《抗體人源化改造策略及相關案例分享》

抗體人源化改造策略及相關案例分享北京義翹神州科技股份有限公司義翹神州CONTENT抗體人源化相關概述1抗體人源化策略2義翹神州抗體人源化改造相關案例分享3抗體人源化相關概述01義翹神州治療性單克隆抗體的發(fā)展4義翹神州鼠源嵌合人源化全人源0%human70%human>90%human100%humanImmunogenicity(HAMA)effectIncreasedADCC,ADCPandCDCbasedtherapyIncreasedDecreased義翹神州HUMIRA(2002)KEVZARA(2017)VECTIBIX(2006)TREMFYA(2017)ILARIS(2009)AIMOVIG(2018)SIMPONI(2009)CRYSVITA(2018)ARZERRA(2009)TAKHZYRO(2018)STELARA(2009)LIBTAYO(2018)XGEVA(2010)GAMIFANT(2018)BENLYSTA(2011)PADCEV(2019)YERVOY(2011)TEPEZZA(2020)ABTHRAX(2012)INMAZEB(2020)OPDIVO(2014)EBANGA(2020)CYRAMZA(2014)EVKEEZA(2021)PRALUENT(2015)RYBREVANT(2021)DARZALEX(2015)ADTRALZA(2021)REPATHA(2015)SAPHNELO(2021)PORTRAZZA(2015)ADUHELM(2021)COSENTYX(2015)XEVUDY(2021)LARTRUVO(2016)TIVDAK(2021)ZINPLAVA(2016)TEZSPIRE(2021)SILIQ(2017)EVUSHELD(2022)BAVENCIO(2017)OPDUALAG(2022)DUPIXENT(2017)IMJUDO(2022）IMFINZI(2017)

OKT3(1986)PROSTASCINT(1996)ZEVALIN(2002)BLINCYTO(2014)LUMOXITI(2018)REOPRO(1993)SYLVANT(2014)RITUXAN(1997)UNITUXIN(2016)SIMULECT(1998)ANTHIM(2016)REMICADE(1998)SARCLISA(2020)ERBITUX(2004)MARGENZA(2020)ADCETRIS(2011)BRIUMVI(2022)SYNAGIS(1998)NUCALA(2015)ENHERTU(2019)HERCEPTIN(1998)TALTZ(2016)BLENREP(2020)MYLOTARG(2000)CINQAIR(2016)TRODELVY(2020)CAMPATH(2001)TECENTRIQ(2016)MONJUVI(2020)XOLAIR(2003)ZINBRYTA(2016)ENSPRYNG(2020)AVASTIN(2004)OCREVUS(2017)VYEPTI(2020)TYSABRI(2004)BESPONSA(2017)UPLIZNA(2020)ACTEMRA(2005)FASENRA(2017)DANYELZA(2020)LUCENTIS(2006)HEMLIBRA(2017)JEMPERLI(2021)SOLIRIS(2007)AJOVY(2018)ZYNLONTA(2021)CIMIZA(2008)EMGALITY(2018)VABYSMO(2022)THERACIM(2008)POTELIGEO(2018)ENJAYMO(2022)PERJETA(2012)TROGARZO(2018)SPEVIGO(2022)GAZYVA(2013)ILUMYA(2018)TZIELD(2022)KADCYLA(2013)ULTOMIRIS(2018)KIMMTRAK(2022)ALZUMAB(2013)SKYRIZI(2019）LUNSUMIO(2022)KEYTRUDA(2014)CABLIVI(2019)TECVAYLI(2022)ENTYVIO(2014)POLIVY(2019）ELAHERE(2022)LEMTRADA(2014)EVENITY(2019)LEQEMBI(2023)EMPLICITI(2015)BEOVU(2019)ZYNYZ(2023)PRAXBIND(2015)ADAKVEO(2019)EPKINLY(2023)FDA批準的上市單抗藥物分類義翹神州2018~2022上市的人源化和全人源抗體數(shù)量對比人源化抗體全人源抗體人源化抗體全人源抗體人源化抗體全人源抗體人源化抗體全人源抗體人源化抗體全人源抗體義翹神州①抗體人源性程度②保持親本抗體的親和力水平③具備親本抗體的生物學活性人源化人源化抗體開發(fā)要求抗體人源化策略02義翹神州義翹神州表面殘基替換CDRFR原表面殘基替換后殘基優(yōu)勢：操作簡便問題：人源化程度不高抗體人源化方法1-表面重塑義翹神州優(yōu)勢：方法成熟，臨床療效良好問題：仍有親和力降低或潛在的免疫原性抗體人源化方法2–CDR移植CDR移植FR替換核心氨基酸保留CDR親本抗體FR人源抗體FR核心氨基酸義翹神州上部核心疏水殘基下部核心疏水殘基VHVLCDR核心親水殘基轉角處結構殘基VH/VL交界面殘基關鍵氨基酸回復突變策略義翹神州親本非人源抗體確定CDR和FR搜索人源模板CDR移植并建模非人源抗體同源建模確認關鍵氨基酸比對確認回復突變抗體人源化流程抗體人源化改造相關案例分享03義翹神州義翹神州TargetCloneIDConc.(mg/L)HumannessSars-Cov2-SpikeMM57MM57-C1-mAb249.5/MM57-C2-chAb141/MM57-436597%MM57-624897.4%MM57-1316596.10%MM57-1419097%MM57-1519897.4%MM57-1810097%MM57-2510697.8%MM57-3017397.8%MM57-3418497.8%MM57-3826797.8%mAb_VLmAb_humanized_VLmAb_VHmAb_humanized_VH案例1-鼠抗人源化義翹神州TargetCloneIDInhibition(%)IC50(μg/ml)(Pseudovirus)Sars-Cov2-SpikeMM57MM57-C1-mAb87%0.548MM57-C2-chAb85%0.341MM57-487%0.268MM57-685%0.685MM57-1381%<0.1MM57-1480%0.41MM57-1581%0.375MM57-1876%0.148MM57-2572%0.458MM57-3074%0.784MM57-3474%0.307MM57-3875%0.438案例1-鼠抗人源化義翹神州TargetCloneIDKD(M)Kon(1/Ms)Koff(1/s)Sars-Cov2-SpikeMM57MM57-C1-mAb1.74E-103.30E+055.74E-05MM57-C2-chAb2.51E-112.79E+056.99E-06MM57-47.52E-122.01E+051.51E-06MM57-6<1.0E-121.91E+05<1.0E-07MM57-13<1.0E-121.91E+05<1.0E-07MM57-14<1.0E-121.89E+05<1.0E-07MM57-154.31E-112.16E+059.30E-06MM57-182.83E-111.73E+054.89E-06MM57-254.85E-112.17E+051.05E-05MM57-301.38E-101.92E+052.65E-05MM57-349.54E-112.07E+051.98E-05MM57-388.53E-111.98E+051.69E-05案例1-鼠抗人源化義翹神州納米抗體結構特點DOI：10.1146/annurev-biochem-063011-092449義翹神州ID表達量(mg/L）KD(M)Kon(1/Ms)Koff(1/s)Nanobdy-C1001.039E-081.327E+050.001379Nanobody-11529.717E-091.136E+050.001104Nanobody-21578.296E-091.292E+050.001072Nanobody-31059.259E-091.050E+050.000972案例2-納米抗體人源化關于“北京義翹神州”堅持自主研發(fā)生產(chǎn)打造中國生命科學研究“一站式”試劑與服務支撐平臺人才與設施榮譽資質設施：---2