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Boston Team Developing PLA2R Antibody Test for Membranous Nephropathy


By Molika Ashford

Researchers from Boston University School of Medicine and the Boston Medical Center are hoping to move a test they’ve developed for membranous nephropathy closer to commercialization.

The team, led by Laurence Beck, an assistant professor of medicine at BUSM, and David Salant, chief of the renal section at BMC, published initial work on their discovery of PLA2R-binding antibodies as a potential biomarker for the disease in 2009 in the New England Journal of Medicine.

Since then, they have created a "crude ELISA" test, which they are offering as part of their research. The group hopes to license its work to a company for commercialization, but licensing issues between the Boston researchers and a co-inventor in Europe, Gerard Lambeau, have made the process longer than the team expected, Beck told ProteoMonitor this week.

In their 2009 study, the group isolated proteins from the glomeruli, the filters within the kidney, which leak proteins in membranous nephropathy. They performed Western blotting of protein extracts from MN patients; from those with other autoimmune diseases; and from controls, using mass spectrometry to analyze the reactive protein bands and confirming the presence of M-typed phospholipase A2 receptor, PLA2R.

Noting that the group plans to release details about the current version of the test in an upcoming publication, Beck declined to describe it in detail, but said that it uses "a portion of the protein where we know the antibodies bind."

"It’s a larger molecule … so we know within about 60 or 70 kilodaltons where the antibodies bind, and have made this in cells and can make a crude ELISA," he said.

Membranous nephropathy is a cause of nephrotic syndrome and a significant risk factor for eventual progression to end-stage kidney disease.

A successful proteomic test could be a good way to diagnose patients with the urine-protein and swelling symptoms that MN shares with several other conditions. The test might require a follow-up biopsy, but could potentially function as a standalone diagnostic, Beck said.

Additionally, the researchers are working to establish whether tracking PLA2R antibodies with their test could also help doctors monitor patient response to treatment and inform drug decisions based on antibody levels.

"While it is a somewhat rare disease, it's not uncommon that we see [membranous nephropathy], and differentiating it from different causes, for example diabetes or some other kidney disease, is important," Beck said.

"We didn't come at it looking for a diagnostic test. We really wanted to understand what the mechanism was in humans. But it so happened that we seem to have found a good biomarker for the disease and disease activity."

According to Beck, it's not clear whether the test would or could replace biopsies. "The way these diseases work, a patient shows up at their doctor's and they've developed [symptoms]. It could be membranous nephropathy, or it could be diabetes, or even some more rare causes,” he said. “So all doctors and nephrologists will send a panel of blood tests initially to look for this, including checking the hemoglobin A1C for diabetes and other specific tests."

Beck said his and Salant's test could be very useful as part of that nephritic syndrome panel, noting that "we've certainly used it for that purpose." But whether a positive result on their anti-PLA2R test would then require further testing with a biopsy, Beck said, remains to be seen.

He said his group has diagnosed MN with its current test and has started patients on treatment without a biopsy, but "only in select cases," where patients are not good biopsy candidates – if, for instance, they are on blood-thinning drugs, a common occurrence because of blood clots associated with nephrotic syndrome.

"In those cases I think this test would be very useful," Beck said.

It's likely, he added, that in terms of numbers, the test would probably be used most often for diagnosis, because MN is just one of several causes of the more common nephrotic syndrome, and all patients with the syndrome would potentially be tested to rule MN in or out.

Additionally, the researchers believe the test could be useful for treatment monitoring. Beck and his team published a study earlier this year in the Journal of the American Society of Nephrology looking at patients treated with rituximab, an anti-B-cell drug marketed as Rituxan by Roche. They examined 35 patients from the Mayo Clinic in Toronto who had already been treated with rituximab, and who had mostly shown a good response.

"If you followed the antibody levels, you could show that after treatment the levels start high and then fall. Most of them disappear, and those patients … have a response clinically with the drug a few months after that. So it essentially predicts the clinical response," said Beck.

"In those who have [a more] slight decrease in their antibody level, they don't have the same response to treatment, and a few of the patients in the study needed to be switched to another immunosuppressive drug," he said.

This suggests that the group's test may be useful for monitoring the "immunologic phase of the disease," he said. "It's such a hard disease to treat – we are throwing these heavy-duty immunosuppressive agents and chemotherapy drugs … and people are treated with this for six, nine, 12 months or even two years. They all have their adverse effects, and we really want to shorten duration of treatment to only what's necessary."

Beck claimed the test could help do this. "Everything we've looked at suggests this will hold up. If we can follow the antibodies and only treat until the antibodies disappear, that can shorten treatment, and [also potentially] tell us what the best treatment for that patient is," he said.

According to Beck, the test is "still in evolution" and its development "has been a lot slower than we had hoped for … It's sort of gotten held up in the paperwork phase," with issues in negotiating licensing between the US and European co-inventors of the test.

Beck said the platform for the test will likely remain ELISA. "We've also talked to our nanotech people at BU” about microfluidic or optical interference-based platforms for the assay, he said. "But because we had hoped this commercialization would go quicker, we haven't pursued it with BU. We're still counting on commercializing and having the company sort of take it from where it is," he said.

While he didn’t specify what entities the group has been in contact with about moving the test to commercialization, he said there have "certainly been a lot of interested companies. But until the licensing gets settled, no one is going to pick this up."

One problem the group is planning to work further on is that the protein PLA2R seems to interfere with cellular replication, making it hard to produce it in large amounts, Beck said.

He said there have been suggestions that another group may have developed a solution to that problem, but that that research has not been published yet.

In the meantime, the Boston group is offering the test as part of its research program. "Unfortunately, that means it's really only available in our lab," Beck said, "which is another reason we want this pushed from a commercial point of view."

Currently, the German company EuroImmun offers an immunofluorescence-based test for antibodies against PLA2R.

Though EuroImmun has a US arm, the test does not appear to be offered in the US, Beck said.

According to Beck, 80 percent of patients with primary autoimmune MN have antibodies to PLA2R, so there are likely other antigens that play a role in the other 20 percent of sufferers. He said the group is currently investigating at least one of these. "Whether that could be a complementary test, we'll see," he said. "We don’t know what that protein is yet, but we know that it exists."

Have topics you'd like to see covered in ProteoMonitor? Contact the editor at mashford [at] genomeweb [.] com.

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