Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex.
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.
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Ganesh
G
Kolumam
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Mark Z
MZ
Chen
Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
Raymond
R
Tong
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Jose
J
Zavala-Solorio
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Lance
L
Kates
Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA.
Nicholas
N
van Bruggen
Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA.
Jed
J
Ross
Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA.
Shelby K
SK
Wyatt
Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA.
Vineela D
VD
Gandham
Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA.
Richard A D
RA
Carano
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Diana Ronai
DR
Dunshee
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Ai-Luen
AL
Wu
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Benjamin
B
Haley
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Keith
K
Anderson
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Søren
S
Warming
Transgenic Technology, Genentech, Inc., South San Francisco, CA 94080, USA.
Xin Y
XY
Rairdan
Biostatistics, Genentech, Inc., South San Francisco, CA 94080, USA.
Nicholas
N
Lewin-Koh
Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
Yingnan
Y
Zhang
ITGR/NTA Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA 94080, USA.
Johnny
J
Gutierrez
ITGR/NTA Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA 94080, USA.
Amos
A
Baruch
Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
Thomas R
TR
Gelzleichter
Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
Dale
D
Stevens
Preclinical & Translational Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
Sharmila
S
Rajan
Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
Travis W
TW
Bainbridge
Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA.
Jean-Michel
JM
Vernes
Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA.
Y Gloria
YG
Meng
Pathology, Genentech, Inc., South San Francisco, CA 94080, USA.
James
J
Ziai
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Robert H
RH
Soriano
Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Matthew J
MJ
Brauer
Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Yongmei
Y
Chen
Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Scott
S
Stawicki
Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Hok Seon
HS
Kim
Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA.
Laëtitia
L
Comps-Agrar
Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
Elizabeth
E
Luis
Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Christoph
C
Spiess
Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Yan
Y
Wu
Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
James A
JA
Ernst
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Owen P
OP
McGuinness
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Andrew S
AS
Peterson
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
Junichiro
J
Sonoda
D052242:Adiponectin / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D000090265:Klotho Proteins; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D011485:Protein Binding / Q000187:drug effects; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000819:agonists* / Q000378:metabolism; D022722:Thermogenesis / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
D052242:Adiponectin; D018033:Antibodies, Bispecific; D007328:Insulin; C538995:KLB protein, human; D008565:Membrane Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000090265:Klotho Proteins
Adiponectin; Adipose tissue browning; Bispecific antibody; Brown adipose tissue; FGF19; FGF21; FGFR1; Hepatosteatosis; Humanized antibody; Insulin resistance; NASH; Obesity; Therapeutic antibody; Thermogenesis; Type 2 diabetes; UCP1; betaKlotho