Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex.

Abstract:

:Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on lipid, body weight, and glucose metabolism and has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to native FGF21, we have developed a monoclonal antibody, mimAb1, that binds to βKlotho with high affinity and specifically activates signaling from the βKlotho/FGFR1c (FGF receptor 1c) receptor complex. In obese cynomolgus monkeys, injection of mimAb1 led to FGF21-like metabolic effects, including decreases in body weight, plasma insulin, triglycerides, and glucose during tolerance testing. Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements in glucose metabolism and body weight. These results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated the essential role of FGFR1c in FGF21 function and suggest fat as a critical target tissue for the cytokine and antibody. Because mimAb1 depends on βKlotho to activate FGFR1c, it is not expected to induce side effects caused by activating FGFR1c alone. The unexpected finding of an antibody that can activate FGF21-like signaling through cell surface receptors provided preclinical validation for an innovative therapeutic approach to diabetes and obesity.

journal_name

Sci Transl Med

authors

Foltz IN,Hu S,King C,Wu X,Yang C,Wang W,Weiszmann J,Stevens J,Chen JS,Nuanmanee N,Gupte J,Komorowski R,Sekirov L,Hager T,Arora T,Ge H,Baribault H,Wang F,Sheng J,Karow M,Wang M,Luo Y,McKeehan W,Wang Z,Vénia

doi

10.1126/scitranslmed.3004690

subject

Has Abstract

pub_date

2012-11-28 00:00:00

pages

162ra153

issue

162

eissn

1946-6234

issn

1946-6242

pii

4/162/162ra153

journal_volume

4

pub_type

杂志文章
  • Quality versus quantity: assessing individual research performance.

    abstract::Evaluating individual research performance is a complex task that ideally examines productivity, scientific impact, and research quality--a task that metrics alone have been unable to achieve. In January 2011, the French Academy of Sciences published a report on current bibliometric (citation metric) methods for evalu...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002249

    authors: Sahel JA

    更新日期:2011-05-25 00:00:00

  • Tmc gene therapy restores auditory function in deaf mice.

    abstract::Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mous...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aab1996

    authors: Askew C,Rochat C,Pan B,Asai Y,Ahmed H,Child E,Schneider BL,Aebischer P,Holt JR

    更新日期:2015-07-08 00:00:00

  • Squeeze-E squeeze-E.

    abstract::Adding an electrical pulse to a microfluidic device that squeezes cells through narrow channels efficiently delivers DNA to the nucleus. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aan0766

    authors: King KR

    更新日期:2017-03-22 00:00:00

  • Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter.

    abstract::Adoptive cell transfer of ex vivo expanded regulatory T cells (Tregs) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such Treg therapies to the clinic has been slow. Because Treg homeostasis is known to require continuous T cell receptor (TCR) ligation and...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaw4744

    authors: Eskandari SK,Sulkaj I,Melo MB,Li N,Allos H,Alhaddad JB,Kollar B,Borges TJ,Eskandari AS,Zinter MA,Cai S,Assaker JP,Choi JY,Al Dulaijan BS,Mansouri A,Haik Y,Tannous BA,van Son WJ,Leuvenink HGD,Pomahac B,Riella LV,

    更新日期:2020-11-11 00:00:00

  • PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors.

    abstract::PTEN (phosphatase and tensin homolog) loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well-described role in cell signaling, PTEN is involved in the maintenance of genomic stability. Loss of PTEN function causes defects in repair of DNA double-strand br...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001538

    authors: Dedes KJ,Wetterskog D,Mendes-Pereira AM,Natrajan R,Lambros MB,Geyer FC,Vatcheva R,Savage K,Mackay A,Lord CJ,Ashworth A,Reis-Filho JS

    更新日期:2010-10-13 00:00:00

  • Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.

    abstract::KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaw7999

    authors: Molina-Arcas M,Moore C,Rana S,van Maldegem F,Mugarza E,Romero-Clavijo P,Herbert E,Horswell S,Li LS,Janes MR,Hancock DC,Downward J

    更新日期:2019-09-18 00:00:00

  • Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants.

    abstract::Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and i...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000976

    authors: Politis M,Wu K,Loane C,Quinn NP,Brooks DJ,Rehncrona S,Bjorklund A,Lindvall O,Piccini P

    更新日期:2010-06-30 00:00:00

  • Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis.

    abstract::In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthrit...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aah3438

    authors: Miner JJ,Cook LE,Hong JP,Smith AM,Richner JM,Shimak RM,Young AR,Monte K,Poddar S,Crowe JE Jr,Lenschow DJ,Diamond MS

    更新日期:2017-02-01 00:00:00

  • Grease fires turn up the heat in autoimmune disease.

    abstract::Restoring reverse cholesterol transport ameliorates the B cell hyperexpansion and autoimmune disease found to be associated with accumulation of cholesterol in CD11c+ antigen-presenting cells. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aal4997

    authors: Bhakta NR

    更新日期:2017-01-25 00:00:00

  • Porous polymeric platform repairs primates after spinal cord injury.

    abstract::Amine-containing polymers immobilized on mesh and placed at trauma sites scavenge biomolecules that initiate a damaging immune response. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aam6068

    authors: Ulery BD

    更新日期:2017-02-22 00:00:00

  • Comment on "A small-molecule antivirulence agent for treating Clostridium difficile infection".

    abstract::New insights into the mechanism of action of ebselen, a small-molecule antivirulence agent that reduces disease pathology in a mouse model of Clostridium difficile infection, suggest a different molecular target may be responsible for its efficacy. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aad8926

    authors: Beilhartz GL,Tam J,Zhang Z,Melnyk RA

    更新日期:2016-12-21 00:00:00

  • Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.

    abstract::Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AIs). We developed ultra high-sensitivity multiplex digital polymerase chain reaction assays for ESR1 mutations in circulating tumor DNA (ctDNA) and investigated the clinical relevance and origin of ESR1 mutations in 171 women with ad...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aac7551

    authors: Schiavon G,Hrebien S,Garcia-Murillas I,Cutts RJ,Pearson A,Tarazona N,Fenwick K,Kozarewa I,Lopez-Knowles E,Ribas R,Nerurkar A,Osin P,Chandarlapaty S,Martin LA,Dowsett M,Smith IE,Turner NC

    更新日期:2015-11-11 00:00:00

  • Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia.

    abstract::Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This st...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaz0463

    authors: Vadakekolathu J,Minden MD,Hood T,Church SE,Reeder S,Altmann H,Sullivan AH,Viboch EJ,Patel T,Ibrahimova N,Warren SE,Arruda A,Liang Y,Smith TH,Foulds GA,Bailey MD,Gowen-MacDonald J,Muth J,Schmitz M,Cesano A,Pockley

    更新日期:2020-06-03 00:00:00

  • PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma.

    abstract::Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chro...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aay0152

    authors: Jiang TY,Pan YF,Wan ZH,Lin YK,Zhu B,Yuan ZG,Ma YH,Shi YY,Zeng TM,Dong LW,Tan YX,Wang HY

    更新日期:2020-09-23 00:00:00

  • Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment.

    abstract::Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combinat...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aav7816

    authors: Zemek RM,De Jong E,Chin WL,Schuster IS,Fear VS,Casey TH,Forbes C,Dart SJ,Leslie C,Zaitouny A,Small M,Boon L,Forrest ARR,Muiri DO,Degli-Esposti MA,Millward MJ,Nowak AK,Lassmann T,Bosco A,Lake RA,Lesterhuis WJ

    更新日期:2019-07-17 00:00:00

  • Astrocytes light up glial heterogeneity.

    abstract::Functionally diverse subpopulations of astrocytes have correlates in the neoplastic adult brain. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aam9858

    authors: Venere M

    更新日期:2017-03-01 00:00:00

  • Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants.

    abstract::Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the on...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3009427

    authors: Shenoi RA,Kalathottukaren MT,Travers RJ,Lai BF,Creagh AL,Lange D,Yu K,Weinhart M,Chew BH,Du C,Brooks DE,Carter CJ,Morrissey JH,Haynes CA,Kizhakkedathu JN

    更新日期:2014-10-29 00:00:00

  • Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance.

    abstract::Central tolerance plays a key role in modulating immune responses to self and exogenous antigens. The absence of self-antigen expression, as in patients with genetic deficiencies, prevents the development of antigen-specific immune tolerance. Hence, a substantial number of patients develop neutralizing antibodies to t...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa1957

    authors: Gupta N,Culina S,Meslier Y,Dimitrov J,Arnoult C,Delignat S,Gangadharan B,Lecerf M,Justesen S,Gouilleux-Gruart V,Salomon BL,Scott DW,Kaveri SV,Mallone R,Lacroix-Desmazes S

    更新日期:2015-02-18 00:00:00

  • Extreme polymorphism in a vaccine antigen and risk of clinical malaria: implications for vaccine development.

    abstract::Vaccines directed against the blood stages of Plasmodium falciparum malaria are intended to prevent the parasite from invading and replicating within host cells. No blood-stage malaria vaccine has shown clinical efficacy in humans. Most malaria vaccine antigens are parasite surface proteins that have evolved extensive...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000257

    authors: Takala SL,Coulibaly D,Thera MA,Batchelor AH,Cummings MP,Escalante AA,Ouattara A,Traoré K,Niangaly A,Djimdé AA,Doumbo OK,Plowe CV

    更新日期:2009-10-14 00:00:00

  • Protein replacement therapies for rare diseases: a breeze for regulatory approval?

    abstract::Protein replacement therapies for rare monogenic diseases have a higher probability of regulatory approval compared with biologics, small molecules, and grant-funded orphan drugs. ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3005007

    authors: Gorzelany JA,de Souza MP

    更新日期:2013-03-27 00:00:00

  • Endomicroscope sheds light on cervical tissue.

    abstract::A pilot study of a handheld fluorescence endomicroscope demonstrates both in vivo imaging and differentiation of normal from precancerous cervical tissue. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aal4989

    authors: Evans CL

    更新日期:2017-01-11 00:00:00

  • Temporal dynamics of the human vaginal microbiota.

    abstract::Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analys...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3003605

    authors: Gajer P,Brotman RM,Bai G,Sakamoto J,Schütte UM,Zhong X,Koenig SS,Fu L,Ma ZS,Zhou X,Abdo Z,Forney LJ,Ravel J

    更新日期:2012-05-02 00:00:00

  • Noninvasive high-resolution electromyometrial imaging of uterine contractions in a translational sheep model.

    abstract::In current clinical practice, uterine contractions are monitored via a tocodynamometer or an intrauterine pressure catheter, both of which provide crude information about contractions. Although electrohysterography/electromyography can measure uterine electrical activity, this method lacks spatial specificity and thus...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aau1428

    authors: Wu W,Wang H,Zhao P,Talcott M,Lai S,McKinstry RC,Woodard PK,Macones GA,Schwartz AL,Cahill AG,Cuculich PS,Wang Y

    更新日期:2019-03-13 00:00:00

  • Turning back the clock.

    abstract::Increased DNA breaks in aging skeletal muscle activate the DNA-PK pathway, whereas blocking this pathway improves mitochondrial density, physical fitness, body weight, and insulin resistance in mice. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aan4290

    authors: Shoemaker AH

    更新日期:2017-05-17 00:00:00

  • Estimating cholera incidence with cross-sectional serology.

    abstract::The development of new approaches to cholera control relies on an accurate understanding of cholera epidemiology. However, most information on cholera incidence lacks laboratory confirmation and instead relies on surveillance systems reporting medically attended acute watery diarrhea. If recent infections could be ide...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aau6242

    authors: Azman AS,Lessler J,Luquero FJ,Bhuiyan TR,Khan AI,Chowdhury F,Kabir A,Gurwith M,Weil AA,Harris JB,Calderwood SB,Ryan ET,Qadri F,Leung DT

    更新日期:2019-02-20 00:00:00

  • Femtosecond laser-assisted cataract surgery with integrated optical coherence tomography.

    abstract::About one-third of people in the developed world will undergo cataract surgery in their lifetime. Although marked improvements in surgical technique have occurred since the development of the current approach to lens replacement in the late 1960s and early 1970s, some critical steps of the procedure can still only be ...

    journal_title:Science translational medicine

    pub_type: 临床试验,杂志文章

    doi:10.1126/scitranslmed.3001305

    authors: Palanker DV,Blumenkranz MS,Andersen D,Wiltberger M,Marcellino G,Gooding P,Angeley D,Schuele G,Woodley B,Simoneau M,Friedman NJ,Seibel B,Batlle J,Feliz R,Talamo J,Culbertson W

    更新日期:2010-11-17 00:00:00

  • The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs.

    abstract::Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. The most common CF-associated mutation is ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant prot...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001868

    authors: Ostedgaard LS,Meyerholz DK,Chen JH,Pezzulo AA,Karp PH,Rokhlina T,Ernst SE,Hanfland RA,Reznikov LR,Ludwig PS,Rogan MP,Davis GJ,Dohrn CL,Wohlford-Lenane C,Taft PJ,Rector MV,Hornick E,Nassar BS,Samuel M,Zhang Y,Richt

    更新日期:2011-03-16 00:00:00

  • Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema.

    abstract::Previous attempts to gain insight into the pathogenesis of psoriasis and eczema by comparing their molecular signatures were hampered by the high interindividual variability of those complex diseases. In patients affected by both psoriasis and nonatopic or atopic eczema simultaneously (n = 24), an intraindividual comp...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3008946

    authors: Quaranta M,Knapp B,Garzorz N,Mattii M,Pullabhatla V,Pennino D,Andres C,Traidl-Hoffmann C,Cavani A,Theis FJ,Ring J,Schmidt-Weber CB,Eyerich S,Eyerich K

    更新日期:2014-07-09 00:00:00

  • Achieving a nationwide learning health system.

    abstract::We outline the fundamental properties of a highly participatory rapid learning system that can be developed in part from meaningful use of electronic health records (EHRs). Future widespread adoption of EHRs will make increasing amounts of medical information available in computable form. Secured and trusted use of th...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001456

    authors: Friedman CP,Wong AK,Blumenthal D

    更新日期:2010-11-10 00:00:00

  • AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer.

    abstract::Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene se...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aac5272

    authors: Hong D,Kurzrock R,Kim Y,Woessner R,Younes A,Nemunaitis J,Fowler N,Zhou T,Schmidt J,Jo M,Lee SJ,Yamashita M,Hughes SG,Fayad L,Piha-Paul S,Nadella MV,Mohseni M,Lawson D,Reimer C,Blakey DC,Xiao X,Hsu J,Revenko A

    更新日期:2015-11-18 00:00:00