靶向EGFR的重組融合蛋白及其抗體偶聯(lián)藥物的抗食管癌活性和作用機(jī)制研究摘要：本研究旨在探究靶向表皮生長(zhǎng)因子受體(EGFR)的重組融合蛋白及其抗體偶聯(lián)藥物在食管癌治療中的作用機(jī)制。首先，我們構(gòu)建了融合蛋白并純化制備其結(jié)構(gòu)域，通過Westernblot和ELISA等技術(shù)鑒定其活性。實(shí)驗(yàn)結(jié)果表明，靶向EGFR的重組融合蛋白和抗體偶聯(lián)藥物能有效殺死食管癌細(xì)胞，且具有較高的選擇性和親和力。此外，我們還探究了其作用機(jī)制，發(fā)現(xiàn)其能抑制EGFR信號(hào)通路、誘導(dǎo)細(xì)胞凋亡和抑制腫瘤細(xì)胞侵襲。因此，靶向EGFR的重組融合蛋白及其抗體偶聯(lián)藥物具有在食管癌治療中的潛在應(yīng)用價(jià)值。

關(guān)鍵詞：靶向EGFR；重組融合蛋白；抗體偶聯(lián)藥物；食管癌；作用機(jī)制

Abstract:Thisstudyaimstoinvestigatethemechanismofactionofrecombinantfusionproteintargetingepidermalgrowthfactorreceptor(EGFR)anditsantibody-drugconjugateinthetreatmentofesophagealcancer.First,weconstructedthefusionproteinandpurifieditsstructuraldomains.TheactivityoftheproteinwasidentifiedbyWesternblotandELISA.Theexperimentalresultsshowedthatthefusionproteinandantibody-drugconjugatetargetingEGFRcouldeffectivelykillesophagealcancercellswithhighselectivityandaffinity.Inaddition,weexploreditsmechanismofactionandfoundthatitcouldinhibittheEGFRsignalingpathway,inducecellapoptosisandinhibittumorcellinvasion.Therefore,therecombinantfusionproteintargetingEGFRanditsantibody-drugconjugatehavepotentialapplicationvalueinthetreatmentofesophagealcancer.

Keywords:targetingEGFR;recombinantfusionprotein;antibody-drugconjugate;esophagealcancer;mechanismofactionEsophagealcancerisacommonandaggressivemalignancythatisdifficulttotreat.Targetedtherapyhasemergedasapromisingstrategyforthetreatmentofesophagealcancer.EGFRisoverexpressedinmanyhumanmalignancies,includingesophagealcancer,andplaysacriticalroleintumorinitiation,progression,andmetastasis.Therefore,targetingEGFRisapromisingstrategyforthetreatmentofesophagealcancer.

Inthisstudy,weconstructedarecombinantfusionproteintargetingEGFR,whichconsistedoftheextracellulardomainofEGFRfusedwiththeFcfragmentofhumanIgG.TherecombinantfusionproteinshowedhighselectivityandaffinityforEGFR-positiveesophagealcancercells.Moreover,wedevelopedanantibody-drugconjugatebyconjugatingtherecombinantfusionproteinwithachemotherapeuticagent.Theantibody-drugconjugateexhibitedenhancedcytotoxicityagainstesophagealcancercellscomparedtothefreedrug.

Furthermore,weinvestigatedthemechanismofactionoftherecombinantfusionproteintargetingEGFR.WefoundthattherecombinantfusionproteincouldinhibittheEGFRsignalingpathway,inducecellapoptosis,andinhibittumorcellinvasion.TheseresultssuggestthattherecombinantfusionproteintargetingEGFRhaspotentialapplicationvalueinthetreatmentofesophagealcancer.

Insummary,wehavedevelopedarecombinantfusionproteintargetingEGFRanditsantibody-drugconjugate,whichshowhighselectivityandaffinityforEGFR-positiveesophagealcancercells.Thesecompoundshavethepotentialtoprovideapromisingtherapeuticapproachforthetreatmentofesophagealcancer.FuturestudiesareneededtoevaluatetheirsafetyandeffectivenessinpreclinicalandclinicaltrialsEsophagealcancerisahighlymalignantcancerwithahighmorbidityandmortalityrate.Currently,availabletreatmentoptionsforesophagealcancerincludesurgery,chemotherapy,radiotherapy,andtargetedtherapy.However,theefficacyofthesetreatmentsislimited,andthereisanurgentneedtodevelopmoreeffectivetherapeuticapproachesforthetreatmentofesophagealcancer.

Theepidermalgrowthfactorreceptor(EGFR)isatransmembranereceptorthatplaysakeyroleincellgrowth,proliferation,anddifferentiation.EGFRisoverexpressedinavarietyofhumancancers,includingesophagealcancer,andisconsideredanattractivetargetforcancertherapy.

SeveralEGFRinhibitors,includingmonoclonalantibodiesandsmallmoleculetyrosinekinaseinhibitors(TKIs),havebeendevelopedandarecurrentlyusedforthetreatmentofvariouscancers,includinglungcancerandheadandneckcancer.However,theclinicalefficacyoftheseagentsinesophagealcancerislimited,andthedevelopmentofresistancetotheseagentsisamajorclinicalchallenge.

Recently,researchershavedevelopedarecombinantfusionproteintargetingEGFRanditsantibody-drugconjugate(ADC)forthetreatmentofesophagealcancer.TherecombinantfusionproteinconsistsofachimericproteincomposedoftheextracellulardomainofEGFRfusedwiththeFcportionofhumanimmunoglobulinG(IgG).TheADCisgeneratedbyconjugatingacytotoxicdrugtotheEGFR-specificantibody.

ThesecompoundshaveshownhighselectivityandaffinityforEGFR-positiveesophagealcancercellsinpreclinicalstudies.TherecombinantfusionproteincanbindtoEGFR-positivecancercellsandinduceantibody-dependentcell-mediatedcytotoxicity(ADCC)andcomplement-dependentcytotoxicity(CDC),leadingtotumorcelldeath.TheADCcanalsospecificallytargetEGFR-positivecancercellsandinduceapoptosis.

Inaddition,thecombinationofEGFRinhibitorswithchemotherapyorradiationtherapyhasshownpromisingresultsinpreclinicalstudies.ThecombinationofTKIswithchemotherapyorradiationtherapyhasbeenshowntoenhancetheantitumoractivityoftheseagentsandovercomeresistancetoTKIs.

Futurestudiesareneededtoevaluatethesafetyandeffectivenessofthesecompoundsinpreclinicalandclinicaltrials.Thedevelopmentofmoreeffectivetherapeuticapproachesforthetreatmentofesophagealcancer,includingtargetingEGFR,willimprovetheclinicaloutcomesandqualityoflifeforpatientswiththishighlymalignantcancerInadditiontotargetingEGFR,thereareseveralotherpromisingmoleculartargetsforthetreatmentofesophagealcancer.Forexample,HER2(humanepidermalgrowthfactorreceptor2)isoverexpressedinapproximately20%ofesophagealadenocarcinomacasesandisassociatedwithpoorprognosis.Trastuzumab,amonoclonalantibodythattargetsHER2,hasbeenshowntoimprovesurvivalinpatientswithHER2-positivebreastcancerandiscurrentlybeingevaluatedinclinicaltrialsforthetreatmentofesophagealcancer.

Anotherpromisingtargetisthevascularendothelialgrowthfactor(VEGF)pathway,whichplaysacrucialroleinangiogenesis,theprocessbywhichnewbloodvesselsareformedtosupplytumorswithnutrientsandoxygen.Bevacizumab,amonoclonalantibodythattargetsVEGF,hasbeenshowntoimprovesurvivalinpatientswithseveraltypesofcancer,includingcolorectalandnon-smallcelllungcancer,andiscurrentlybeingevaluatedinclinicaltrialsforthetreatmentofesophagealcancer.

Inadditiontothesetargetedtherapies,immunotherapyisemergingasapromisingapproachforthetreatmentofesophagealcancer.Immunecheckpointinhibitors,suchaspembrolizumabandnivolumab,havebeenshowntoimprovesurvivalinpatientswithvarioustypesofcancer,includingesophagealcancer.Thesedrugsworkbyblockingtheinteractionbetweenimmunecheckpointproteins,suchasPD-1andCTLA-4,andtheirligands,whichallowstheimmunesystemtomountastrongerattackagainstcancercells.

Overall,thedevelopmentoftargetedtherapiesandimmunotherapiesforthetreatmentofesophagealcancerrepresentsasignificantadvanceinthefieldofoncology.Thesetreatmentshavethepotentialtoimproveclinicaloutcomesandqualityoflifeforpatientswiththisdevastatingdisease.However,furtherresearchisneededtooptimizethesetherapiesandidentifybiomarkersthatcanpredictresponsetotreatment.Inaddi