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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.

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