A Fully Human, Allosteric Monoclonal Antibody That Activates the Insulin Receptor and Improves Glycemic Control

Abstract

Many patients with diabetes mellitus (both type 1 and type 2) require therapy to maintain normal fasting glucose levels. To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. XMetA was found to function as a specific partial agonist of INSR, eliciting tyrosine phosphorylation of INSR but not the IGF-IR. Although this antibody activated metabolic signaling, leading to enhanced glucose uptake, it neither activated Erk nor induced proliferation of cancer cells. In an insulin resistant, insulinopenic model of diabetes, XMetA markedly reduced elevated fasting blood glucose and normalized glucose tolerance. After 6 weeks, significant improvements in HbA1c, dyslipidemia, and other manifestations of diabetes were observed. It is noteworthy that hypoglycemia and weight gain were not observed during these studies. These studies indicate, therefore, that allosteric monoclonal antibodies have the potential to be novel, ultra-long acting, agents for the regulation of hyperglycemia in diabetes.

Selective Allosteric Antibodies to the Insulin Receptor for the Treatment of Hyperglycemic and Hypoglycemic Disorders

“…This activation did not block insulin action. 7 Similarly, XMetA partially stimulated the phosphorylation of Akt, a major intracellular mediator of INSR signaling ( Figure 3C). This activation of pAkt allowed XMetA to fully stimulate 2-deoxy-D-glucose uptake ( Figure 3D).…”

“…7 XMetA did not alter the affinity of insulin binding to the human INSR ( Figure 3A). Moreover, XMetA partially activated the INSR as demonstrated by enhanced INSR autophosphorylation ( Figure 3B).…”

“…Although XMetA activated pAkt, in contrast to insulin it did not significantly activate pERK. 7 While XMetA had a major effect on the INSR, it had no effect on the closely related IGF-1R receptor. 7 To evaluate the in vivo activity of XMetA, we utilized an animal model of insulinopenic, insulin-resistant diabetes, the multi-low-dose streptozotocin, high-fat diet (MLDS/HFD) mouse.…”

“…7 While XMetA had a major effect on the INSR, it had no effect on the closely related IGF-1R receptor. 7 To evaluate the in vivo activity of XMetA, we utilized an animal model of insulinopenic, insulin-resistant diabetes, the multi-low-dose streptozotocin, high-fat diet (MLDS/HFD) mouse. 28 In this diabetic animal, fasting blood glucose levels were elevated to nearly 500 mg/dL compared to normal animals whose fasting blood glucose levels were approximately 150 mg/dL.…”

“…6 We have recently produced allosteric antibodies that regulate INSR signaling by either direct activation, or positive or negative modulation. [7][8][9][10] These types of antibodies have been classified as selective INSR modulators.…”