NEW YORK – UK-based diagnostics firm Binding Site is developing a MALDI mass spectrometry-based test for plasma cell disorders using an approach licensed from the Mayo Clinic.
The company plans to launch a CE-IVD version of the test in 2021 and anticipates the launch of a US Food and Drug Administration-cleared test shortly thereafter, said Stephen Harding, Binding Site's chief scientific officer.
He added that the company will develop and sell its own platform for running the test and that it is currently in discussions with mass spec vendors about sourcing that portion of the system.
Harding said Binding Site envisions the instrument and assay as the first part of a larger move into mass spec.
"I think that this [mass spec-based] approach and the patents we have submitted around this approach are absolutely applicable to other disease types and other serum markers," he said. "We have a pipeline of assays which we will start to feed through following the launch of the [initial test]."
Described in a paper published last month in Clinical Chemistry, the test uses immunoenrichment combined with MALDI mass spec for direct detection of monoclonal free light chains, which are indicative of plasma cell disorders like multiple myeloma.
"An immunoglobulin usually consists of a heavy and a light chain, but some of these [dysregulated] plasma cells will make unattached light chains," said David Murray, a clinical pathologist at Mayo's Rochester, Minnesota campus and senior author on the study.
Currently, clinicians test for the presence of unattached light chains by looking at the ratio of κ and λ light chains present in patient serum, with an abnormal ratio indicating the production by abnormal plasma cells of unattached monoclonal protein (M-protein) light chains.
The problem, Murray said, is that skewed κ-λ ratios aren't always specific for monoclonal protein production.
"Sometimes you can have something like [the inflammatory disorder] igG4 disease, and so we are looking for a way to confirm that the skew is actually due to monoclonal protein production," he said. "The more skewed the ratio is, the more suspicious you are, but we get maybe 5 percent of samples where you have a slightly abnormal κ-λ ratio and you're left scratching your head because you can't confirm it by any other method."
"I get a lot of calls from physicians [in such cases] asking, 'What do we do?'" Murray said. "And so we were hoping to provide more evidence of the fact that there is a monoclonal protein there."
By combining MALDI mass spec with upfront antibody enrichment of free light chains, the Mayo researchers hoped to achieve enough sensitivity to measure the presence of free light chains directly in patient serum independent of κ-λ ratio, which would allow them to provide confirmation of abnormal κ-λ ratio results.
Murray and his colleagues previously developed a MALDI mass spec method for measuring M-protein levels called Mass-Fix that improved upon the throughput and sensitivity of conventional gel electrophoresis-based assays.
He said that Mayo has been offering that test since July 2018 and has run nearly 15,000 samples thus far.
Conventional electrophoresis-based methods are able to confirm abnormal κ-λ ratios in roughly 5 percent of cases, while the MASS-FIX assay is able to confirm them in around 25 percent of cases, Murray said. The assay presented in the most recent Clinical Chemistry study confirmed abnormal ratios in around 85 percent of cases.
Key to the assay's performance is the upfront enrichment using antibodies against free light chains developed by Binding Site for its Freelite assays, which measures κ-λ ratio.
Binding Site was formed in 1982 as a spinout of Birmingham University focused on the development of antibodies and tests for diagnosing and managing blood cancers and immune system disorders.
Harding said that the company, which counts around 1,100 employees worldwide, has had a relationship with Mayo Clinic for around two decades. It entered a collaboration agreement to commercialize the test developed by Murray's group in 2016, establishing shortly after that a research and development facility in Rochester, Minnesota, where Mayo is headquartered. The company hired David Barnridge, lab operations manager at Mayo and co-author on the first Clinical Chemistry paper, as lab director.
Harding said that Murray approached the company as he was developing the Mass-Fix assay and asked if it might be something that could be turned into an in vitro diagnostic kit.
"We had begun scientific discussion on how his great idea might make its way to the clinical chemistry laboratory under a routine and regulated environment," he said, adding that given the company's work in the myeloma and monoclonal gammopathy space, "it made absolute sense for us to be developing a next-generation assay."
Harding said that the assay will address what he said was "a real appetite" in the field for more sensitive tests for assessing a patient's disease burden.
"We know that patients with multiple myeloma benefit from reaching minimal residual disease, but we know that tumor burden [at minimal residual disease] is 10-6, and the sensitivity of gel electrophoresis is somewhere on the order of 10-2," he said. "So there's a real desire for this technology."
The assay will be the first that Binding Site offers on a mass spec platform, but Harding said he expects the company's expertise in assay development and commercialization to translate to the new technology.
"The full product includes a preanalytical handling system, software which [covers] the preanalytical handling system and the MALDI, and also does automatic peak picking," he said. "This is a first for us in terms of mass spec, but it is by no means a first for us in bead manufacturing and antibody manufacturing and the QC steps needed to show reproducibility of assays."
Harding said the free light chain assay is the first of what Binding Site expects will be a number of mass spec tests developed by the company, noting the greater sensitivity and specificity provided by mass spec compared to standard electrophoresis-based methods.
"You have immune-purification so you don't get confounded by interfering substances and then a separation on charge and mass that can be used to really focus our attention to specific proteins," he said. "That makes it a very attractive tool to develop assays for difficult protein targets, and that is definitely where I see this playing in the future."
He suggested that the prevalence of MALDI mass spec within clinical microbiology has increased clinicians' familiarity with the technology, which could ease the path to adoption of the technique.
That said, the experience of Murray and his Mayo colleagues suggests some convincing of clinicians may be required. In a previous interview discussing the original Mass-Fix assay, Murray observed that "there is a lot of education that has to happen, and people have to get used to the technology.
"I always say that if I had to do it over again, I would never show a hematologist multiply charged spectra," he joked.
Discussing the method recently Murray noted that while Mayo uses the mass spec method for all of its patients, it still runs traditional electrophoresis assays for a subset of outside clients not yet accustomed to the new technique.
Murray and his colleagues developed both the Mass-Fix assay and the free light chain MALDI assay using a Bruker MicroFlex instrument, which is the same instrument used in Bruker's MALDI Biotyper clinical microbiology system.
Harding declined to say what mass spec vendor the company was looking to for sourcing the MALDI component of its platform but Bruker would be a likely choice given the company's dominance in the MALDI space and its existing clinical platform. Shimadzu also makes a MALDI instrument that is used clinically as part of BioMérieux's Vitek MS clinical microbiology system.