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

ABSTRACT: Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klotho? (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.

SUBMITTER: Baruch A

PROVIDER: S-EPMC7682391 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Baruch Amos A Wong Chin C Chinn Leslie W LW Vaze Anjali A Sonoda Junichiro J Gelzleichter Thomas T Chen Shan S Lewin-Koh Nicholas N Morrow Linda L Dheerendra Suresh S Boismenu Richard R Gutierrez Johnny J Wakshull Eric E Wilson Maria E ME Arora Puneet S PS

Proceedings of the National Academy of Sciences of the United States of America 20201102 46

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 ...[more]

PMID: 33139537

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Dataset Information

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

Publications

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

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