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humanized antibody

Humanized antibody vs tib neeg antibody

Muab lo rau  Cuaj hlis 29, 2020, Kho los ntawm Jason, Qeb  
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Humanized antibody yog dab tsi?

Tib neeg lub cev tiv thaiv kab mob feem ntau yog hais txog kev rov qhia tus nas cov kab mob monoclonal hloov kho los ntawm kev hloov pauv noob thiab DNA kev sib txuas thev naus laus zis. Feem ntau ntawm nws cov amino acid ib theem zuj zus tau hloov los ntawm tib neeg ua ntu zus, uas ib txwm khaws cov kev nyiam thiab qhov tshwj xeeb ntawm niam txiv nas cov kab mob monoclonal, thiab txo qis heterogeneity tib lub sijhawm. Nws daim ntawv thov yuav muaj txiaj ntsig zoo rau tib neeg lub cev.

humanized antibody
humanized antibody

Tib neeg lub cev tiv thaiv kab mob txhais tau tias thaj av tas li ntawm tshuaj tiv thaiv (CH thiab CL cheeb tsam) lossis tag nrho cov tshuaj tiv thaiv kab mob los ntawm tib neeg cov tshuaj tiv thaiv kab mob. Thiab tib neeg cov tshuaj tiv thaiv kab mob tuaj yeem txo qis kev tiv thaiv kab mob tshwm sim los ntawm cov tshuaj tiv thaiv kab mob sib kis rau tib neeg lub cev.

Kev faib tawm ntawm tib neeg cov tshuaj tiv thaiv kab mob

Raws li cov hauv paus ntsiab lus ntawm kev nqis tes ua, tib neeg cov tshuaj tiv thaiv kab mob tuaj yeem faib ua plaub pawg: tib neeg-nas chimeric antibody, hloov cov tshuaj tiv thaiv, cov tshuaj tiv thaiv rov qab thiab tib neeg cov tshuaj tiv thaiv.

1. Tib neeg-nas chimeric antibody

Dab tsi yog chimeric antibody? Tib neeg-nas chimeric antibody, uas yog, thaj av hla ntawm tshuaj tiv thaiv yog muab los ntawm cov nas me me McAb, thaum thaj tsam tas li tau muab los ntawm tib neeg cov tshuaj tiv thaiv kab mob. Cov tshuaj tiv thaiv no tsis tsuas yog tswj hwm qhov tshwj xeeb thiab kev nyiam ntawm thawj McAb, tab sis kuj tseem txo qis kev tiv thaiv kab mob hauv tib neeg lub cev.

Chimeric tshuaj tiv thaiv ntxig rau lub teeb thiab hnyav saw sib txawv thaj tsam noob ntawm heterologous cov kab mob monoclonal rau hauv kab lus qhia uas muaj thaj tsam tas li ntawm tib neeg tshuaj tiv thaiv, hloov cov tsiaj txhu tsiaj txhu los nthuav qhia chimeric antibody los ntawm DNA recombination technology. V thaj tsam ntawm lub teeb thiab cov saw hnyav yog sib txawv, thaum thaj tsam C yog tib neeg keeb kwm, yog li ze li 2/3 ntawm tag nrho cov tshuaj tiv thaiv kab mob hauv lub cev yog tib neeg keeb kwm. Cov tshuaj tiv thaiv kab mob tsim tawm hauv txoj kev no txo ​​qis kev tiv thaiv kab mob sib txawv ntawm cov tshuaj tiv thaiv kab mob thaum khaws lub peev xwm ntawm niam txiv cov tshuaj tiv thaiv tshwj xeeb rau khi rau antigen.

2. Hloov kho cov tshuaj tiv thaiv kab mob

Hloov kho cov tshuaj tiv thaiv kab mob kuj tseem hu ua CDR npaj cov tshuaj tiv thaiv kab mob. CDR ntawm thaj tsam sib txawv hauv cov tshuaj tiv thaiv yog thaj av uas cov tshuaj tiv thaiv tau lees paub thiab khi rau cov antigen, uas ncaj qha txiav txim siab qhov tshwj xeeb ntawm cov tshuaj tiv thaiv. CDR ntawm nas cov kab mob monoclonal tau hloov pauv mus rau thaj tsam sib txawv ntawm tib neeg cov tshuaj tiv thaiv kab mob los hloov CDR ntawm tib neeg cov tshuaj tiv thaiv kab mob, yog li tib neeg cov tshuaj tiv thaiv kab mob tau txais cov tshuaj tiv thaiv kab mob tshwj xeeb ntawm nas monoclonal antibody thaum txo nws qhov sib txawv. Txawm li cas los xij, txawm hais tias cov tshuaj tiv thaiv kab mob feem ntau cuam tshuam nrog CDR ntawm cov tshuaj tiv thaiv, thaj tsam FR feem ntau cuam tshuam rau kev teeb tsa ntawm CDR.

Yog li ntawd, tom qab hloov pauv thaj av FR los ntawm tib neeg, thaj av V uas cov nas-tau txais CDR thiab tib neeg-los ntawm FR tau teeb tsa tuaj yeem hloov pauv CDR kev teeb tsa ntawm tib lub antigen, thiab lub peev xwm los khi cov antigen yuav txo lossis txo qis. . Txawm hais tias nws muaj peev xwm ua tiav cov qauv tsim ntawm cov tshuaj tiv thaiv kab mob thiab qhia qee yam tseem ceeb ntawm cov nas FR hauv cheeb tsam mus rau tib neeg FR thaj chaw, yog tias teeb tsa kom raug, lawv qhov kev sib raug zoo tuaj yeem sib npaug ntawm tus nas thawj. tshuaj tiv thaiv, tab sis tib neeg cov tshuaj tiv thaiv feem ntau ua tsis tiav kom muaj kev sib raug zoo ntawm thawj tus nas monoclonal antibody.

3. Resurface cov tshuaj tiv thaiv

Kev kho cov tshuaj tiv thaiv saum npoo yog hais txog kev hloov pauv tib neeg ntawm cov amino acid seem ntawm qhov chaw ntawm cov tshuaj tiv thaiv kab mob sib txawv. Lub hauv paus ntsiab lus ntawm txoj kev no yog hloov pauv tsuas yog thaj tsam uas muaj qhov sib txawv ntawm SAR ntawm tib neeg cov tshuaj tiv thaiv kab mob.

Los ntawm kev tswj hwm cov tshuaj tiv thaiv kab mob thiab txo qis kev sib txawv, cov amino acid hloov pauv zoo ib yam li qhov seem ntawm tib neeg cov tshuaj tiv thaiv kab mob yuav tsum raug xaiv; ntxiv rau, qhov hloov pauv ntu yuav tsum tsis txhob ntau dhau. Thiab sim tsis hloov cov seem uas cuam tshuam rau qhov loj me, them nqi, hydrophobicity ntawm cov saw sab, lossis tuaj yeem tsim cov ntawv cog lus hydrogen kom cuam tshuam rau kev hloov pauv ntawm cov tshuaj tiv thaiv kev ua kom tiav thaj tsam (CDR).

4. Tib neeg cov tshuaj tiv thaiv

Tib neeg cov tshuaj tiv thaiv hais txog kev hloov pauv tib neeg cov tshuaj tiv thaiv kab mob los ntawm transgene lossis transchromosome thev naus laus zis los hloov tag nrho tib neeg cov tshuaj tiv thaiv kab mob rau tib neeg los ntawm kev tsim cov tsiaj nrog cov tshuaj tiv thaiv kab mob tshem tawm, yog li cov tsiaj tuaj yeem nthuav tawm tib neeg cov tshuaj tiv thaiv kom ua tiav tib neeg lub hom phiaj tshuaj tiv thaiv.

5. Humanized antibody vs tib neeg antibody

Raws li qhov chaw sib txawv ntawm cov kab mob monoclonal, lawv tuaj yeem faib ua cov tshuaj tiv thaiv nas, chimeric antibody, humanized tshuaj tiv thaiv thiab tib neeg cov tshuaj tiv thaiv. Neeg thiaj li hu ua neeg monoclonal tshuaj tiv thaiv txhais tau tias 100% ntawm cov noob tau los ntawm tib neeg. Txawm li cas los xij, qhov tseeb, tib neeg cov tshuaj tiv thaiv kab mob monoclonal kuj tau tsim tawm hauv cov nas.

humanized antibody vs tib neeg antibody
humanized antibody vs tib neeg antibody

Los ntawm kev hloov tib neeg cov noob cuam tshuam nrog kev tsim cov tshuaj tiv thaiv kab mob rau cov nas, cov qauv ntawm cov tshuaj tiv thaiv kab mob hauv cov nas tuaj yeem zoo ib yam li tib neeg cov tshuaj tiv thaiv kab mob. Yog li ntawd, tib neeg cov tshuaj tiv thaiv ≠ cov tshuaj tiv thaiv tau ncaj qha los ntawm tib neeg cov cell, tab sis cov qauv ntawm cov tshuaj tiv thaiv yog 100% nkag los raws li tib neeg cov noob. Tib neeg cov tshuaj tiv thaiv kab mob monoclonal feem ntau yog tib neeg tau los thiab tau sib xyaw nrog cov khoom tsim los ntawm nas. Nyob rau xyoo tsis ntev los no, cov kws tshawb fawb tau txhob txwm khaws cia cov txiaj ntsig tseem ceeb ntawm cov qauv ua haujlwm ntawm cov nas nyob hauv tib neeg lub cev los ntawm kev tsim caj ces, uas ua lub luag haujlwm tshwj xeeb, ib yam li ua kom zoo dua qub.

Piv txwv li, Ichizumab (tib neeg cov tshuaj tiv thaiv kab mob monoclonal) khaws 1.8% ntawm cov khoom xyaw uas tau los ntawm nas, uas suav nrog cov noob muaj txiaj ntsig, yog li nws ua tiav kev sib raug zoo thiab pib ua haujlwm sai.

Kev tsim kho ntawm tib neeg cov tshuaj tiv thaiv kab mob

1. Antibody Humanization

Tib neeg cov tshuaj tiv thaiv kab mob yog ib feem tseem ceeb ntawm kev tshawb fawb txog kev tsim khoom thiab npaj cov tshuaj tiv thaiv kab mob sib kis (monoclonal antibodies). Kev tsim cov tshuaj tiv thaiv tib neeg yog txheej txheem ntawm kev tsim los ntawm cov tshuaj tiv thaiv nas mus rau tib neeg cov tshuaj tiv thaiv.

Ntau tshaj li ib puas xyoo dhau los, kev tshawb pom ntawm cov hauv paus ntsiab lus ntawm cov tshuaj tiv thaiv kab mob-antigen tshwj xeeb thiab kev tiv thaiv kab mob tsis zoo ntawm cov tshuaj tiv thaiv kab mob tau qhib txoj hauv kev tshiab ntawm kuaj kab mob. Lub advent ntawm monoclonal tshuaj tiv thaiv thev naus laus zis xyoo 1975 ua kom nrawm rau kev siv thoob plaws txoj hauv kev no. Hauv thawj theem, feem ntau ntawm cov tshuaj tiv thaiv kab mob monoclonal siv hauv tsev kho mob yog nas monoclonal antibodies. Vim yog hom tsiaj tshwj xeeb ntawm tib neeg thiab nas, muaj ntau yam kev txwv ntawm kev siv lawv.

Txawm hais tias cov tshuaj tiv thaiv nas tshwj xeeb rau lub hom phiaj antigen thiab tuaj yeem tshwj xeeb khi rau lub hom phiaj antigen, nws tsis tuaj yeem ua kom muaj kev cuam tshuam tib neeg cov txiaj ntsig kev ua haujlwm, xws li tshuaj tiv thaiv kab mob-tiv thaiv cell-mediated cytotoxicity (ADCC), ua tiav-nyob ntawm cytotoxicity (CDC), thiab lwm yam, yog li cov tshuaj tiv thaiv antigen-antibody tsis tuaj yeem tshwm sim ib txwm muaj.

Ib qho ntxiv, cov tshuaj tiv thaiv nas nkag rau tib neeg lub cev ua neeg txawv teb chaws protein, uas yuav ua rau tib neeg lub cev tiv thaiv kab mob los teb thiab tsim cov tshuaj tiv thaiv tshwj xeeb noj cov tshuaj tiv thaiv nas li antigen, uas yog, tib neeg cov tshuaj tiv thaiv nas nas. Feem ntau heterologous protein nrog ib nrab-lub neej luv yuav raug tshem tawm sai hauv tib neeg lub cev. Vim muaj ntau yam kev txwv hauv kev siv tshuaj tiv thaiv kab mob nas, tib neeg siv cov thev naus laus zis thev naus laus zis DNA los ua tib neeg cov tshuaj tiv thaiv nas rau tib neeg cov tshuaj tiv thaiv.

2. Ntsiab Cai

Kev tsim tib neeg ntawm cov tshuaj tiv thaiv nas yog ua kom nws muaj cov ntaub ntawv zoo sib xws rau cov tshuaj tiv thaiv kab mob hauv tib neeg lub cev los ntawm kev hloov kho caj ces, yog li ua rau tsis lees paub los ntawm tib neeg lub cev tiv thaiv kab mob thiab zam kev pib ntawm HAMA cov lus teb. Kev tsim tib neeg cov tshuaj tiv thaiv kab mob yuav tsum ua raws ob lub hauv paus ntsiab lus, uas yog, txhawm rau tswj hwm lossis txhim kho kev sib raug zoo thiab qhov tshwj xeeb ntawm cov tshuaj tiv thaiv: txo qis lossis tshem tawm ntau yam immunogenicity ntawm cov tshuaj tiv thaiv.

Cov txheej txheem ntawm tshuaj tiv thaiv tib neeg tau dhau los ntawm peb theem: tib neeg-nas chimeric antibody, tib neeg cov tshuaj tiv thaiv thiab tib neeg cov tshuaj tiv thaiv. Raws li cov hauv paus ntsiab lus ntawm kev nqis tes ua, tib neeg cov tshuaj tiv thaiv kab mob tuaj yeem faib ua plaub hom: tib neeg-nas chimeric antibody, hloov cov tshuaj tiv thaiv, cov tshuaj tiv thaiv rov qab, thiab tib neeg cov tshuaj tiv thaiv.

3. Nas antibody VS humanized antibody

 Nas antibodyTib neeg lub cev tiv thaiv kab mobTib neeg cov tshuaj tiv thaiv
Hom Tshuaj AntibodyRecombinant antibodyRecombinant antibodyRecombinant antibody
qauvOb qhov sib txawv thiab thaj tsam tas li tau muab los ntawm cov tshuaj tiv thaiv nasCheeb tsam sib txawv yog los ntawm me (loj) nas McAb, thiab thaj av tas li yog los ntawm tib neeg cov tshuaj tiv thaiv kab mobOb qhov sib txawv thiab thaj chaw tsis tu ncua yog muab los ntawm tib neeg cov tshuaj tiv thaiv
Kev Siv Tshuaj Tiv Thaivmuaj zogmuaj zogmuaj zog
Ua kom tib neeg muaj kev tiv thaiv kab mobYooj yim ua rau tib neeg tiv thaiv kab mob thiab tsim HAMATsis muaj zogTsis muaj zog
Cov ntaub ntawv kho mobKev txwv loj, daim ntawv thov me meThoob plawsThoob plaws
Nyuaj rau kev npajIb qho yooj yimnyuajnyuaj

4. Daim ntawv thov

Nyob rau xyoo tsis ntev los no, qhov tshwm sim ntawm humanized antibody thiab tib neeg cov tshuaj tiv thaiv kab mob tau coj kev cia siab tshiab rau kev siv tshuaj kho mob. Lawv qhia cov txiaj ntsig zoo hauv kev kho mob qog nqaij hlav, kab mob autoimmune thiab kab mob plawv, nrog rau kev tiv thaiv kev hloov pauv thiab tiv thaiv kab mob. Lawv tuaj yeem txo qhov kev phom sij ntawm kev siv tshuaj kho qog nqaij hlav ib txwm muaj, tiv thaiv kev ua haujlwm ntawm kev hloov pauv hauv nruab nrog cev, thiab yog qhov pib ntawm kev kho lub cev hloov pauv.

Tebchaws Asmeskas FDA tau pom zoo thawj tus neeg-nas chimeric Fab antibody (ReoPro) hauv xyoo 1994. Cov tshuaj no tau siv dav hauv kev kho mob ntawm ntau yam kab mob plawv, feem ntau yog siv los tiv thaiv kom tsis txhob rov qab los tom qab tsim cov hlab plawv. Kev tshawb fawb nyob rau xyoo tsis ntev los no qhia tias tib neeg cov tshuaj tiv thaiv kab mob tau tshawb pom los tiv thaiv kab mob (xws li HBV, HCV, HIV thiab lwm yam kab mob sib kis).

xaus

Tib neeg cov tshuaj tiv thaiv kab mob yog humanized antibody. Humanized antibody txhais tau tias thaj av tas li ntawm cov tshuaj tiv thaiv kab mob (CH thiab CL cheeb tsam) lossis tag nrho cov tshuaj tiv thaiv yog cim los ntawm noob neej cov tshuaj tiv thaiv kab mob. Thaum tib neeg cov tshuaj tiv thaiv txhais tau tias txhua qhov tshuaj tiv thaiv tau nkag los ntawm tib neeg cov tshuaj tiv thaiv kab mob, tso cai rau tsiaj kom nthuav tawm tib neeg cov tshuaj tiv thaiv.

Xav kawm paub ntau ntxiv txog antigens thiab tshuaj tiv thaiv kab mob? Nyeem txog FC sawv ntaub ntawv.

References

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