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Adaptive TCR Technologies Offers Sequencing-Based Immune System Profiling Service

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By Julia Karow

Banking on recently developed methods to analyze an individual's T-cell and B-cell repertoire by next-generation sequencing, Adaptive TCR Technologies, a Seattle-based startup, has set out to turn immune system profiling into a business.

A couple of months ago, the Fred Hutchinson Cancer Research Center spinoff started offering sequencing-based T-cell receptor profiling services to a group of early-access customers. Within the next two months, the firm plans to launch its service more widely and to expand it to other types of immune system molecules. In addition, the company is using its technology internally to develop diagnostic tests for autoimmune disease, to monitor disease states, and to discover new drug targets.

The company's technology is based on a new method to amplify and sequence rearranged T-cell receptor genes at high throughput. "We provide a tool that allows for a much more in-depth look at the immune system [than before]," said Chad Robins, Adaptive TCR's president and CEO.

Robins founded the company last September, along with his brother Harlan, a computational biologist with a PhD in theoretical physics, and Christopher Carlson, a geneticist and former Roche Molecular Systems employee. The latter two remain faculty members at the Hutch (see Paired Ends).

Last December, the company, which has 10 employees and plans to increase its staff in the near future, closed its first funding round of just over $4 million from angel investors and added another $500,000 in March. In addition, it was awarded a $185,000 grant from the Juvenile Diabetes Research Foundation.

The firm "had opportunities to be funded by venture capital," Robins said, but decided to forego VC funding for now. It is not planning to raise additional capital in the near future, hoping to become self-sustaining using the existing funds.

Adaptive TCR's profiling service is based on a method developed by Harlan Robins, Carlson, Edus Warren, and their colleagues at the Hutch and published in Blood last summer.

Company researchers amplify the rearranged CDR3 region of the T-cell receptor gene — which is responsible for most TCR diversity — in the TCR beta chain using multiplex PCR, and sequence the amplicons using Illumina's Genome Analyzer, generating up to tens of millions of TCR sequences per sample with read lengths of about 60 base pairs, enough to span most CDR3 regions.

Targeting all possible combinations of V, D, and J segments in the CDR3 region by PCR is not trivial, according to Robins, and the company has filed patent applications for its multiplex PCR primer design, as well as for the use of TCRs in diagnostics.

It has also recently expanded its assay to other gene loci, including antibodies and the TCR alpha chain, and is in the process of filing additional patents. Profiling services for these types of molecules will probably be available in six to eight weeks, Robins said.

According to the company's website, pricing for the TCR repertoire profiling service differs depending on the sequencing depth, ranging from $500 to $7,500 per sample.

At present, Adaptive TCR owns a single Genome Analyzer IIx but is waiting to receive one or two HiSeq 2000 instruments in the near future. Although the company's assay can run on any sequencing platform, "the Illumina platform is the best platform for our needs because we are much more interested in the number of reads, as opposed to the read length," Robinson explained. He said the company also looked into the Applied Biosystems SOLiD but found the Illumina to be "better suited to our needs at this point."

Along with sequencing services — and equally important — the company offers its customers tools to analyze the data. "The value proposition that we are offering is not only that we can sequence your samples but that we can provide you with tools and applications that allow you to interpret and visualize your data in a meaningful way," Robins said.

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Customers can order services and track their samples through a LIMS system and analyze their data online via cloud computing, using various applications. For example, they can select a group of samples from their sample set, analyze them for a specific feature, and obtain the results in a format suitable for publication.

Adaptive TCR is targeting both immunology researchers and vaccine makers as customers. So far, it has seen "a flood of interest" from academic researchers, Robins said, who study, for example, autoimmune diseases or how the immune system reconstitutes after transplantation. It is also "in serious discussions" with several pharmaceutical companies about using its technology to help determine vaccine efficacy in clinical trials of vaccines.

In addition to providing services, the company is developing assays to diagnose disease or to monitor therapy, in collaboration with academic researchers.

With Hutchinson researcher Colleen Delaney, for example, the company is studying how the immune system reconstitutes in patients who have undergone a core blood transplant, and whether the diversity of T-cell receptors regenerated can help determine which drugs the patient should take or stop taking.

In another project, company researchers are trying to find TCR sequences that overlap between patients with type 1 diabetes and could serve as diagnostic biomarkers for the disease. TCRs specific for an autoimmune disease like type 1 diabetes could also serve as therapeutic targets.

The goal is to offer laboratory-developed tests, which will take several years to develop, Robins said, and the firm is currently evaluating whether to partner with a CLIA-certified laboratory or to obtain in-house CLIA certification.

"There are so many applications," Robins said, and the firm's internal R&D is "just focusing on the highest-probability success experiments at this point."

Rob Holt, a senior scientist and head of sequencing at the British Columbia Cancer Agency's Genome Sciences Centre in Vancouver, agreed that immune repertoire profiling has a lot of potential applications. "Since immune repertoire diversity is an indicator of immunocompetence, there are applications in any situation where people are immunocompromised or immune challenged — for example, oncology, infectious disease, autoimmunity, transplantation medicine."

Last year, Holt and his colleagues published a method for profiling rearranged T-cell receptor variants that is similar in principle to Adaptive TCR's method (IS 6/30/2009), though he said there are "some methodological differences in preparing the sequencing libraries and handling the data."

Robins claimed that Adaptive TCR currently does not have any direct competitors. Beckman Coulter offers a test called the IOTest Beta Mark kit, which uses flow cytometry to quantitatively determine the TCR V beta repertoire, but this and other tests, such as spectratyping, are "very low-resolution tests," he said.

However, according to Holt, a San Francisco-based startup called MLC Dx is planning to employ sequencing-based T-cell receptor profiling as well. The firm's CEO declined to provide further information about the firm or its plans at this time.

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