Antibodies and venom peptides: new modalities for ion channels


Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for myriad neurological, cardiovascular and metabolic diseases as well as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small-molecule drugs has been challenging, and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom-derived peptides. In parallel, after initial studies with polyclonal antibodies demonstrated the technical feasibility of inhibiting channel function with antibodies, multiple preclinical programmes are now using the full spectrum of available technologies to generate conventional monoclonal and engineered antibodies or nanobodies against extracellular loops of ion channels. After a summary of the current state of ion channel drug discovery, this Review discusses recent developments using the purinergic receptor channel P2X purinoceptor 7 (P2X7), the voltage-gated potassium channel KV1.3 and the voltage-gated sodium channel NaV1.7 as examples of targeting ion channels with biologics.

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Fig. 1: Small molecules targeting ion channels.
Fig. 2: Structures of peptide toxins targeting ion channels.
Fig. 3: Antibodies and antibody derivatives being investigated to target ion channels.


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The authors thank A. Karatt Vellatt at IONTAS for providing the Protein Data Bank (PDB) file of the X-ray coordinates of a KnotBody antigen-binding fragment (Fab) for figure 3. The authors are supported by the CounterACT Program, US National Institutes of Health Office of the Director (NIH OD) and the US National Institute of Neurological Disorders and Stroke (NINDS) (grant numbers U54NS079202 and NS100294 to H.W.); and the Singapore Ministry of Health’s National Ministry Research Council under its Clinician–Scientist Individual Research Grant (NMRC/CIRG/1427/2015) and the Singapore Ministry of Education Academic Research Fund Tier 1 (2015-T1-022-047) and Tier 2 (MOE2016-T2-2-032) (to K.G.C).

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P.Ch. is a full-time employee of Saniona A/S. P.Co. is a full-time employee of TetraGenetics Inc. The other authors declare no competing interests.

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Supplementary information


Patch-clamp technology

Patch-clamp is an electrophysiological technique in which a glass pipette is sealed tightly to the cell membrane of an individual cell. In the most common voltage-clamp configurations, voltage across the cell membrane is controlled by the experimenter, and the resulting currents are recorded. Patch-clamp is considered the gold-standard in the ion channel field and has been automated for higher throughput.

Giga seal electrophysiological recordings

Electrophysiological recordings in which a glass pipette is sealed so tightly to the membrane of a cell that it creates a giga seal, meaning a >109 Ohm leak resistance. This causes low noise and excellent mechanical stability, which allows recording of single ion channels in patches of membranes as well as of all channels in a cell.


A synaptic bouton is a button-like swelling on the terminal ends of axons. Synaptic boutons are typically the sites where synapses with other neurons are found and where neurotransmitters are stored and released to communicate with other neurons via these synapses.


The state or period after a seizure (time from the ending of an epileptic event until full mental recovery is achieved).

Antibody-dependent cellular cytotoxicity

A process in which an effector cell of the immune system (such as a natural killer cell, a macrophage, a neutrophil or an eosinophil) actively lyses a cell whose membrane surface antigens have been bound by antibodies. The crystallizable fragment (Fc) portion of the antibody allows the immune cell to bind the antibody.

Complement-dependent cytotoxicity

The killing of an antibody-coated target cell via recruitment of the complement system (a set of circulating plasma proteins).

Antibody-dependent cellular phagocytosis

The engulfment of an antibody-coated cell by phagocytes such as macrophages, neutrophils or dendritic cells.

FcRn-mediated transcytosis

The neonatal crystallizable fragment (Fc) receptor (FcRn) is an Fc receptor that is capable of transporting immunoglobulin G (IgG) from mother’s milk across the epithelium of the gastrointestinal tract or across the placenta to the fetus. Binding to FcRn can be used to try and transport antibodies across epithelia.

Epitope binning analysis

An epitope or antigenic determinant is the part of the antigen that is recognized by an antibody. Epitope binning analysis refers to the process of first characterizing and then sorting a library of monoclonal antibodies into groups binding to the same or closely related epitopes on the basis of their ability to block each other’s binding.

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Wulff, H., Christophersen, P., Colussi, P. et al. Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov 18, 339–357 (2019).

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