Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes 英文参考文献.docVIP

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Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes 英文参考文献.doc

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Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes 英文参考文献

Rationale-BasedEngineeringofaPotentLong-Acting FGF21AnalogfortheTreatmentofType2Diabetes RandyHecht1,Yue-ShengLi1,JeonghoonSun1,EdBelouski1,MichaelHall3,ToddHager3,JunmingYie2, WeiWang1,DwightWinters1,StephenSmith1,ChrisSpahr1,Lei-TingTam1,ZhongnanShen1, ShanakaStanislaus2,NarumolChinookoswong2,YvonneLau3,AllenSickmier1,MarkLeoMichaels1, ThomasBoone1,MurielleM.Ve′niant2,JingXu2* 1DepartmentofProteinSciences,AmgenInc.,ThousandOaks,California,UnitedStatesofAmerica,2DepartmentsofMetabolicDisorders,AmgenInc.,ThousandOaks, California,UnitedStatesofAmerica,3DepartmentofPharmacokineticsandDrugMetabolism,AmgenInc.,ThousandOaks,California,UnitedStatesofAmerica Abstract Fibroblastgrowthfactor21(FGF21)isapromisingdrugcandidateforthetreatmentoftype2diabetes.However,theuseof wildtypenativeFGF21ischallengingduetoseverallimitations.Amongtheseareitsshorthalf-life,itssusceptibilitytoin vivo proteolytic degradation and its propensity to in vitro aggregation. We here describe a rationale-based protein engineering approach to generate a potent long-acting FGF21 analog with improved resistance to proteolysis and aggregation.ArecombinantFc-FGF21fusionproteinwasconstructedbyfusingtheFcdomainofhumanIgG1totheN- terminusofhumanmatureFGF21viaalinkerpeptide.TheFcpositionedattheN-terminuswasdeterminedtobesuperior to the C-terminus as the N-terminal Fc fusion retained the bKlotho binding affinity and the in vitro and in vivo potency similartonativeFGF21.TwospecificpointmutationswereintroducedintoFGF21.Theleucinetoargininesubstitutionat position98(L98R)suppressedFGF21aggregationathighconcentrationsandelevatedtemperatures.Theprolinetoglycine replacement at position 171 (P171G) eliminated a site-specific proteolytic cleavage of FGF21 identified in mice and cynomolgusmonkeys.ThederivedFc-FGF21(RG)moleculedemonstratedasignificantlyimprovedcirculatinghalf-lifewhile maintainingtheinvitroactivitysimilartothatofwildtypeprotein.Thehalf-lifeofFc-FGF21(RG)was11hinmiceand30hin monkeysascomparedto1-2hforna