BERKELEY, Calif.—XOMA Corp. recently announced the online publication of its latest results on XMetA, its fully human allosteric monoclonal antibody for the insulin receptor. The antibody is reportedly the first of its kind specific for the insulin receptor that has been shown to correct hyperglycemia in mouse models of diabetes. The antibody was investigated in a study by XOMA and confirmed by researchers at the University of California, San Francisco (UCSF), and proved to have the potential to serve as a long-acting agent to control diabetes patients' blood glucose levels."
Through insights into the regulation of signaling pathways gained using XOMA's ModulX! technology, we have discovered three distinct classes of allosteric antibodies that act differentially on the insulin receptor," Dr. Patrick J. Scannon, executive vice president and chief scientific officer of XOMA, said in a press release. "XMetA, an antibody from one such class, selectively activates pathways leading to glucose-lowering while avoiding pathways leading to cellular proliferation. We believe this profile is unique and offers a new approach to treatment of diabetes."
While monoclonal antibodies bind at the ligand-receptor binding sites, XOMA's XMet antibodies bind to other sites found on receptors, known as allosteric sites. While binding at the ligand-receptor sites leads to complete activation or inhibition, binding at the allosteric sites allows for modulation.
"It has also been reported that allosteric antibodies, antibodies that do not bind at the ligand binding site of receptors, can activate cell signaling," the paper adds. "In theory, these allosteric antibodies have the potential to activate receptors more selectively than either orthosteric antibodies or the natural ligand itself, in that they do not recognize the binding determinants within a receptor that may cross-react with multiple ligands."
Dr. Vinay Bhaskar of the Preclinical Research Department at XOMA, corresponding author for the study, notes that the XMetA antibody demonstrates a variety of benefits.
"As an antibody, we feel that this is something to have a long half-life, particularly compared to insulin itself," Bhaskar notes. "When you administer normal, short-acting insulin, that has a relatively short-half life, only minutes to hours. Extremely long-acting insulin really doesn't have a half-life longer than maybe a day or two. This actually has a half-life that's several days."
That extended half-life will have to be investigated in animals higher up the testing chain than mice, he adds, but it could potentially mean that the antibody could be administered just once a week.
In addition, results so far indicate that the antibody doesn't run the risk of the hypoglycemia or weight gain associated with insulin.
"It doesn't appear to have the same propensity for hypoglycemia. It's not clear right now whether we'll see hypoglycemia till we get to higher species, but in mice we don't see it at all," says Bhaskar. "So that suggests that unlike insulin, it would be potentially more difficult to overdose and become hypoglycemic, which can be a pretty serious consequence of insulin therapy in type 1 and type 2 diabetics."
Those characteristics offer an improvement for diabetes patients, since, as the paper notes, current insulin treatments have inherent side effects that diminish their helpfulness.
"Long-acting, or basal, insulins, such as insulin detemir and insulin glargine, are insulin analogs that are now used therapeutically in patients with diabetes. Although these agents are effective at lowering fasting blood glucose, they must be administered subcutaneously, once or twice daily," the paper notes. "As insulin analogs, they carry the risk of hypoglycemic episodes and weight gain, both of which are associated with poor cardiovascular outcomes. Therefore, longer-acting molecules that activate the insulin receptor without hypoglycemia would be helpful in the treatment of diabetes."
The study found that XMetA brought about significant reductions in elevated fasting blood glucose levels, and also normalized glucose tolerance in mice that had been rendered diabetic. After six weeks of treatment, hemoglobin A1c levels had shown a statistically significant reduction in XMetA-treated animals compared to the controls, and elevated non-HDL cholesterol levels had also improved compared to the controls.
"In the treatment of diabetes, novel and improved therapeutic modalities for patients with impaired insulin secretory function are needed," Dr. Ira. D. Goldfine, professor emeritus at the Department of Medicine and the Diabetes Center at UCSF, as well as a XOMA Distinguished Scientific Fellow, said in a press release. "XMetA has shown potential to deliver a long-acting, glucose-regulating effect without generating hypoglycemia. The characteristics of this molecule may result in an opportunity to leverage this potential therapeutic option earlier in the treatment of diabetes."
The next step, according to Bhaskar, will be to study the antibody in higher species to see if the extended half-life and lack of hypoglycemia and weight gain will hold true.
"It's important to follow up and make sure [hypoglycemia and weight gain] actually aren't occurring. And if they are, to what extent are they occurring … Even if hypoglycemia or weight gain does occur in a higher species, it would be to a lesser extent," says Bhaskar. "So to characterize that understanding would be important."