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

Vinay Bhaskar; Ira D. Goldfine; Daniel H. Bedinger; Angela Lau; Hua F. Kuan; Lisa M. Gross; Masahisa Handa; Betty A. Maddux; Susan R. Watson; Shirley Zhu; Ajay J. Narasimha; Raphael Levy; Lynn Webster; Sujeewa D. Wijesuriya; Naichi Liu; Xiaorong Wu; David Chemla-Vogel; Catarina Tran; Steve R. Lee; Steve Wong; Diane Wilcock; Mark L. White; John A. Corbin


Diabetes. 2012;61(5):1263-1271. 

In This Article

Abstract and Introduction


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.


Absolute or relative insulinopenia are features of diabetes. Type 1 diabetes (T1DM) occurs in ~10% of patients with diabetes and is associated with absolute insulinopenia.[1] In most individuals who develop type 2 diabetes (T2DM), both insulin resistance and relative insulinopenia are present.[2–12] It has been estimated that β-cell function has declined by 80% at the time of the initial diagnosis of T2DM.[13] In late T2DM, as in T1DM, many patients are administered a long-acting insulin to control fasting blood glucose.

Insulin acts by binding to the insulin receptor (INSR) on the cell surface, a process that activates cell signaling.[14] When activated, the INSR undergoes autophosphorylation, followed by the recruitment of insulin receptor signaling molecules, including the IRS proteins and members of the phosphotidylinositol 3-kinase (PI3K)/Akt pathway.[15] As a result, there is translocation of glucose transporters, including GLUT4, to the cell surface.[16] These processes are impeded in the insulin resistant state of T2DM and further compromised under conditions of insufficient insulin.[17] Activation of INSR also stimulates Erk phosphorylation, a mitogenic signal postulated to contribute to inflammation, cancer cell proliferation, and deleterious cardiovascular outcomes.[18]

Long-acting, or basal, insulins, such as insulin detemir and insulin glargine, are insulin analogs that are now used therapeutically in patients with diabetes.[19] Although these agents are effective at lowering fasting blood glucose, they must be administered subcutaneously, once or twice daily. As insulin analogs, they carry the risk of hypoglycemic episodes and weight gain, both of which are associated with poor cardiovascular outcomes.[20] Therefore, longer-acting molecules that activate the insulin receptor without hypoglycemia would be helpful in the treatment of diabetes.

Antibodies have been shown to activate the INSR, including both spontaneously occurring human autoantibodies and mouse monoclonal antibodies.[21–23] In humans, autoantibodies to the INSR typically bind at the insulin binding site (the orthosteric site). In most cases, these antibodies block insulin binding, causing severe insulin resistance and diabetes.[24–27] However, it has been reported that in some individuals, orthosteric INSR autoantibodies mimic insulin and stimulate the INSR, causing hypoglycemia.[26,28–30]

Orthosteric antibodies that mimic ligand signaling have also been reported for other receptors.[31–34] It has also been reported that allosteric antibodies, antibodies that do not bind at the ligand binding site of receptors, can activate cell signaling.[35] 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 (e.g., the INSR is activated not only by insulin but also by IGFs). Allosteric regulation of the insulin receptor by glucose and peptides has been described previously.[36–39] It is possible, therefore, that allosteric antibodies to receptors, such as the INSR, could be generated and be of benefit for the treatment of disease, including diabetes. To date, therapeutic allosteric antibodies to the INSR have not been reported.

To identify such antibodies, we selectively screened human phage display libraries for allosteric antibodies that activated the INSR. We selected one such allosteric antibody, XMetA, for further characterization both in vitro and in vivo. In cultured cells, XMetA activated INSR signaling and promoted glucose uptake. In diabetic mice, XMetA normalized fasting blood glucose for 6 weeks without hypoglycemia and improved metabolic parameters of diabetes.


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