Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex.

Kolumam G, Chen MZ, Tong R, Zavala-Solorio J, Kates L, van Bruggen N, Ross J, Wyatt SK, Gandham VD, Carano RA, Dunshee DR, Wu AL, Haley B, Anderson K, Warming S, Rairdan XY, Lewin-Koh N, Zhang Y, Gutierrez J, Baruch A, Gelzleichter TR, Stevens D, Rajan S, Bainbridge TW, Vernes JM, Meng YG, Ziai J, Soriano RH, Brauer MJ, Chen Y, Stawicki S, Kim HS, Comps-Agrar L, Luis E, Spiess C, Wu Y, Ernst JA, McGuinness OP, Peterson AS, Sonoda J
EBioMedicine. 2015 2 (7): 730-43

PMID: 26288846 · PMCID: PMC4534681 · DOI:10.1016/j.ebiom.2015.05.028

Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/βKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/βKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/βKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/βKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/βKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin.

MeSH Terms (20)

Adiponectin Adipose Tissue, Brown Animals Antibodies, Bispecific Cell Line Energy Metabolism Fibroblast Growth Factors HEK293 Cells Humans Insulin Macaca fascicularis Male Membrane Proteins Mice, Inbred BALB C Mice, Inbred C57BL Mice, Obese Protein Binding Receptor, Fibroblast Growth Factor, Type 1 Thermogenesis Weight Loss

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