NEW YORK (GenomeWeb) – Researchers at Arizona State University's Biodesign Institute have found that immunosignatures of healthy human subjects stay constant over time.
The results, detailed in a paper published last month in Molecular & Cellular Proteomics, suggest that longitudinal testing of individuals may prove effective for early detection of a variety of diseases, said ASU researcher Phillip Stafford, the first author on the paper.
Immunosignature profiling uses random-sequence peptide microarrays to capture antibodies in patient blood samples. Based on the levels and patterns of antibody binding, researchers build antibody expression profiles that can then be correlated with various disease states.
The method has potential advantages over conventional protein biomarker-based tests in that it detects broad immune responses, which may provide a more comprehensive picture of disease states than a smaller set of markers. Further, the immune cell replication involved in the immune response provides a natural amplification of the signal, potentially making it possible to detect disease earlier than with conventional protein markers.
Development of the ASU immunosignature platform has been led by the lab of Biodesign researcher Steven Johnston who, along with his ASU colleagues Neal Woodbury and John Rajasekaran, in 2010 spun out diagnostics company HealthTell to commercialize the technology.
HealthTell CEO Bill Colston told GenomeWeb this week that the company plans to release its first test based on the immunosignature technology early next year. The company's initial focus will be on autoimmune disease, he said, though he did not specify what type. He added that HealthTell has "preliminary feasibility data across multiple different diseases and clinical sites that indicate our test is well suited for this application."
HealthTell will undertake final clinical validation of the tests in the latter part of 2016, Colston said. It has also begun building the CLIA lab through which it plans to offer the test. The company had previously targeted an initial test launch by the end of 2015.
One challenge both HealthTell and its academic partners at ASU have encountered is manufacturing reproducible peptide arrays for immunosignature profiling. Colston said that HealthTell now has in place a manufacturing capability that is "reproducible and commercially ready" and has sufficient capacity to meet the firm's project demands in 2017 and 2018.
Likewise, the Biodesign MCP study and longitudinal immunosignaturer profiling more generally are enabled by improvements in platform stability, Stafford told GenomeWeb. Changes in the array surface and method of depositing the peptides have enabled the researchers to build arrays that are stable over time and across batches, he said.
This, he noted, means that if subjects were to send in serial blood samples year after year, they could run them on arrays from different batches and expect reproducible results rather than having to run the entire set of samples on arrays from the same production batch to ensure good data.
In the MCP study, the researchers looked at the immunosignatures of healthy persons over brief periods of time,sampling once per hour over 12 hours; intermediate periods of time,sampling once per day over 32 days; and long periods of time, sampling once per year over five years. In each case, they found individual immunosignatures to remain stable over time.
"If they are not sick or they haven't been exposed to something, the signature is very stable, like a real fingerprint," Stafford said. "And that is a big deal when you want to use that person's baseline to monitor for things you have never seen before."
Biomarker-based testing typically uses population-wide baselines, comparing individual results to "normal" ranges, based on the general population. Stafford and his colleagues are pursuing such an approach with their immunosignature technology in, for instance, their work on early detection of breast cancer.
Stafford, noted, however, that the findings of the MCP paper and other work suggest that, particularly for complicated diseases like cancer or Alzheimer's, longitudinal sampling in which patient immunosignatures are compared to each other could prove a more sensitive approach.
"From the studies we have done, it looks like the longitudinal comparison is best for picking up things early," he said. "More often than not, sensitivity goes up when you compare a person to [himself or herself], especially immunologically. There are some things that everybody develops an antibody to, especially if it is something small, like a virus. But if it is something really odd or complicated like cancer or Alzheimer's, then the immune response can be just as complicated as the genetics."
He added that work like the MCP study was intended to demonstrate the feasibility of longitudinal immunosignature profiling and the stability of healthy individuals' immunosignatures in order to lay the groundwork for use of the method in clinical biomarker work.
"We want to establish the longitudinal study as an accepted method so that when we do start publishing these early detection methods, there is not going to be a pushback against our analysis," he said. "So I think this is probably an important intermediate step."
Interest in longitudinal testing is growing in protein biomarker circles more generally. For instance, SISCAPA Assay Technologies Founder and CEO Leigh Anderson has been exploring use of his company's SISCAPA mass spec assays for tracking protein biomarkers in individuals over time. In particular, he analyzes longitudinal samples collected via dried blood spots, which have advantages in terms of durability and ease of shipping compared to conventional blood draws.
Stafford and his colleagues have likewise applied their approach to dried blood spots, which he said work very well. Such samples, he said, are also useful in getting samples for infectious disease work from places where it might be difficult to get traditional samples.
He gave the example of Brazil, where the recent emergence of the Zika virus has drawn researchers' interest. "It's almost impossible to get frozen samples from Brazil right now, but people are a lot more prone to take samples and put them on a [filter paper] and put it in the mail, and it is reproducible and stable," he said.
While the Biodesign researchers are looking into a variety of diseases, including several cancer types, Stafford said that he and his colleagues' main focus at the moment is on using the immunosignature approach for studying infectious disease. This year, he received a $584,630 grant from the National Institute of Biomedical Imaging and Bioengineering for work developing an immunosignature assay that could test for a variety of infectious diseases as part of blood bank screening processes.
Blood donations are typically tested for a variety of diseases, with a different test used for each, he said.
"Immunosignaturing could test for all the different diseases with just one platform," he said. "So what I would like to do is replace the existing system and have just one multiplex system that has one datatype and is very sensitive, and if there is a new disease, you can just add it."
The MCP paper identified as one potential challenge to using the platform for infectious disease detection the fact that even healthy subjects from areas where a particular disease is endemic will often mount an immune response to that disease.
For instance, in past work, he and his colleagues demonstrated that healthy subjects who have lived in the Phoenix, Arizona area for more than six years have immunosignatures characteristic of Valley Fever infection.
It is still possible to distinguish between healthy individuals that have been exposed and individuals with an ongoing infection, Stafford said, but it requires careful selection of controls to make sure they have similar exposures as cases.