NEW YORK (GenomeWeb) – Somalogic has developed a new variety of its Slow Off-rate Modified Aptamer, or Somamer, affinity agent that the company expects will help it reach its goal of building reagents against the full human proteome.
The new Somamers, which the company detailed in a study published this month in Proceedings of the National Academy of Sciences, feature two sidechain modifications instead of the single modification present on the current generation of reagents. This extra modification provides a boost in chemical diversity that will allow Somalogic to expand its Somamer library beyond the current count of around 5,000, said Nebojsa Janjic, the company's chief science officer and senior author on the study.
He added that Somalogic is also counting on the new structure to help shore up competitive advantages the company lost when patents to certain key technologies underpinning the Somamer reagents expired several years ago.
Somamers are a variety of aptamers, which are short strands of nucleic acids that bind proteins or other targets, much like antibodies. After binding, Somamers can be quantified using microarrays or other readout technologies, with the quantity of a given Somamer corresponding to the quantity of its target.
According to Janjic, Somamers provide generally equivalent performance to antibodies while being cheaper, easier, and faster to produce and characterize given that they are made via chemical synthesis, as opposed to antibodies which are produced using biological systems.
One challenge to producing large numbers of different Somamers, though, has been the limited chemical diversity afforded by their nucleic acid-based structure.
"What protein-based ligands [like antibodies] have going for them is that there are 20 amino acids from which to choose chemical diversity compared to only four bases that we have," Janjic said. Additionally, he noted, the four bases composing nucleic acids are more chemically similar than are the 20 amino acids that make up proteins.
This limited chemical diversity constrains Somalogic and other aptamer developers as they screen their molecules against targets to identify the best-performing reagents.
To an extent, Janjic said, the company has "made up for this lower chemical diversity through sheer numbers."
"The advantage we have is that we can start with these enormous libraries from which we select ligands from [collections of] 1015 molecules, which is not achievable with most protein-based techniques," he said.
However, he noted, this approach has its limits, and so the company has moved to increase the chemical diversity of its molecules by adding modifications similar to the sidechain modifications found on antibodies.
Current Somamers contain one sidechain, and through this addition Somalogic has managed to develop affinity agents to more than 5,000 proteins. Its ultimate goal, though, is to develop reagents against the full human proteome, and to do this it needs to further increase the molecules' chemical diversity.
Adding a second modification "will allow us to get all the way to the full human proteome," Janjic said. The addition of the second modification significantly expands the potential search space by allowing for many different combinations of modifications.
"What we are currently working on is understanding within the two modified nucleotides which pairs of modifications give us the best results with protein binding," Janic said. "So you can imagine that there are quite a few combinations we can explore."
The doubly-modified Somamers also exhibit higher affinity for their targets, he said, which could help in developing reagents to certain proteins that are difficult to capture.
They are also "more efficiently encoded," Janjic said, meaning that they can consist of shorter sequences than the current generation of Somamers. This could mean lower synthesis costs, he said.
The doubly-modified Somamers are also more resistant to degradation by nucleases, making them more stable. This is not particularly important for protein detection work, Janjic said, as the singly-modified molecules are already resistant enough to remain effective throughout a typical experiment's incubation period, but it could be significant for efforts using Somamers as therapeutics. The company is mainly focused on diagnostics development and biomarker services, but it does have some ongoing therapeutic work, including a collaboration with Otsuka Pharmaceutical investigating Somamers as potential drugs.
The move to the new structure is also important from an intellectual property standpoint, Janjic said. Patents on the Systematic Evolution of Ligands by Exponential enrichment, or SELEX method for aptamer discover, which was developed in part by Somalogic Chairman and Founder Larry Gold, expired in 2014, making the technology more widely available.
"There are many people now making aptamers, quite a few companies, and quite a few academic labs, since the main SELEX patents expired," Janjic said. "So we want to make sure we stay at the leading edge of aptamer development. And the way to do this is through chemistry innovation and by understanding the kinds of modifications that make the biggest differences in selection."
He said the company has patents covering aspects of the new molecules.
Somalogic has traditionally focused on using its Somamers for internal diagnostics development, and the company does have several in-house diagnostics programs ongoing, the most advanced of which is a panel for predicting risk of adverse events in coronary heart disease patients.
In recent years, though, the company's main source of revenue has come from its SomaScan platform, through which it offers its Somamer technology to outside companies and research institutions.
The current commercial version of the platform can measure 1,310 proteins, and the company maintains for internal use a custom platform it developed in collaboration with Novartis that can measure more than 5,000 proteins. As Janjic noted, Somalogic ultimately hopes to expand the platform to cover the full human proteome, around 20,000 targets not including variants and modified forms.