Ion channels as therapeutic antibody targets

Abstract

It is now well established that antibodies have numerous potential benefits when developed as therapeutics. Here, we evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. Additionally, we discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted.

Keywords: Ion channel; antibodies; biologics; therapeutic.

Figure 1.

Market opportunities and global clinical pipeline for ion channel drug targets. (a) Market opportunities for targeting ion channels which represent the second largest membrane protein target class after GPCRs, adapted from Santos et al 2017.⁵ (b) Ion channel drugs in development and the clinical pipeline (sourced from Pharmaprojects as of March/April 2016).

Figure 2.

Ion channel extracellular domains can influence the difficulty in generating functional antibodies. A comparison of the structural topology of P2X, acid sensing (ASIC), voltage-gated (VGIC) and transient-receptor potential (TRP) ion channel families is shown with the relative mass of the extracellular domains (ECDs) highlighted by dashed red lines. Structural information was adapted from the Protein Data Bank (PDB) figures for P2X4 (3I5D)³¹, VGCC (4MTO)³², TRPA1 (3J9P)³³ and ASIC1 (6AVE)³⁴. The plasma membrane is represented by blue horizontal lines. Channels with large ECDs (e.g. P2X and ASIC) are expected to display a proportionally larger epitope target area than channels with much smaller ECDs (e.g. VGIC and TRP) and would therefore present less challenging targets in antibody discovery campaigns. Conversely, VGICs and TRP channels that display much smaller epitope target areas represent more challenging targets.

Figure 3.

Therapeutic opportunities in the ion channel antibody target landscape shown by therapeutic area. The percentage values in the outer ring represent the number of ion channels implicated for that therapeutic area from the >150 potential antibody targets identified. The inner ring depicts each therapeutic area with the number of clinically (in Phase 2 or further development) validated targets in bold font and the number of preclinically validated targets indicated in bold italicized font and bracketed for distinction. In a few instances, an ion channel has presented targeting opportunities in multiple indications within a therapeutic area and therefore different levels of validation have been presented. Therefore, the highest level of validation is taken to avoid duplication, for example, P2X3 in different respiratory conditions. However, where there are ion channels representing a targeting opportunity in multiple therapeutic areas these have been treated separately and accordingly can demonstrate different levels of validation, for example, K_v1.3 (implicated in autoimmune conditions, such as type 1 diabetes, psoriasis, cutaneuous lupus; respiratory indications (asthma); inflammatory conditions (uveitis and dry eye disease), K_Ca3.1 (implicated in autoimmune condtions, such as IBD, multiple sclerosis, rheumatoid arthritis; oncology (glioma, renal cancer, NSCLC), respiratory indications (asthma), sickle cell anemia) and TRPC6 (pain; respiratory; metabolic; autoimmune/inflammation; oncology). For further details of the role of each of these ion channels in disease, refer to the main text. There are at least 35 ion channels with clinical or a preclinical level of validation provided by small molecule or peptidic approaches that are suitable for targeting with therapeutic antibodies. Abbreviations: DED dry eye disease; RP retinitis pigmentosa.

Figure 4.

Ion channel targeting antibody programs in the R&D pipeline. Shown is a comparison between 2016 (a) and 2018 (b). Several ion channel targeting programs are undisclosed, such as Integral Molecular, Merck, Amgen, MedImmune, Theranyx, Ablynx and Innovative Targeting Solutions. The range of ion channel targets under investigation has broadened with 37 programs listed in 2016 compared to 56 programs in 2018. These antibody programs are directed to at least 17 targets in 2016 compared to at least 23 targets of interest in 2018, as can be observed by the increase in number of pie sectors. Selected targets of interest are denoted within the piechart layout with the number of programs indicated in brackets as the color coding of the pie sectors shifts due to the delisting of TRPM8 and the emergence of P2X2/P2X3. Since 2016, the number of programs underway for targeting Orai1 has decreased; there is a noticeable Increase in activity for K_v1.3 and P2X3; whereas Na_v1.7 and Na_v1.8 activity remains at a similar level. The P2X family is indicated by the black bracket line. Each target is color coded as depicted in the key to the right-hand side of each piechart. Information sourced from the public domain, such as scientific literature, company websites, etc. c. Shown are the ion channel antibodies in the R&D pipeline by stage depicting progress since 2016 to date. There is only 1 antibody program in clinical development (Ph1): nfP2X7 for basal cell carcinoma (Biosceptre). Some ion channel targets have more than one program for different therapeutic indications (for example, K_v1.3, P2X7 and CACNA2D1). Inactive programs include TRPA1 (Juno Therapeutics) and nAchR (NIH) and are listed as inactive (but not as terminated, unlike TRPM8 which is not currently listed).