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Xoma Thinks 'Dimmer Switch' Antibodies Have Bright Future

By Anette Breindl
Science Editor

Researchers from XOMA Corp. have identified an antibody that, in preclinical experiments, improved glucose control and other symptoms of diabetes.

XOMA hopes to develop the antibody, which the company has named XMetA, as a very long-acting diabetes treatment. The firm's executive vice president and chief scientific officer, Patrick Scannon, told BioWorld Today the company ultimately views the antibody "as a product that would be given somewhere between weekly and monthly."

And on the scientific side, the antibody has several novel features.

First, Scannon said, to the best of his knowledge it would be the first therapeutic antibody to activate its target – the insulin receptor. "All approved antibodies are pure inhibitors," he said.

Furthermore, the drug does not bind to the insulin binding site, but to another part of the insulin receptor, making it a so-called allosteric inhibitor. And Scannon and his colleagues at XOMA and the University of California at San Francisco contended that the allosteric inhibition is what prevents the antibody from inducing hypoglycemia – one of the big risks of overly intense activation of the insulin receptor – even at quite high doses.

Orthosteric therapies – which bind at the same site as a receptor's natural binding partner – act "more like an on/off switch," Scannon explained.

But for an optimum therapeutic effect, it is often – perhaps more often than not – best to turn down the activity of a target or signaling pathway without turning it off altogether. Scannon named antibodies that target the immune system as one example.

"Allosteric inhibitors have more of a dimmer switch approach. . . . What allosteric modulation does is to allow the system to work, only to work better."

In other words, the allosteric activator strengthens the response to the insulin that is naturally secreted after a meal, allowing it to work more effectively.

Essentially, Scannon said, XMetA allows Type II diabetics to "get more out of the insulin that they have."

Fully active antibodies, especially if they were long-acting, "would run a very high risk of driving blood glucose down to very low levels."

In contrast, the modulatory antibodies were not able to induce dangerously low levels of blood sugar, or hypoglycemia, in mice, even when the animals were treated with 10 times the minimal therapeutic dose. Nor did XMetA treatment lead to weight gain. In diabetic mice, six weeks of treatment with XMetA normalized fasting glucose levels and glucose tolerance, and it improved nonfasting glucose levels and levels of hemoglobin A1c, an important metabolic marker in diabetes.

The team will publish their findings, which are now available online, in the May 2012 print issue of Diabetes.

Finally, the insulin receptor affects several cell signaling pathways. But the antibody only activates one of those pathways, the metabolic glucose control pathway. And that's a good thing, because the other pathway – the mitogenic pathway – leads to cell proliferation.

Scannon said that whether XMetA's specific activation of metabolic pathways is related to the fact that it binds allosterically is not yet clear. "We are still investigating the mechanism of action of the biased activation that we see."

The company is looking for a partner to bring XMetA into clinical trials. Since they don't have one yet, Scannon said that "I can't give you a timeframe" for when XMetA might get into the clinic. But XOMA is "moving forward" with the lead described in the Diabetes paper.

And on the scientific side, Scannon and his team plan to publish on allosteric antibodies in more detail. Though the concept of developing allosteric antibodies was fairly simple – allosteric inhibitors are frequent in the world of small molecules – execution, he said, turned out to be harder, and the ModulX technology the company developed to find such antibodies is "largely proprietary." But with the company's success, "we have opened up a new class of antibodies."