Discovery of Functional Antibodies Targeting Ion Channels

Abstract

Ion channels play critical roles in physiology and disease by modulation of cellular functions such as electrical excitability, secretion, cell migration, and gene transcription. Ion channels represent an important target class for drug discovery that has been largely addressed, to date, using small-molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative formats of biologics. Antibodies display high specificity and affinity for their target antigen, and they have the potential to target ion channels very selectively. Nevertheless, isolating antibodies to this target class is challenging due to the difficulties in expression and purification of ion channels in a format suitable for antibody drug discovery in addition to the complexity of screening for function. In this article, we will review the current state of ion channel biologics discovery and the progress that has been made. We will also highlight the challenges in isolating functional antibodies to these targets and how these challenges may be addressed. Finally, we also illustrate successful approaches to isolating functional monoclonal antibodies targeting ion channels by way of a number of case studies drawn from recent publications.

Evaluation of recombinant monoclonal antibody SVmab1 binding to NaV1.7 target sequences and block of human NaV1.7 currents

“…Despite this attraction and the demonstrated involvement of ion channel antibodies in diverse autoimmune diseases 2 , no antibody-based ion channel therapeutic has progressed to the clinic, due to challenges in developing both optimal immunogens and robust screening processes to identify channel modulators 3 .…”

Ion channels as therapeutic antibody targets

“…Given the advances made in targeting GPCRs over the past decade, 20 there is now substantial interest from the biotechnology and pharmaceutical industries to extend these capabilities to therapeutic mAbs that target ion channels. [348][349][350][351] Several efforts are ongoing to succeed with this target class, and, whilst the pipeline is in its infancy, the ion channel-antibody pipeline in 2016 was reminiscent of the early stage GPCR-antibody pipeline 10 years ago (Figure 4(a)). A review of information available in the public domain that includes company websites, publications, conferences and searches on commercial databases, such as Pharmaprojects, has identified over 20 ion channels that are the focus of research and development activities.…”

Screening Strategies for the Discovery of Ion Channel Monoclonal Antibodies

“…Due to the structural and functional diversity of ion channels, different strategies need to be considered for generation of antigen formats of the ion channel or antigens derived from the channel (Wilkinson, Gardener, & Williams, ). While peptides derived from the ion channel can be used as antigens (Cox et al., ), it is usual to use a conformationally relevant form of the channel as the antigen (Bednenko et al., ).…”