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抗体介导的 FGFR1/Klothoβ 复合物激活可纠正肥胖人群的代谢功能障碍并改变其食物偏好。

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

机构信息

Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080.

ProSciento, Inc., Chula Vista, CA 91911.

出版信息

Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28992-29000. doi: 10.1073/pnas.2012073117. Epub 2020 Nov 2.

DOI:10.1073/pnas.2012073117
PMID:33139537
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7682391/
Abstract

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.

摘要

成纤维细胞生长因子 21（FGF21）通过脂肪细胞、胰腺腺泡细胞和神经系统中表达的 FGF 受体 1/klothoβ（FGFR1/KLB）复合物来控制代谢器官的稳态和摄食/饮水行为。在啮齿动物、非人灵长类动物和人类中，重组 FGF21 或工程化变体的慢性给药可改善代谢健康；然而，这些分子的快速周转限制了其治疗用途。在这里，我们证明了双特异性抗 FGFR1/KLB 激动剂抗体 BFKB8488A 可诱导肥胖食蟹猴明显减重，同时升高血清脂联素和脂肪组织中 FGFR1 靶基因的表达，表明其作为 FGF21 模拟物的作用。在超重/肥胖人类参与者中进行的一项随机、安慰剂对照、单次递增剂量研究中，皮下注射 BFKB8488A 可导致体重短暂减轻，持续改善心血管代谢参数，并倾向于减少对甜味和碳水化合物的摄入。这些数据表明，在人类中特异性激活 FGFR1/KLB 复合物可作为治疗肥胖相关代谢缺陷的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/fc5390e05412/pnas.2012073117fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/94a9b10aee24/pnas.2012073117fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/7ddeb70fae75/pnas.2012073117fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/e19cb3a34c4a/pnas.2012073117fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/fc5390e05412/pnas.2012073117fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/94a9b10aee24/pnas.2012073117fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/7ddeb70fae75/pnas.2012073117fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/e19cb3a34c4a/pnas.2012073117fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/800d/7682391/fc5390e05412/pnas.2012073117fig04.jpg

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