A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys

Abstract

XMetA is a fully human, allosteric monoclonal antibody that binds the insulin receptor with high affinity and mimics the glucoregulatory, but not the mitogenic, actions of insulin. Here we evaluated the efficacy of both single and repeat s.c. administrations of XMetA in reducing hyperglycemia in obese cynomolgus monkeys with naturally developed type 2 diabetes, a model that shares many features of human diabetes. The data show that a single s.c. administration of XMetA at dose levels ranging from 1.5 to 10 mg/kg markedly reduced fasting hyperglycemia, with a peak effect occurring 1 to 2 days after administration, and sustained for up to 1 week. XMetA's effect on hyperglycemia was observed without elevations in serum insulin and was concomitant with reduced serum C-peptide levels, even at the lowest dose. Subchronic effects were evaluated via once weekly s.c. administration of XMetA, 10 mg/kg, for 6 weeks. XMetA treatment resulted in robust weekly decreases in fasting glucose levels averaging approximately 30% throughout the study, along with a significant absolute reduction from the vehicle control baseline of 1.2% in hemoglobin A1c, a marker of long-term glycemic status. XMetA treatment was well tolerated with no injectionsite reactions, no body weight gain, and no episodes of clinical hypoglycemia. Thus, XMetA shows acute and subchronic improvements in glycemic control in spontaneously diabetic cynomolgus monkeys with a broad safety margin. This profile supports the development of XMetA as a novel glucose-lowering therapeutic agent for the management of type 2 diabetes.

Anti-Insulin receptor antibodies improve hyperglycaemia in a mouse model of human insulin receptoropathy

“…However, such bivalent antibodies can also bind and activate WT human INSR (14), and naturally occurring polyclonal anti-INSR antibodies induce hypoglycaemia at low titres, and extreme insulin resistance at high titres in humans (19). On the other hand, monoclonal human anti-INSR antibodies have been suggested as a therapeutic strategy in common forms of diabetes, without evaluation of effects on receptor expression (9)(10)(11)(12).…”

“…With therapeutic humanised monoclonal antibodies now well established as treatments both for cancer and non-cancer indications (7), interest in biological therapies targeting the INSR has recently rekindled. Inhibitory INSR antibodies are now in Phase 1 human trials(8) while stimulatory antibodies have been shown to ameliorate diabetes in rodents(9-11) and primates (12). Given the high clinical need in recessive insulin receptoropathy, we previously assessed the effect of monoclonal anti-INSR antibodies(13-17) on a series of disease-causing mutant INSRs in cell culture models, corroborating and extending prior findings by demonstrating an action of antibodies against a panel of mutant receptors (18).…”

“…A specific concern relates to the documented effect of naturally occurring anti-INSR autoantibodies, which are partial agonists when tested acutely on cellular models, to downregulate INSR signalling when present at high concentrations in vivo, inducing acquired severe IR, known as "type B" IR (19). Such an effect has not been assessed in preclinical testing of anti-INSR antibodies reported to date (9)(10)(11)(12), but is a critical concern in efforts to develop safe, efficacious biological therapies targeting the INSR.…”

Novel therapies in type 2 diabetes: insulin resistance

“…In diet‐induced obese mice, XMetA normalised fasting glucose, corrected glucose tolerance and improved non‐HDL cholesterol with no weight gain or hypoglycaemia . Similar results were found recently in a study in diabetic cynomolgus monkeys …”

Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models

“…Interest in biological therapies targeting the INSR has recently rekindled, with inhibitory antibodies in Phase 1 human trials [11] and stimulatory antibodies shown to ameliorate diabetes in rodents [12][13][14] and primates [15]. Given the high clinical need in recessive insulin receptoropathy, we assessed the effect of monoclonal anti-INSR antibodies [16][17][18][19][20] on a series of disease-causing mutant INSRs.…”