Strategies for extended serum half-life of protein therapeutics

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1、Availableonlineatwww.sciencedirect.comStrategiesforextendedserumhalf-lifeofproteintherapeuticsRolandEKontermannWithagrowingnumberofproteintherapeuticsbeingadministrationandpharmacokineticaswellaspharma-developed,manyofthemexhibitingashortplasmahalf-life,co

2、dynamicproperties.half-lifeextensionstrategiesfindincreasingattentionbythebiotechandpharmaceuticalindustry.Extensionofthehalf-lifeHalf-lifeextensionstrategiescanhelptoreducethenumberofapplicationsandtolowerSeveralmechanismsareinvolvedinclearanceofproteindos

3、es,thusarebeneficialfortherapeuticbutalsoeconomicdrugsfromcirculationincludingperipheralblood-reasons.Here,acomprehensiveoverviewofcurrentlymediatedeliminationbyproteolysis,renalandhepaticdevelopedhalf-lifeextensionstrategiesisprovidedincludingelimination,a

4、ndeliminationbyreceptor-mediatedendo-thoseaimingatincreasingthehydrodynamicvolumeofacytosis[2].Moleculespossessingasmallsize,thatis,alowproteindrugbutalsothoseimplementingrecyclingprocessesmolecularmass,arerapidlyclearedbyrenalfiltrationandmediatedbytheneon

5、atalFcreceptor.degradation,withathresholdintherangeof40–50kDa.ResponsibleforrenalclearanceistheglomerularfiltrationAddressbarrier(GBM)formedbythefenestratedendothelium,Institutfu¨rZellbiologieundImmunologie,Universita¨tStuttgart,theglomerularbasementmembran

6、eandtheslitdia-Allmandring31,70569Stuttgart,Germanyphragmlocatedbetweenthepodocytefootprocesses[3].Whilethefenestraebetweentheglomerularendo-Correspondingauthor:Kontermann,RolandE(roland.kontermann@izi.uni-stuttgart.de)thelialcellsareratherlarge(50–100nm)a

7、llowingfreediffusionofmolecules,theslitdiaphragmrepresentstheultimatemacromolecularbarrier,forminganisoporous,CurrentOpinioninBiotechnology2011,22:868–876zipper-likefilterstructurewithnumeroussmall,4–5nmThisdiameterporesandalowernumberof8–10nmdiameterreview

8、comesfromathemedissueonPharmaceuticalbiotechnologypores[4,5].Furthermore,proteoglycansoftheendothelialEditedbyLuisAngelFerna´ndezandSergeMuyldermanscellsandtheGBMformananionicbarrier,whichpartiallypreventsthe