A recent (and rather heroic) review of molecular drug targets1 identifies ion channels as one of four privileged families of proteins – alongside GPCRs, nuclear receptors and kinases – which continue to dominate drug discovery. However, the rate of drug approvals in this particular target class between 1991 and 2015 appears to be slowing. One possible reason may be the notorious difficulty in producing ‘clean’ small molecules for ion channel targets given the close structural homology between family members, and the very real (and costly) risk of off-target effects involving ion channels of the heart and the disruption of normal cardiac rhythm. A solution to improve target specificity may arise from another current growth area in drug discovery: the use of monoclonal antibodies and antibody-drug conjugates.
The field of antibody therapy has already brought about treatments for cancer, cardiovascular, inflammatory and ophthalmic diseases, and the prevention of transplant rejection. This field is currently weighted towards targeting circulating cytokines, growth factors, inflammatory mediators and their receptors – all protein targets which have extracellular domains readily accessible for antibody generation. Until recently the same has been true in the area of respiratory research, but a recent article by Douthwaite et al2 reviews progress in targeting more complex membrane-bound proteins that are key effectors in respiratory disease processes, namely ion channels and GPCRs.
So what governs the prospect of ion channels as antibody targets in lung disease? The potential advantages of antibody specificity are clear, beyond that achieved by small molecule approaches to drug design. The challenges are two-fold: firstly, with multiple trans-membrane domains, these proteins have complex topology with limited extracellular domains for antigen generation. Secondly, their close association with the lipid bilayer of a cell membrane makes isolating the proteins with the correct structural conformation difficult – the same problem that has hampered efforts to generate their crystal structures over the years. Yet progress has been made using a synthetic peptide system known as CLiPS (chemical linkage of peptides to scaffolds), resulting in functional antibodies to the complex G-protein receptor structure CXCR2. Combining this finding with reports of successful polyclonal antibody generation to the third extracellular loop of a number of ion channels (a region common to calcium, potassium, sodium and TRP channels) the authors suggest that the same approach may be extended to ion channels for monoclonal antibody generation. Other means of targeting antigens (cell-based over-expression systems and viral methods) are also reviewed in the article and have recently led to the generation of a monoclonal antibody antagonist of the TRPA1 ion channel – a promising target for asthma and airway inflammation. Its functional effectiveness was assessed by measuring calcium uptake in response to TRPA1-mediated cellular stimulation by mustard oil, cold temperature and osmotic pressure. Although efficacy was less than that of current small molecule antagonists (reducing cellular signal by 50% as opposed to full block), the trial proved the effectiveness of the particular antibody targeting and generation strategy used and provides a good basis on which to test measures to improve efficacy.
As the authors point out, respiratory drug targets are usually members of complex networks of mediators and receptors with functional redundancy. Within these networks spatial or temporal interplay may be a factor in target activation and subsequent biological effect. Coupled with phenotypically diverse patient populations seen with asthma, CF and COPD, picking a single molecular target such as an ion channel or GPCR may not provide a ‘one-size-fits-all’ therapy. It might, however, provide an effective low-risk component of a combination approach. Inhalation would give ready access to membrane-bound ion channel targets of the airway mucosa (vital in the maintenance of mucus viscosity and airway surface liquid height), and with a naturally long half-life antibodies may bring the advantage of low dosing frequency – particularly beneficial in chronic conditions. Offering a variety of mechanisms of action (inhibition, agonism, receptor internalisation, cell depletion, state-dependent recognition/interaction) alongside the possibility of drug conjugation, there is much potential in the relationship between monoclonal antibodies and ion channels, providing significant opportunity in the area of respiratory research.
Blog by Sarah Lilley
1 Santos et al (2017)
2Douthwaite et al (2017)