EBioMedicine (Jul 2015)
Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex
- Ganesh Kolumam,
- Mark Z. Chen,
- Raymond Tong,
- Jose Zavala-Solorio,
- Lance Kates,
- Nicholas van Bruggen,
- Jed Ross,
- Shelby K. Wyatt,
- Vineela D. Gandham,
- Richard A.D. Carano,
- Diana Ronai Dunshee,
- Ai-Luen Wu,
- Benjamin Haley,
- Keith Anderson,
- Søren Warming,
- Xin Y. Rairdan,
- Nicholas Lewin-Koh,
- Yingnan Zhang,
- Johnny Gutierrez,
- Amos Baruch,
- Thomas R. Gelzleichter,
- Dale Stevens,
- Sharmila Rajan,
- Travis W. Bainbridge,
- Jean-Michel Vernes,
- Y. Gloria Meng,
- James Ziai,
- Robert H. Soriano,
- Matthew J. Brauer,
- Yongmei Chen,
- Scott Stawicki,
- Hok Seon Kim,
- Laëtitia Comps-Agrar,
- Elizabeth Luis,
- Christoph Spiess,
- Yan Wu,
- James A. Ernst,
- Owen P. McGuinness,
- Andrew S. Peterson,
- Junichiro Sonoda
Affiliations
- Ganesh Kolumam
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Mark Z. Chen
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Raymond Tong
- Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA
- Jose Zavala-Solorio
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Lance Kates
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Nicholas van Bruggen
- Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA
- Jed Ross
- Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA
- Shelby K. Wyatt
- Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA
- Vineela D. Gandham
- Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA
- Richard A.D. Carano
- Biomedical Imaging, Genentech, Inc., South San Francisco, CA 94080, USA
- Diana Ronai Dunshee
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Ai-Luen Wu
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Benjamin Haley
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Keith Anderson
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Søren Warming
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Xin Y. Rairdan
- Transgenic Technology, Genentech, Inc., South San Francisco, CA 94080, USA
- Nicholas Lewin-Koh
- Biostatistics, Genentech, Inc., South San Francisco, CA 94080, USA
- Yingnan Zhang
- Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080, USA
- Johnny Gutierrez
- ITGR/NTA Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA 94080, USA
- Amos Baruch
- ITGR/NTA Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA 94080, USA
- Thomas R. Gelzleichter
- Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA
- Dale Stevens
- Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA
- Sharmila Rajan
- Preclinical & Translational Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA
- Travis W. Bainbridge
- Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA
- Jean-Michel Vernes
- Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA
- Y. Gloria Meng
- Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA
- James Ziai
- Pathology, Genentech, Inc., South San Francisco, CA 94080, USA
- Robert H. Soriano
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Matthew J. Brauer
- Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Yongmei Chen
- Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
- Scott Stawicki
- Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
- Hok Seon Kim
- Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
- Laëtitia Comps-Agrar
- Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA
- Elizabeth Luis
- Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA
- Christoph Spiess
- Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
- Yan Wu
- Antibody Engineering, Genentech, Inc., South San Francisco, CA 94080, USA
- James A. Ernst
- Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA
- Owen P. McGuinness
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Andrew S. Peterson
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- Junichiro Sonoda
- Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA
- DOI
- https://doi.org/10.1016/j.ebiom.2015.05.028
- Journal volume & issue
-
Vol. 2,
no. 7
pp. 730 – 743
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/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.
Keywords
- Brown adipose tissue
- Therapeutic antibody
- Thermogenesis
- Adipose tissue browning
- Humanized antibody
- Adiponectin
- FGF21
- FGF19
- FGFR1
- betaKlotho
- UCP1
- Bispecific antibody
- Insulin resistance
- Obesity
- Type 2 diabetes
- Hepatosteatosis
- NASH
