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Publication
Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized
Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/ßKlotho
Complex.
Authors 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
Submitted By Submitted Externally on 7/20/2016
Status Published
Journal EBioMedicine
Year 2015
Date Published 7/1/2015
Volume : Pages 2 : 730 - 43
PubMed Reference 26288846
Abstract 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/ßKlotho complex, a common receptor for FGF21 and FGF19. Using
this molecule, we show that antibody-mediated activation of FGFR1/ßKlotho
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/ßKlotho 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/ßKlotho activation occurs even before the
onset of weight loss in a manner that is independent of adiponectin. Together,
selective activation of FGFR1/ßKlotho 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.




Strains




Genes
SymbolDescription
Adipoqadiponectin, C1Q and collagen domain containing

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