Cell Research:高福院士课题组研制出预防治疗作用的MERS抗体

 

研究人员通过表达MERS病毒刺突蛋白（S）上与病毒受体相互作用的结构域（MERS-RBD）免疫小鼠，筛选到了两株抗MERS病毒的中和抗体——4C2和2E6。进一步研究表明这两株中和抗体能够竞争病毒S蛋白与受体（CD26）的结合，从而抑制病毒侵入宿主细胞。随后，研究组通过保留4C2抗体分子上一种氨基酸残基，对4C2进行了最大限度的人源化改造。

 

改造后的抗体保留了接近于鼠源抗体的中和活性。值得关注的是，研究人员用小鼠模型证明了人源化的4C2无论在病毒感染前还是感染后使用均能有效清除病毒。

 

原文链接：http://www.nature.com/cr/journal/vaop/ncurrent/full/cr2015113a.html

 

AhumanizedneutralizingantibodyagainstMERS-CoVtargetingthereceptor-bindingdomainofthespikeprotein

 

摘要：Thenewly-emergingMiddleEastrespiratorysyndromecoronavirus(MERS-CoV)cancausesevereandfatalacuterespiratorydiseaseinhumans.Despiteglobalefforts,thepotentialforanassociatedpandemicinthefuturecannotbeexcluded.Thedevelopmentofeffectivecounter-measuresisurgent.MERS-CoV-specificanti-viraldrugsorvaccinesarenotyetavailable.Usingthespikereceptor-bindingdomainofMERS-CoV(MERS-RBD)toimmunizemice,weidentifiedtwoneutralizingmonoclonalantibodies(mAbs)4C2and2E6.BothmAbspotentlybindtoMERS-RBDandblockvirusentryinvitrowithhighefficacy.WefurtherinvestigatedtheirmechanismsofneutralizationbycrystallizingthecomplexbetweentheFabfragmentsandtheRBD,andsolvedthestructureofthe4C2Fab/MERS-RBDcomplex.Thestructureshowedthat4C2recognizesanepitopethatpartiallyoverlapsthereceptor-bindingfootprintinMERS-RBD,therebyinterferingwiththevirus/receptorinteractionsbybothsterichindranceandinterface-residuecompetition.2E6alsoblocksreceptorbinding,andcompeteswith4C2forbindingtoMERS-RBD.Basedonthestructure,wefurtherhumanized4C2bypreservingonlytheparatoperesiduesandsubstitutingtheremainingaminoacidswiththecounterpartsfromhumanimmunoglobulins.Thehumanized4C2(4C2h)antibodysustainedsimilarneutralizingactivityandbiochemicalcharacteristicstotheparentalmouseantibody.Finally,weshowedthat4C2hcansignificantlyabatethevirustitersinlungsofAd5-hCD26-transducedmiceinfectedwithMERS-CoV,thereforerepresentingapromisingagentforprophylaxisandtherapyinclinicalsettings.