靶向EGFR的重组融合蛋白及其抗体偶联药物的抗食管癌活性和作用机制研究

靶向EGFR的重组融合蛋白及其抗体偶联药物的抗食管癌活性和作用机制研究摘要：本研究旨在探究靶向表皮生长因子受体(EGFR)的重组融合蛋白及其抗体偶联药物在食管癌治疗中的作用机制。首先，我们构建了融合蛋白并纯化制备其结构域，通过Westernblot和ELISA等技术鉴定其活性。实验结果表明，靶向EGFR的重组融合蛋白和抗体偶联药物能有效杀死食管癌细胞，且具有较高的选择性和亲和力。此外，我们还探究了其作用机制，发现其能抑制EGFR信号通路、诱导细胞凋亡和抑制肿瘤细胞侵袭。因此，靶向EGFR的重组融合蛋白及其抗体偶联药物具有在食管癌治疗中的潜在应用价值。

关键词：靶向EGFR；重组融合蛋白；抗体偶联药物；食管癌；作用机制

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