<scp>XMetA</scp>, an allosteric monoclonal antibody to the insulin receptor, improves glycaemic control in mice with diet‐induced obesity

Bhaskar, Vinay; Lau, Angela; Goldfine, Ira D.; Narasimha, Ajay J.; Groß, Lisa; Wong, Stephen; Cheung, Bruno Man-Hon; White, Mark L.; Corbin, John

doi:10.1111/dom.12019

Cited by 15 publications

(26 citation statements)

References 13 publications

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“…Antidiabetic Activity of a Long-Acting IR Partial Agonist levels, potentially supporting an insulin/b-cell sparing mechanism. Reductions in both hyperglycemia and C-peptide levels are consistent with the previous studies in insulinopenic diabetic mice (Bhaskar et al, 2012) and in hyperinsulinemic DIO mice after 4 weeks of dosing (Bhaskar et al, 2013). HbA1c levels reflect long-term exposure to elevated glucose levels (i.e., functions as a measure of glycemic control in the previous 8-12 weeks in these monkeys), considering that the lifespan of a macaque erythrocyte is 60-85 days (Moore, 2010).…”

Section: Discussionsupporting

confidence: 86%

“…at 10 mg/kg twice per week for 4 weeks normalized fasting glucose without contributing to weight gain. XMetA treatment also corrected glucose tolerance, improved non-high-density lipoprotein cholesterol, and decreased elevated C-peptide levels in the DIO mice (Bhaskar et al, 2013). Furthermore, recent data indicate that a single s.c. administration of XMetA at 10 mg/kg to insulin-dependent spontaneous type 2 diabetic rhesus monkeys substantially reduced fasting hyperglycemia for several days along with a modest effect on nonfasting hyperglycemia (Zhao et al, 2014).…”

Section: Introductionmentioning

confidence: 88%

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

Bezwada

Zhao

Der

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 88%

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

Bezwada

Zhao

Der

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…7,8 Moreover, the blood glucose response to exogenous insulin was improved. 7,8 These observations suggested the interesting possibility that antibodies such as XMetA, by activating INSR, both in vitro and in vivo, have the potential to improve glycemic control in a model of insulinopenic diabetes without causing hypoglycemia or promoting weight gain. To our knowledge, XMetA is the first fully human monoclonal antibody to the INSR reported to correct hyperglycemia and improve diabetes in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Issafras

Bedinger

Corbin

et al. 2014

J Diabetes Sci Technol

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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.

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“…XMetA is also active on the mouse and monkey IR. 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).…”

Section: Introductionmentioning

confidence: 99%

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

Bedinger

Goldfine

Corbin

et al. 2015

J Pharmacol Exp Ther

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The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathwaybiased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.

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XMetA, an allosteric monoclonal antibody to the insulin receptor, improves glycaemic control in mice with diet‐induced obesity

Cited by 15 publications

References 13 publications

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

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

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

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

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