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

Abstract

Recombinant monoclonal antibodies, by blocking cellular pathways that are dysregulated, are powerful targeted therapeutics for certain severe diseases. 1-2 However, these cellular pathways, when functioning normally, also have important roles in normal physiology. Therefore successful treatment of these diseases may require modulation, rather than complete inhibition, of signaling pathways to restore a normal physiological state with a potentially low side-effect profile. Monoclonal antibodies also have the potential to treat disease states by either stimulating or enhancing biological signaling pathways. This class of antibodies has the potential to maintain the spatial and temporal aspects of endogenous ligands such as hormones, cytokines, and neurotransmitters. The site on receptors at which the endogenous ligand binds is defined as the orthosteric site (Figure 1A). Sites on the receptor at which nonligand molecules bind are termed allosteric sites. 1 Regulation of receptor activity by molecules binding to allosteric sites has been recognized as common mechanism for the control of enzyme activity and protein function. 3 We previously described a new approach to target disease using an allosteric antibody approach based on the modulation of ligand-receptor binding kinetics. 2 Both allosteric and orthosteric antibodies can induce conformational changes in receptors that may markedly activate or modulate receptor function. This approach has been previously employed to regulate receptors using small molecules. 3 Allosteric antibodies have the potential to bind and regulate receptors more selectively than orthosteric antibodies (Figure 1). This selectivity is due to lower sequence and structural homology at allosteric sites relative to orthosteric sites. 4,5 This selectivity of allosteric molecules is particularly useful for targeting closely related receptors that bind to similar natural ligands. Moreover, because of their noncompetitive nature 529886D STXXX10.

Differential Effects of Camel Milk on Insulin Receptor Signaling – Toward Understanding the Insulin-Like Properties of Camel Milk

“…This observation supports the existence of an allosteric effect of camel milk on ERK1/2 phosphorylation, which may depend on the allosteric potentiation of the conformation of hIR–Grb2 complexes as shown in Figures 2 and 3 . Such allosteric modulation on insulin receptor has been recently reported when selective antibodies were used in combination with insulin stimulation arguing for the existence of functional allosteric binding sites on hIR ( 36 , 37 ). Regarding the interaction of hIR with IRS1 and Akt phosphorylation, camel milk affected neither the BRET signal between hIR–Rluc and IRS1–YFP nor Akt activation, both the basal and insulin-mediated response.…”

Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody

“…In rodent models of diabetes (Bhaskar et al, 2012(Bhaskar et al, , 2013, and in spontaneously diabetic primates (Zhao et al, 2014), XMetA decreases fasting blood glucose levels. Moreover, XMetA did not cause hypoglycemia in these diabetic animals (Bhaskar et al, 2012(Bhaskar et al, , 2013Issafras et al, 2014).…”

Novel Monoclonal Antibody Is an Allosteric Insulin Receptor Antagonist That Induces Insulin Resistance

“…Corbin and colleagues (34,35) identified another allosteric IR mAb antagonist, XMetD, which appears to be Figure 5-IRAB-B induces hyperglycemia and weight loss in vivo. Blood glucose was measured in normal C57 mice treated with IRAB-B or isotype.…”