Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans.
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.
['Baruch|Amos|A|0000-0003-3831-3806', 'Wong|Chin|C|0000-0002-4404-9231', 'Chinn|Leslie W|LW|0000-0003-3127-6758', 'Vaze|Anjali|A|0000-0003-4392-3246', 'Sonoda|Junichiro|J|', 'Gelzleichter|Thomas|T|', 'Chen|Shan|S|', 'Lewin-Koh|Nicholas|N|', 'Morrow|Linda|L|0000-0003-3252-4477', 'Dheerendra|Suresh|S|', 'Boismenu|Richard|R|0000-0002-0570-3720', 'Gutierrez|Johnny|J|', 'Wakshull|Eric|E|', 'Wilson|Maria E|ME|0000-0002-9104-5444', 'Arora|Puneet S|PS|0000-0001-6450-1224']
D052242:Adiponectin D000273:Adipose Tissue D000293:Adolescent D000328:Adult D000368:Aged D000818:Animals D000906:Antibodies D015415:Biomarkers D001835:Body Weight D005260:Female D005346:Fibroblast Growth Factors D005518:Food Preferences D006706:Homeostasis D006801:Humans D008252:Macaca fascicularis D008297:Male D051379:Mice D008875:Middle Aged D009765:Obesity D051496:Receptor, Fibroblast Growth Factor, Type 1 D015431:Weight Loss D055815:Young Adult
metabolism food preference obesity weight loss FGF21 receptor activation