Antibodies Targeting KV Potassium Channels: A Promising Treatment for Cancer

Abstract

Voltage-gated potassium channels are transmembrane proteins that allow flow of potassium across the membrane to regulate ion homeostasis, cell proliferation, migration, cell volume, and specific processes such as muscular contraction. Aberrant function or expression of potassium channels can underlie pathologies ranging from heart arrhythmia to cancer; the expression of potassium channels is altered in many types of cancer and that alteration correlates with malignancy and poor prognosis. Targeting potassium channels therefore constitutes a promising approach for cancer therapy. In this review, we discuss strategies to target a particular family of potassium channels, the voltage-gated potassium channels (K_V) where a reasonable structural understanding is available. We also discuss the possible obstacles and advantages of such a strategy.

Keywords: antibodies; cancer; immunotherapy; potassium channels.

FIG. 1.

Comparison of the structures of an immunoglobulin (red; IgG1, PDB1HZH) and K_V10.1 (white; PDB5K7L). A single-domain antibody (nanobody, blue; PBD5SV4) is depicted for comparison. The gray band indicates the approximate thickness of the membrane.

FIG. 2.

(A) Cryo-EM structure of K_V10.1 (PDB ID 5k7l) represented as a side view of the tetramer; each monomer is indicated with a different color, and the gray band indicates the plasma membrane (extracellular is represented on the upper part). (B) Depicts the channel seen from the extracellular side at the same scale. (C) and (D) Zoom onto the pore area where mAb56 binds; in the surface representation (D), the epitopes for the blocking antibody (mAb56, magenta) and the nonblocking antibody mAb62 (green) are indicated. Note that both face away from the permeation pathway in the center of the structure. In the structure of the open K_V11.1 (E; PDB ID 5va1), the corresponding regions still face toward the periphery of the channel.

FIG. 3.

(A) Structure of the scFv62-TRAIL construct. The fusion consists of an scFv (the variable regions of both heavy [red] and light [green] chains bound by a flexible linker) and the full sequence of soluble TRAIL (purple). The cytokine drives formation of trimers. (B) The structures of a TRAIL trimer (PDB 1DG6) and an scFv monomer (PDB 14PI, tones of blue) are depicted. This is not a structural model of the construct; the molecules have been drawn together only to give an idea of the size of the trimeric construct.