Synthetic antibodies, also commonly termed aptamers, have started a step-change in the antibody world. After their slow beginnings of scientists tinkering with alternative affinity reagents in labs, synthetic antibodies are now coming to the fore as reagents for use in biological research and medicine. This is evidenced by the high investment in and numerous acquisitions of companies that have the capabilities to produce these marvellous molecules.
Being smaller in size than their traditional monoclonal and polyclonal counterparts, allows synthetic antibodies increased access to tissue and also the smaller, more hidden epitopes that antibodies can’t reach. They are not limited by the immune system, which allows us to generate synthetic antibodies to a wider repertoire of targets including highly toxic targets and to proteins that show a high degree of homology, theoretically it is possible to generate synthetic antibodies to any target one could desire. The fact that these molecules are not generated in mammalian systems also gives them the advantage of less variability between batches, thus a more reliable product, that are easily modifiable with different dyes and labels according to users’ needs.
As antibodies have increasingly been realised for their failures, of a large size, lack of specificity and high variability, more and more people are seemingly switching to synthetic antibodies, which allow us to engineer in positive function while removing the drawbacks. So if the switch is to be made to a more reliable and functional synthetic antibody, which one should you try? With a plethora of choice available out there we thought we’d take a look at some of the more popular choices to help you make up your mind.
While synthetic antibodies constructed from nucleic acids showed initial physical limitations in offering a small range of possible conformations, chemical limitations in the type of bonds that can be formed and a highly charged molecular backbone that presented both stability issues and non-specific protein binding, groups have worked to overcome these issues by modifying the nucleotide side chains to make them more closely resemble proteins.
Aimed primarily at the diagnostics market, the SOMAscan platform from SOMAlogic has used this approach with DNA-based aptamers to identify biomarkers for diseases such as non-small cell lung cancer and Alzheimer’s disease. Spiegelmers are enantiomeric RNA molecules, which their manufacturer’s NOXXON Pharma are targeting at the therapeutics market, with a number already in phase II clinical trials.
The larger conformational range available using protein-based molecules compared to nucleic acids means that the chances of isolating a highly specific synthetic antibody to the protein target are increased. As a result scientists have tended to move further towards protein-based aptamers.
The Z domain of protein A has been utilised by Affibody as the scaffold for their synthetic antibody and has resulted in a number of promising candidates currently in clinical trials, such as an anti-HER2 Affibody for use as an imaging agent and an anti-IL1 Affibody for the treatment of inflammation and autoimmune disorders. DARPins are an alternative scaffold based on the ankyrin repeat motif that have also yielded pipeline with many encouraging synthetic antibodies for Molecular Partners, including a VEGF targeted molecule that is due to enter phase III clinical trials this year.
The common theme amongst these leading synthetic antibody producers seems to be a focus on the therapeutic market. Avacta Life Science has developed Affimer technology with a clear view to provide improved affinity reagents to the research community in the first instance. With all the desired features of a synthetic antibody, including easy intracellular folding, a small size, and a biochemically inert and biophysically stable backbone, Affimer binders are intended to address the limitations researchers have experienced with traditional antibodies, offering a real practical alternative affinity reagent to this community.