Derailing diabetes
New antibody corrects hyperglycemia without evidence of hypoglycemia, weight gain
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Through insights into the regulation of signaling pathwaysgained using XOMA's ModulX! technology, we have discovered three distinctclasses of allosteric antibodies that act differentially on the insulinreceptor," Dr. Patrick J. Scannon, executive vice president and chiefscientific officer of XOMA, said in a press release. "XMetA, an antibody fromone such class, selectively activates pathways leading to glucose-loweringwhile avoiding pathways leading to cellular proliferation. We believe thisprofile is unique and offers a new approach to treatment of diabetes."
While monoclonal antibodies bind at the ligand-receptorbinding sites, XOMA's XMet antibodies bind to other sites found on receptors,known as allosteric sites. While binding at the ligand-receptor sites leads tocomplete activation or inhibition, binding at the allosteric sites allows formodulation.
"It has also been reported that allosteric antibodies,antibodies that do not bind at the ligand binding site of receptors, canactivate cell signaling," the paper adds. "In theory, these allostericantibodies have the potential to activate receptors more selectively thaneither orthosteric antibodies or the natural ligand itself, in that they do notrecognize the binding determinants within a receptor that may cross-react withmultiple ligands."
Dr. Vinay Bhaskar of the Preclinical Research Department atXOMA, corresponding author for the study, notes that the XMetA antibodydemonstrates a variety of benefits.
"As an antibody, we feel that this is something to have along half-life, particularly compared to insulin itself," Bhaskar notes. "Whenyou administer normal, short-acting insulin, that has a relatively short-halflife, only minutes to hours. Extremely long-acting insulin really doesn't havea half-life longer than maybe a day or two. This actually has a half-lifethat's several days."
That extended half-life will have to be investigated inanimals higher up the testing chain than mice, he adds, but it couldpotentially mean that the antibody could be administered just once a week.
In addition, results so far indicate that the antibodydoesn't run the risk of the hypoglycemia or weight gain associated withinsulin.
"It doesn't appear to have the same propensity forhypoglycemia. It's not clear right now whether we'll see hypoglycemia till weget to higher species, but in mice we don't see it at all," says Bhaskar. "Sothat suggests that unlike insulin, it would be potentially more difficult tooverdose and become hypoglycemic, which can be a pretty serious consequence ofinsulin therapy in type 1 and type 2 diabetics."
Those characteristics offer an improvement for diabetespatients, since, as the paper notes, current insulin treatments have inherentside effects that diminish their helpfulness.
"Long-acting, or basal, insulins, such as insulin detemirand insulin glargine, are insulin analogs that are now used therapeutically inpatients with diabetes. Although these agents are effective at lowering fastingblood glucose, they must be administered subcutaneously, once or twice daily,"the paper notes. "As insulin analogs, they carry the risk of hypoglycemicepisodes and weight gain, both of which are associated with poor cardiovascularoutcomes. Therefore, longer-acting molecules that activate the insulin receptorwithout hypoglycemia would be helpful in the treatment of diabetes."
The study found that XMetA brought about significantreductions in elevated fasting blood glucose levels, and also normalizedglucose tolerance in mice that had been rendered diabetic. After six weeks oftreatment, hemoglobin A1c levels had shown a statistically significantreduction in XMetA-treated animals compared to the controls, and elevatednon-HDL cholesterol levels had also improved compared to the controls.
"In the treatment of diabetes, novel and improvedtherapeutic modalities for patients with impaired insulin secretory functionare needed," Dr. Ira. D. Goldfine, professor emeritus at the Department ofMedicine and the Diabetes Center at UCSF, as well as a XOMA DistinguishedScientific Fellow, said in a press release. "XMetA has shown potential todeliver a long-acting, glucose-regulating effect without generatinghypoglycemia. The characteristics of this molecule may result in an opportunityto leverage this potential therapeutic option earlier in the treatment ofdiabetes."
The next step, according to Bhaskar, will be to study theantibody in higher species to see if the extended half-life and lack ofhypoglycemia and weight gain will hold true.
"It's important to follow up and make sure [hypoglycemia andweight gain] actually aren't occurring. And if they are, to what extent arethey occurring … Even if hypoglycemia or weight gain does occur in a higherspecies, it would be to a lesser extent," says Bhaskar. "So to characterizethat understanding would be important."
