Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

Autor: Chin Wong, Thomas Gelzleichter, Junichiro Sonoda, Amos Baruch, Linda Morrow, Suresh Dheerendra, Leslie W. Chinn, Richard Boismenu, Eric Wakshull, Maria E. Wilson, Puneet S. Arora, Shan Chen, Anjali Vaze, Johnny Gutierrez, Nicholas Lewin-Koh
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
obesity
Medical Sciences
FGF21
Adipose tissue
Mice
0302 clinical medicine
Weight loss
Homeostasis
Medicine
Multidisciplinary
biology
Middle Aged
Biological Sciences
Adipose Tissue
Female
Adiponectin
Antibody
medicine.symptom
FGF21 receptor activation
Adult
Agonist
medicine.medical_specialty
Adolescent
medicine.drug_class
030209 endocrinology & metabolism
Antibodies
Food Preferences
Young Adult
03 medical and health sciences
Internal medicine
Weight Loss
Animals
Humans
Receptor
Fibroblast Growth Factor
Type 1
Aged
business.industry
Fibroblast growth factor receptor 1
Body Weight
medicine.disease
Obesity
Fibroblast Growth Factors
stomatognathic diseases
Macaca fascicularis
030104 developmental biology
Endocrinology
biology.protein
food preference
business
metabolism
Biomarkers
Zdroj: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.2012073117
Popis: Significance Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes. Here we show that a bispecific anti-FGFR1/KLB agonist antibody, BFKB8488A, mimics the actions of FGF21 in monkeys and humans. BFKB8488A induced marked weight loss in obese monkeys while elevating expression of FGFR1 target genes in adipose tissue. A clinical study in overweight human participants demonstrated that a single dose of BFKB8488A caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that antibody-mediated activation of the FGFR1/KLB complex in humans recapitulates the effects of FGF21 and can be used as therapy for obesity-related metabolic defects.
Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.
Databáze: OpenAIRE
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