Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity.
The potassium channel ether à go-go has been directly linked to cellular proliferation and transformation, although its physiologic role(s) are as of yet unknown. The specific blockade of human Eag1 (hEag1) may not only allow the dissection of the role of the channel in distinct physiologic processes, but because of the implication of hEag1 in tumor biology, it may also offer an opportunity for the treatment of cancer. However, members of the potassium channel superfamily are structurally very similar to one another, and it has been notoriously difficult to obtain specific blockers for any given channel. Here, we describe and validate the first rational design of a monoclonal antibody that selectively inhibits a potassium current in intact cells. Specifically blocking hEag1 function using this antibody inhibits tumor cell growth both in vitro and in vivo. Our data provide a proof of concept that enables the generation of functional antagonistic monoclonal antibodies against ion channels with therapeutic potential. The particular antibody described here, as well as the technique developed to make additional functional antibodies to Eag1, makes it possible to evaluate the potential of the channel as a target for cancer therapy.
Gómez-Varela
David
D
Max-Planck Institute of Experimental Medicine, Göttingen, Germany.
Zwick-Wallasch
Esther
E
Knötgen
Hendrik
H
Sánchez
Araceli
A
Hettmann
Thore
T
Ossipov
Dmitri
D
Weseloh
Rüdiger
R
Contreras-Jurado
Constanza
C
Rothe
Mike
M
Stühmer
Walter
W
Pardo
Luis A
LA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D026902:Potassium Channel Blockers