Attenuation of Insulin Action by an Allosteric Insulin Receptor Antibody in Healthy Volunteers

Johnson, Kirk W.; Neale, Ann; Gordon, Allan; Roessig, Julie M.; Bezwada, Padma; Vukelich, Sabine; Goldfine, Ira D.; Rubin, Paul

doi:10.1210/jc.2017-00822

Cited by 17 publications

(16 citation statements)

References 29 publications

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“…7 In healthy volunteers, a single dose of XMetD resulted in a significant elevation of postprandial plasma glucose concentration and a significant attenuation of the decrease in plasma glucose induced by insulin in the setting of an insulin tolerance test. 8 Our study extends these findings in a mouse model relevant to the human condition of endogenous hyperinsulinemic hypoglycemia. Although SUR-1 ¡/¡ mice are relatively normoglycemic in the fed state, 9,10 they develop hypoglycemia with fasting, which allowed us to test the potential for an insulin receptor allosteric inhibitor to normalize fasting plasma glucose in the absence of functional K ATP channels.…”

Section: Discussionsupporting

confidence: 68%

“…7 In a Phase 1 clinical study, a single infusion of XMetD resulted in a dosedependent reduction in insulin sensitivity in healthy adults. 8 We have now examined the effect of XMetD on fasting plasma glucose and other parameters of glucose and energy metabolism in a mouse model of K ATP HI, the SUR-1 ¡/¡ mice. 9,10 initiation of treatment, including body weight, fasting and fed plasma glucose and fasting plasma insulin, followed by randomization to treatment with XMetD or control antibody (KLH2G2) ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism

Patel

Charles

Corbin

et al. 2018

mAbs

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Loss-of-function mutations of the ß-cell ATP-sensitive potassium channels (K) cause the most common and severe form of congenital hyperinsulinism (KHI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with KHI are typically unresponsive to medical therapy and require pancreatectomy for intractable hypoglycemia. We tested the hypothesis that inhibition of insulin receptor signaling may prevent hypoglycemia in KHI. To test this hypothesis, we examined the effect of an antibody allosteric inhibitor of the insulin receptor, XMetD, on fasting plasma glucose in a mouse model of KHI (SUR-1 mice). SUR-1 and wild-type mice received twice weekly intraperitoneal injections of either XMetD or control antibody for 8 wks. Treatment with XMetD significantly decreased insulin sensitivity, and increased hepatic glucose output and fasting plasma glucose. These findings support the potential use of insulin receptor antagonists as a therapeutic approach to control the hypoglycemia in congenital hyperinsulinism.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism

Patel

Charles

Corbin

et al. 2018

mAbs

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“…A number of new therapeutic developments are likely to improve treatment options for CHI in the near future. In addition to soluble glucagon formulations currently in trial, other products in development include a monoclonal antibody that is a negative allosteric modulator of the insulin receptor which reduces insulin's action on glucose . The glucagon‐like peptide‐1 (GLP‐1) receptor is also a putative target with potential to reduce insulin secretion as evidenced by a drug trial of exendin 9‐39 in older children and adults .…”

Section: Other Medicationsmentioning

confidence: 99%

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism

Worth

Yau²,

Estebanez

et al. 2020

Clinical Endocrinology

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Congenital Hyperinsulinism (CHI) is a rare disease of hypoglycaemia but is the most common form of recurrent and severe hypoglycaemia causing brain injury and neurodisability in children. The management of CHI is complex due to the limited choice of medications, all with a limited therapeutic window, often lacking efficacy and associated with serious side effects. The therapeutic strategy in CHI is to recognize and treat hypoglycaemia promptly, thereby optimizing long-term neurological outcomes; this should be achieved through individualized treatment plans that deliver glycaemic stability while minimizing side effects. Further, such a strategy should consider the likelihood of reduction in disease severity over time, with dose adjustments and medication withdrawal as indicated to optimize both safety and tolerability. The option for pancreatic surgery should also be considered in specific circumstances as appropriate for the patient's best long-term interests. K E Y W O R D Scongenital hyperinsulinism, glucose, hypoglycaemia, insulin, management, medication

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“…With therapeutic humanized monoclonal antibodies now well established as treatments both for cancer and noncancer indications ( 9 ), interest in biological therapies targeting the INSR has been recently rekindled. Inhibitory INSR antibodies are now in phase 1 human trials ( 10 ), while stimulatory antibodies have been shown to ameliorate diabetes in rodents ( 11 – 13 ) and primates ( 14 ). Given the high clinical need in recessive insulin receptoropathy, we previously assessed the effect of monoclonal anti-INSR antibodies ( 15 – 19 ) 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 ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy

et al. 2020

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Loss-of-function mutations in both alleles of the human insulin receptor gene (INSR) cause extreme insulin resistance (IR) and usually death in childhood, with few effective therapeutic options. Bivalent antireceptor antibodies can elicit insulin-like signaling by mutant INSR in cultured cells, but whether this translates into meaningful metabolic benefits in vivo, wherein the dynamics of insulin signaling and receptor recycling are more complex, is unknown. To address this, we adopted a strategy to model human insulin receptoropathy in mice, using Cre recombinase delivered by adeno-associated virus to knockout endogenous hepatic Insr acutely in floxed Insr mice (liver insulin receptor knockout [L-IRKO] + GFP), before adenovirus-mediated add back of wild-type (WT) or mutant human INSR . Two murine anti-INSR monoclonal antibodies, previously shown to be surrogate agonists for mutant INSR, were then tested by intraperitoneal injections. As expected, L-IRKO + GFP mice showed glucose intolerance and severe hyperinsulinemia. This was fully corrected by add back of WT but not with either D734A or S350L mutant INSR. Antibody injection improved glucose tolerance in D734A INSR-expressing mice and reduced hyperinsulinemia in both S350L and D734A INSR-expressing animals. It did not cause hypoglycemia in WT INSR-expressing mice. Antibody treatment also downregulated both WT and mutant INSR protein, attenuating its beneficial metabolic effects. Anti-INSR antibodies thus improve IR in an acute model of insulin receptoropathy, but these findings imply a narrow therapeutic window determined by competing effects of antibodies to stimulate receptors and induce their downregulation.

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Attenuation of Insulin Action by an Allosteric Insulin Receptor Antibody in Healthy Volunteers

Abstract: Single X358 infusions were well tolerated and resulted in a dose-dependent reduction in insulin sensitivity. Clinical development of X358 in hyperinsulinemic, hypoglycemic conditions is proceeding.

Cited by 17 publications

References 29 publications

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism

Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy

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Attenuation of Insulin Action by an Allosteric Insulin Receptor Antibody in Healthy Volunteers

Abstract: Single X358 infusions were well tolerated and resulted in a dose-dependent reduction in insulin sensitivity. Clinical development of X358 in hyperinsulinemic, hypoglycemic conditions is proceeding.

Cited by 17 publications

References 29 publications

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1−/− mouse model of KATP hyperinsulinism

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1−/− mouse model of KATP hyperinsulinism

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism

Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy

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Product

Resources

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A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1^−/− mouse model of KATP hyperinsulinism