Antibody Fragments Against the Insulin Receptor and Uses Thereof to Treat Hypoglycemia

Abstract

The present disclosure relates, in general, to methods of treating or preventing hypoglycemia using a negative modulator antibody fragment that binds to the insulin receptor and modulates the action of insulin at the insulin receptor.

Description

[0001]This application claims the priority benefit of U.S. Provisional Patent Application 62 / 202,143, filed Aug. 6, 2015, and U.S. Provisional Patent Application 62 / 280,675, filed Jan. 19, 2016, herein incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present disclosure relates, in general, to the use of a negative modulator antibody fragment specific for the insulin receptor that modulates the binding of insulin to the insulin receptor in the treatment and prevention of hypoglycemia, e.g., due to endogenous or exogenous hyperinsulinemia, insulin overdose, drug-induced hypoglycemia, insulin-induced hypoglycemia, hypoglycemia that occurs after eating in patients who have undergone bariatric, or gastric bypass surgery, and disease hypoglycemic states characterized by abnormal glucose levels, as well as complications and conditions related to hyperinsulinemia.BACKGROUND OF THE INVENTION[0003]The present disclosure relates to novel modulators of the insulin-ins...

AI Technical Summary

Benefits of technology

[0024]In various embodiments, the invention provides a method for treating or preventing nocturnal hypoglycemia comprising administering to a subject in need thereof an antibody or fragment thereof that is a negative modulator of insulin binding to the insulin receptor and / or insulin action at the insulin receptor in an amount effective to ameliorate or prevent nocturnal hypoglycemia.

[0031]In various embodiments, administering the antibody fragment reduces complications associated with hyperinsulinemia or excess insulin signaling in the subject.

[0041]In various embodiments, the administration of the antibody or fragment thereof prevents or ameliorates one or more symptoms of hypoglycemia selected from the group consisting of pancreatic nesidioblastosis, islet cell enlargement, islet cell hyperplasia, β cell budding, tachycardia, diaphoresis, flushing and reduced cognitive function.

[0042]In various embodiments, the administration of the antibody or fragment thereof reduces or eliminates hypoglycemia within 20 minutes, optionally within 15 minutes.

[0050]The disclosure further contemplates that the antibodies or fragments thereof of the disclosure modulate binding between the INSR and insulin, insulin analogs or insulin mimetics. In various embodiments, the antibodies or fragments thereof of the disclosure also exhibit desirable biological properties including, but not limited to, decreasing glucose uptake in vitro or in vivo in animal models, and preferably the glucose uptake induced by exogenous insulin or insulin production induced by other pharmacological treatment such as sulfonylureas and other drugs. In some embodiments, the antibodies or fragments thereof are capable of decreasing the rate or total amount of glucose uptake, or both.

[0055]Administration to an at-risk patient before or at the beginning of symptoms can reduce the need for alternate or current standard of care treatments, reduce the need for a pancreatectomy, and reduce the number of doctor visits for the treated subject.

Problems solved by technology

Abnormal increases in insulin secretion can lead to profound hypoglycemia or low blood sugar, a state that may result in significant morbidities including epilepsy and cerebral damage.

Recurrent episodes of hypoglycemia impair the body's defenses against subsequent falling plasma glucose concentrations and thus cause a vicious cycle of recurrent hypoglycemia.

Hypoglycemia results in a variety of symptoms including; lack of coordination, confusion, loss of consciousness, seizures, and even death.

However, when the hypoglycemic patient cannot take oral glucose supplements, because of confusion, unconsciousness or other reasons, parenteral therapy is required.

A commonly observed side effect of gastric bypass surgery is “dumping,” which is a consequence of the ingestion of simple sugars and rapid emptying of food into the small intestine.

Unlike with dumping, nutrition modification does not alleviate the symptoms of post-prandial hypoglycemia (PPH).

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