Regeneron Pharmaceuticals, Inc.

Haruka Okamoto

Joyce Harp

Jesper Gromada

Mark Sleeman

Andrew J Murphy

Samuel H Davis

Yang Wei

Stephen R Jaspers

Jee Hwan Kim

William C Olson

Amy Han

Mark W Sleeman

Xiping Cheng

The present disclosure relates to antibodies or antigen-binding fragments thereof that bind specifically to the glucagon-like peptide 1 receptor (GLP1R) protein, and methods of use thereof. In various embodiments, the antibodies or antigen-binding fragments thereof are fully human antibodies that bind to GLP1R. In some embodiments, the antibodies or antigen-binding fragments thereof are useful for attenuating GLP1R activity, thus providing a means of treating, preventing, or alleviating a disease, disorder or condition associated with GLP1R in humans. In some embodiments, the antibodies or antigen-binding fragments thereof elevate glucose levels when administered to a subject and thereby treat hypoglycemia, such as post-bariatric hypoglycemia (PBH), by attenuating insulin secretion from pancreatic beta cells and decreasing insulin expression.

Polynucleotides encoding anti-glucagon-like peptide 1 receptor (GLP1R) antagonist antibodies

Described herein are protein-drug conjugates and compositions thereof that are useful, for example, for targeting glucagon-like peptide 1 receptor (GLP1R). In certain embodiments, provided are peptidomimetic payloads and linker-payloads and methods of making same. More specifically, GLP1 peptidomimetics, antibody-drug conjugates, and compositions which comprise anti-GLP1R antibodies and GLP1 peptidomimetic payloads and methods of treating GLP1R-associated conditions are provided.

Antibody-drug conjugates comprising GLP1 peptidomimetics and uses thereof

The present invention provides antibodies that bind to the human glucagon receptor, designated GCGR and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human GCGR. The antibodies of the invention are useful for lowering blood glucose levels and blood ketone levels and are also useful for the treatment of diseases and disorders associated with one or more GCGR biological activities, including the treatment of diabetes, diabetic ketoacidosis and long-term complications associated with diabetes, or other metabolic disorders characterized in part by elevated blood glucose levels.

Human antibodies to the human glucagon receptor (HGCGR) and methods of use thereof to lower blood glucose or ketone levels

Provided herein are methods of treating a subject with hyperammonemia or a urea cycle disorder. The methods comprise administering to a subject in need thereof a therapeutic amount of a glucagon signaling pathway inhibitor, such that ammonia levels are lowered or that amino acid metabolism enzymes are down-regulated, or a condition or disease characterized by hyperammonemia is mediated, or at least one symptom or complication associated with the condition or disease is alleviated or reduced in severity. The glucagon signaling pathway inhibitor can be a small molecule inhibitor of the signaling pathway, an antisense inhibitor of the signaling pathway, shRNA, siRNA, a GCG neutralizing monoclonal antibody, a GCGR antagonist, a peptide inhibitor of the signaling pathway, a DARPin, a Spiegelmer, an aptamer, engineered Fn type-III domains, etc. The therapeutic methods are useful for treating a human suffering from hyperammonemia or a urea cycle disorder.

Methods of treating urea cycle disorders by interfering with glucagon receptor signaling

The present invention provides modified glucagon-like peptide 1 (GLP1) polypeptides, fusion proteins comprising modified GLP1 polypeptides, and methods of use thereof. In various embodiments of the invention, the fusion proteins are GLP1 receptor agonists that comprise a modified GLP1 fused to a stabilizing domain. In some embodiments, the fusion proteins comprising modified GLP1 are useful for treating or ameliorating a symptom or indication of a disorder such as obesity and diabetes.

Glucagon-like peptide 1 receptor agonists and uses thereof

Antibodies which bind to glucagon-like peptide 1 receptor (GLP1R)

Provided herein are methods of treating a patient with severe insulin resistance. The methods comprise administering to a patient in need thereof a therapeutic amount of a GCG/GCGR signaling pathway inhibitor, such that blood glucose or beta-hydroxybutyrate levels are lowered or that the severe insulin resistance is mediated, or a condition or disease characterized by severe insulin resistance is mediated, or at least one symptom or complication associated with the condition or disease is alleviated or reduced in severity. The GCG/GCGR signaling pathway inhibitor can be a small molecule inhibitor of the signaling pathway, an antisense inhibitor of the signaling pathway, a GCG neutralizing monoclonal antibody, a GCGR antagonist, a peptide inhibitor of the signaling pathway, a DARPin, a Spiegelmer, an aptamer, engineered Fn type-III domains, etc. The therapeutic methods are useful for treating a human suffering from severe insulin resistance.

Methods of treating severe insulin resistance by interfering with glucagon receptor signaling

Human antibodies to the human glucagon receptor and methods of use thereof to lower blood glucose or ketone levels

Nucleic acid molecules encoding antibodies to the human glucagon receptor

Human antibodies to the glucagon receptor and methods of use thereof for lowering blood glucose or ketone levels

The present invention provides antibodies that bind to glucagon and methods of using the same. According to certain embodiments, the antibodies of the invention bind human GCG with high affinity. The antibodies of the invention may be fully human antibodies. The antibodies of the invention are useful for the treatment of various diseases or disorders characterized by elevated blood glucose levels, as well as other GCG-related disorders.

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New York, NY, United States of America

Haruka Okamoto