of two-pore domain potassium channels (K2P). Under physiological conditions, KCNK9 is primarily expressed in the brain where it serves to maintain cellular membrane potentials. However, overexpression of KCNK9 has been detected in breast, lung, skin, and other cancers, and is thought to contribute to malignancy by promoting cell survival and resistance to hypoxia and potentially serve as a cell surface tumor-associated antigen. In breast and lung cancer patients, high KCNK9 expression correlated with reduced overall survival. Genetic inhibition of KCNK9 has been shown to attenuate cancer cell proliferation, but development of KCNK9-selective small molecule inhibitors has been unsuccessful due to high sequence homology and structural similarity between K2P subtypes. Failure to develop KCNK9-specific ligands has precluded efforts to target this channel for cancer therapy, and hampered research into the precise role of KCNK9 in normal and disease states. By specifically targeting a poorly conserved extracellular region of KCNK9, these novel antibodies and/or conjugate derivatives may succeed where small molecules have failed, and act potentially both as a therapeutic drug as well as a research tool.
 
Technical Overview:
JHU researchers show that the anti-KCNK9 antibody (Y4) with the highest affinity binding inhibits KCNK9 ion channel function by inducing 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. Data supporting both Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity as mechanisms of anti-tumor response are available.  Altogether, the data suggests that
antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies.
 
Stage of Development:
The inventors have created a series of selective, high affinity monoclonal antibodies against human KCNK9 with therapeutic potential as conventional biologic monoclonal antibodies as an immune-based oncology drug or cytotoxic antibody-conjugate for a variety of KCNK9-expressing cancers. These antibodies also have potential value as research reagents.
 
Publication(s):

1. Sun, H. et al. Nat. Commun. 7:10339 doi: 10.1038/ncomms10339 (2016).
2. WO2016149621

 

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