Regeneron Pharmaceuticals, Inc.

Regeneran Pharmaceuticals, Inc.

Panayiotis Stevis

Jesper Gromada

Andrew J Murphy

Judith Altarejos

Jee Hwan Kim

Ivan Borisovich Lobov

Yonaton Ray

William C Olson

Yashu Liu

David Esopi

Jorge Haller

Ivan B Lobov

Provided herein are therapeutic methods of treatment using agonist leptin receptor (LEPR) antibodies, antigen-binding fragments thereof, or compositions comprising the LEPR antibodies or antigen-binding fragments thereof. Such therapeutic methods include treatment for conditions related to metabolic dysfunction, including for example, lipodystrophy, adiposity or obesity, reducing body weight, non-alcoholic fatty liver disease, hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, hepatic steatosis, and infertility.

Methods of treatment using a leptin receptor agonist antibody

The present invention provides antibodies and antigen-binding fragments of antibodies that bind to leptin receptor (LEPR), and methods of using the same. According to certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR and activate LEPR signaling. In other embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind to LEPR and enhance sensitization of LEPR to an antigen. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR in the presence and absence of leptin. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that induce signaling in cells expressing LEPR mutants that otherwise exhibit defective or impaired signaling in the presence of leptin. The antibodies and antigen-binding fragments of the present invention are useful for the treatment of lipodystrophies and other diseases and disorders associated with or caused by leptin deficiency or leptin resistance.

Antigen-binding proteins that activate the leptin receptor

The present invention relates to antigen-binding molecules, including bispecific antigen-binding molecules that bind human GP130 and/or human leptin receptor (LEPR), and the use of such antigen-binding molecules for the treatment of conditions and disorders related to leptin deficiency or leptin resistance. The bispecific antigen-binding molecules of the present invention can be, e.g., bispecific antibodies comprising a first antigen-binding domain that specifically binds human GP130 and a second antigen-binding domain that specifically binds human LEPR. The bispecific antigen-binding molecules of the present invention are useful in therapeutic applications where induced leptin and/or LEPR-mediated signaling would be beneficial, e.g., in the treatment of obesity, lipodystrophies and other diseases and disorders associated with or caused by leptin deficiency or leptin resistance.

Bispecific antigen binding molecules that bind leptin receptor and/or GP130, and methods of use thereof

The present invention provides apelin receptor (APLNR) modulators that bind to APLNR and methods of using the same. The invention includes APLNR modulators such as antibodies, or antigen-binding fragments thereof, which inhibit or attenuate APLNR-mediated signaling. The invention includes APLNR modulators such as antibodies, or antibody fusion proteins thereof, that activate APLNR-mediated signaling. According to certain embodiments of the invention, the antibodies or antigen-binding fragments or antibody fusion proteins are fully human antibodies that bind to human APLNR with high affinity. The APLNR modulators of the invention are useful for the treatment of diseases and disorders associated with APLNR signaling and/or APLNR cellular expression, such as cardiovascular diseases, angiogenesis diseases, metabolic diseases and fibrotic diseases.

Method of treatment with a fusion protein comprising apelin and an anti-APLNR antibody

The present invention provides antibodies and antigen-binding fragments of antibodies that bind to leptin receptor (LEPR), and methods of using the same. According to certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR and antagonize LEPR signaling. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR in the presence or absence of leptin. In other embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that exhibit partial agonism of LEPR signaling. The antibodies and antigen-binding fragments of the present invention are useful for the treatment of various conditions, including but not limited to congestive heart failure cachexia, pulmonary cachexia and cancer cachexia, autoimmune disorders such as inflammatory bowel disease, lupus erythematosus, multiple sclerosis, psoriasis, cardiovascular diseases, elevated blood pressure, neurodegenerative disorders, depression, cancer such as hepatocellular carcinoma, melanoma, breast cancer, and other diseases and disorders associated with or caused by elevated leptin signaling.

Antigen-binding proteins that antagonize leptin receptor

Screening methods as well as kits for identifying modulators of hydroxysteroid (17-beta) dehydrogenase (HSD17B) family member proteins, such as HSD17B13, are provided. The methods comprise screening molecules for their capacity to modulate the HSD17B family member protein, including inhibiting the HSD17B family member protein, as measured by substrate depletion, product concentration from the HSD17B family member protein substrate conversion or NADH concentration, levels of labeled substrate, luciferin light emission, or combinations thereof. Inhibitors of HSD17B family member proteins identified through the screening methods may be used to treat liver diseases, disorders, or conditions in which the HSD17B family member protein plays a role.

Assays for screening activity of modulators of members of the hydroxy steroid (17-beta) dehydrogenase (HSD17B) family

Fusion protein comprising apelin and an anti-APLNR antibody

The present invention provides apelin receptor (APLNR) modulators that bind to APLNR and methods of using the same. The invention includes APLNR modulators such as antibodies, or antigen-binding fragments thereof, that inhibit or attenuate APLNR-mediated signaling. The invention includes APLNR modulators such as antibodies, or antibody fusion proteins thereof, that activate APLNR-mediated signaling. According to certain embodiments of the invention, the antibodies or antigen-binding fragments or antibody fusion proteins are fully human antibodies that bind to human APLNR with high affinity. The APLNR modulators of the invention are useful for the treatment of diseases and disorders associated with APLNR signaling and/or APLNR cellular expression, such as cardiovascular diseases, angiogenesis diseases, metabolic diseases and fibrotic diseases.

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West Orange, NJ, United States of America

Panayiotis Stevis