Insulin is the key metabolic hormone for regulating blood sugar and exerts its action on cells by signaling through the insulin receptor. Highly specific human antibodies that activate or deactivate the insulin receptor offer new direct mechanisms for treating abnormal metabolic states.
We discovered new classes of fully human monoclonal antibodies that regulate insulin receptor activity thus providing distinct new therapeutic approaches to the treatment of patients with abnormal metabolic states. These programs are highly novel as the antibodies bind to allosteric sites on the insulin receptor, unlike currently marketed drugs.
XOMA 358 (originally described as XMetD for ‘deactivate’) is a fully human allosteric modulating monoclonal antibody that binds to insulin receptors and attenuates insulin action. XOMA 358 is being investigated as a novel treatment for hyperinsulinemic hypoglycemia (low blood glucose caused by excessive insulin production) and other related disorders. A therapy that safely and effectively mitigates insulin-induced hypoglycemia has the potential to address a significant unmet therapeutic need for certain rare medical conditions associated with hyperinsulinism.
Congenital Hyperinsulinism (CHI) is a genetic disorder in which the insulin cells of the pancreas (beta cells) secrete inappropriate and excessive insulin. Ordinarily, beta cells secrete just enough insulin to keep blood sugar in the normal range. In people with CHI, the secretion of insulin is not properly regulated, causing excess insulin secretion at times when it is not essential and, hence, frequent episodes of low blood sugar (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications, such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, coma, and possibly death. About 60 percent of infants with CHI experience a hypoglycemic episode within the first month of life. Other affected children develop hypoglycemia by early childhood. Current treatments for CHI are limited to medical therapy and surgical removal of part or all of the pancreas (pancreatectomy).
Post-bariatric Surgery (PBS) Hypoglycemia [aka post-gastric bypass hypoglycemia (PGBH)]
As the number of gastric bypass surgeries to treat severe obesity has increased, so too has the awareness that this population may experience severe hypoglycemic periods – especially postprandial (low blood glucose following a meal). This disorder typically develops months or years following the gastric bypass surgery. The mild end of the spectrum may be managed largely through diet modification. The most severe forms are more prevalent in patients who underwent a Roux-en-Y procedure and result in severe refractory postprandial hyperinsulinemic hypoglycemia with neuroglycopenic symptoms (altered mental status, loss of consciousness, seizures) that cannot be managed through diet modification. As available pharmacologic agents often do not resolve the condition, these patients may receive either a partial pancreatectomy or attempted reversal of the gastric bypass.