NEW YORK (GenomeWeb) – As Adaptive Biotechnologies expands its business from immune repertoire sequencing into therapeutics, it is developing tools that it can use to identify biomarkers to help in the development of immunotherapies.
The company recently presented some of its work in this area at the American Association of Immunologists meeting in Seattle. In addition, following the meeting, Adaptive CSO Harlan Robins spoke to GenomeWeb about a new assay the company has developed called MIRA, for multiplexed identification of T cell receptor antigen specificity.
In an abstract at the meeting, the company described using the assay to look for 270 different antigens, including over 100 derived from pathogens, which enabled the company to detect 500 clonotypes at frequencies as low as one in a million. Clonotypes were specific to pathogen antigens including cytomegalovirus, flu, rotavirus, and others.
Robins said the assay is similar to immune response tests like ELISPOT, but that it also gives the sequence of the T cell receptor that binds to that antigen.
Scientists at the firm published a proof of principle of MIRA last year in PLoS One. The assay enables the identification of T cell receptor sequences that bind to specific antigens, and enables multiple antigens to be assessed simultaneously.
Essentially, a blood sample is divided into a certain number of wells. The antigens are then added to a specific pattern of wells. For instance, antigen A could be added to wells 1, 3, 5, 7, and 9, and antigen B added to 2, 4, 6, and 8. Then an immune assay is done in those wells followed by sequencing of the T cell repertoires. Each well will be enriched for different T cells in response to the specific antigen that is added in the well, Robins explained.
In the initial PLoS One study, the researchers demonstrated that they could multiplex 30 different antigens. From five individuals, they detected 427 antigen-specific clonotypes. Some of those clonotypes had previously been published, and they validated other clonotypes with methods like ELISPOT.
Now, Robins said, they have scaled the MIRA assay up to be able to assess up to around 1,000 antigens.
Robins said that the assay could have applications in infectious disease, vaccine development, and oncology. Although Adaptive Biotech does not currently have plans to commercialize the assay or offer it as a service — like it does with its ImmunoSeq assay for sequencing immune repertoires —the firm is collaborating with partners for specific projects, Robins said.
Internally, he said, the company is focused on using MIRA in its immunoncology research, in particular to help identify biomarkers around which to develop immunotherapies.
For example, after identifying mutations in a tumor, the MIRA assay can be used to "tile across those mutations and test each one to see which is inducing an immune response," Robins said. That enables the researchers to determine which T cell receptors respond to which tumor-specific antigens, which could help design better immunotherapies.
MIRA "improves our total offering to create a system where we can leverage a lot of our technologies for our different partners to advance therapeutics in multiple different ways," Robins said.
Adaptive Biotechnologies began moving into the therapeutics space last year, establishing a therapeutics business unit and raising $195 million in a Series F financing round that it said would be used in part to advance that portion of the company. In addition, it struck up a research collaboration with Pfizer earlier this year to identify patients who may benefit from immunotherapy.
The MIRA assay will help expand the firm's opportunities to develop immunotherapies based on T cell receptors. Currently, many companies are focused on using B cell receptors in immunotherapy development, Robins said, by essentially attaching B cell receptors that bind to tumor antigens to T cells so that the "souped up T cells" kill tumor cells that have the tumor antigen.
However, the problem with that approach is that B cells can only bind to tumor antigens expressed on the cell surface, whereas T cells can bind to and kill cells that have internal antigens, Robins said. The key is identifying the specific T cell receptors that bind to those internal tumor antigens, so that they can be harnessed and used to selectively kill the tumor cells.
Another area where MIRA could be useful is in vaccine development, for example, in determining which immunoacids in the vaccine the immune system is responding to. If a given vaccine has 200 immunoacids, Robins said, the MIRA assay could be used to figure out the specific T cell receptors that are being induced and their sequence.
In a second abstract that the company presented at the American Association of Immunologists meeting, the researchers described sequencing the immune repertoire of 528 individuals — 240 of whom were positive for cytomegalovirus and 288 of whom were negative for the virus. The goal was to sequence T cell receptors to determine which ones correlated with CMV infection.
That study represents the firm's "long-term vision and dream with these technologies," Robins said. "The immune system has long-term memory for every perturbation you've ever had." By sequencing the immune repertoire, the goal is to identify which T cell receptor sequences correlate with which perturbations. Robins said that in this study, they looked at CMV because it is a highly immunogenic, chronic pathogen, so would be less complex to evaluate than a cancer, for instance.
Robins said that the researchers can now sequence a person's T cell receptor repertoire to assess whether that person has been exposed to CMV with around 90 percent accuracy. Although he said it does not make sense to develop a diagnostic assay based on immune sequencing for CMV, if the firm is able to find immune signatures of other infectious diseases and could develop a panel of at least 10 to 15 pathogens, that could potentially be commercialized.