Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency
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Published:2023-11-22
Issue:723
Volume:15
Page:
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ISSN:1946-6234
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Container-title:Science Translational Medicine
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language:en
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Short-container-title:Sci. Transl. Med.
Author:
Altarejos Judith Y.1ORCID, Pangilinan Jeffrey1, Podgrabinska Simona1ORCID, Akinci Baris2ORCID, Foss-Freitas Maria3ORCID, Neidert Adam H.3ORCID, Ray Yonaton1ORCID, Zheng Wenjun1, Kim Steven1ORCID, Kamat Vishal1ORCID, Huang Meilin1ORCID, Min Soo1, Mastaitis Jason1ORCID, Dominguez-Gutierrez Giselle1, Kim Jee-Hae1, Stevis Panayiotis1, Huang Tammy1ORCID, Zambrowicz Brian1ORCID, Olson William C.1ORCID, Godin Stephen1, Bradley Elizabeth1, Gewitz Andrew D.1, Baker Mark3, Hench Rita3, Davenport Matthew S.4, Chenevert Thomas L.4ORCID, DiPaola Frank5, Yancopoulos George D.1, Murphy Andrew J.1ORCID, Herman Gary A.1ORCID, Musser Bret J.1ORCID, Dansky Hayes1ORCID, Harp Joyce1, Gromada Jesper1, Sleeman Mark W.1ORCID, Oral Elif A.3ORCID, Olenchock Benjamin A.1ORCID
Affiliation:
1. Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. 2. Izmir Biomedicine and Genome Center, 35340 Izmir, Turkey. 3. Brehm Center for Diabetes Research, Caswell Diabetes Institute, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA. 4. Department of Radiology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA. 5. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Abstract
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
1 articles.
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1. Antibodies achieve leptin balancing act;Nature Reviews Drug Discovery;2023-12-06
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