Cov tshuaj Oligonucleotide tau tsim los rau ntau tshaj 40 xyoo txij li thawj tus yug hauv xyoo 1978. Txawm li cas los xij, lawv txoj kev loj hlob tau qeeb dua lwm hom tshuaj vim lawv qhov tsis ruaj khov thiab tsis muaj cellular uptake efficiency. Qhov tshwm sim ntawm kev xa khoom tshiab thiab cov kev hloov kho tshuaj lom neeg tau txhim kho cov teeb meem no zoo heev, thiab cov tshuaj oligonucleotide tau pom tias muaj kev loj hlob sai hauv xyoo tas los no. Tam sim no, twb muaj cov lus qhia thiab kev lag luam dawb cov ntaub ntawv ntawm kev ntsuam xyuas immunogenicity ntawm cov tshuaj tiv thaiv kab mob thiab lwm yam biologics, tab sis tseem muaj ob peb cov lus ceeb toom txog kev tiv thaiv kab mob ntawm cov tshuaj oligonucleotide nyob rau hauv cov tsiaj lossis cov neeg mob, thiab tsis muaj kev taw qhia. Kev nkag siab tsis txaus ntawm kev tiv thaiv kab mob ntawm cov tshuaj oligonucleotide kuj tseem txwv txoj kev loj hlob ntawm cov tshuaj no.
Tus yuam sij rau tshuaj immunogenicity yog los txiav txim siab seb lub cev tiv thaiv kab mob puas tuaj yeem lees paub cov tshuaj raws li nws tus kheej thiab zam rau nws, thiab lwm yam uas cuam tshuam rau immunogenicity suav nrog txoj kev tswj hwm thiab cov kab mob tshwj xeeb raug kho (Daim duab 1).
Daim duab 1 Txoj hauv kev cuam tshuam rau kev tiv thaiv kab mob (Pom. Immunol., 18 Lub Yim Hli 2020 Sec. Tshuaj Tiv Thaiv thiab Kev Kho Mob Molecular)
Cov yam ntxwv ntawm cov tshuaj: Piv nrog rau feem ntau cov tshuaj biologics (xws li monoclonal antibodies), cov tshuaj oligonucleotide kuj me me, muaj tsawg dua cov epitopes ntau dua li cov protein ntau dua, yog li lawv feem ntau suav tias muaj kev tiv thaiv kab mob tsawg. Txawm li cas los xij, kev sib cuam tshuam ntawm oligonucleotide molecules thiab lub cev tiv thaiv kab mob yog qhov nyuaj, nrog lub peev xwm los txhawb kev tiv thaiv hauv lub cev. Cov kev tshawb fawb yav dhau los tau pom tias siRNA cov kab ke tuaj yeem cuam tshuam rau kev tiv thaiv kab mob los ntawm tus xov tooj -zoo li receptors (TLRs), thiab siRNA sequences nplua nuj nyob rau hauv guanine thiab uracil bases yuav ua rau muaj kev tiv thaiv kab mob ntau dua. Txhawm rau txhim kho kev ruaj ntseg, kev nyab xeeb, cellular uptake thiab kev ua tau zoo ntawm cov tshuaj oligonucleotide, kev hloov kho tshuaj feem ntau yog siv rau lawv nyob rau hauv txoj kev loj hlob ntawm tiam tshiab oligonucleotide tshuaj. Kev hloov kho ntawm cov pob txha nucleic acid, glycosyl ib feem ntawm ribose thiab nucleobase tau siv dav, thiab cov kev hloov kho no yuav ua rau muaj kev tiv thaiv kab mob. Tsis tas li ntawd, nucleic acid sequences zoo ib yam li cov kab mob kuj tseem muaj lub zog tiv thaiv kab mob, yog li cov kab mob oligonucleotide tshiab tuaj yeem muaj kev tiv thaiv kab mob ntau dua.
Txoj kev ntawm kev tswj hwm: Cov tshuaj Oligonucleotide tuaj yeem ua los ntawm ntau txoj hauv kev ntawm kev tswj hwm, xws li kev txhaj tshuaj hauv cov hlab ntsha thiab cov ntaub so ntswg, kev txhaj tshuaj ntawm qhov ncauj thiab subcutaneous (Daim duab 2).
Daim duab 2 Oligonucleotide tshuaj txoj kev ntawm kev tswj hwm thiab kev xa khoom (Nat. Nanotechnol. 16, 630–643 (2021).)
Tam sim no, cov tshuaj oligonucleotide tau pom zoo feem ntau ua los ntawm kev xa mus rau lub cev tsis muaj zog- qhov chaw txwv, tab sis kev xa cov tshuaj oligonucleotide zoo rau ntau cov ntaub so ntswg tseem yog ib qho nyuaj rau kev txhim kho tshuaj oligonucleotide vim qhov nyuaj ntawm oligonucleotides dhau los ntawm daim nyias nyias. Txoj kev loj hlob ntawm cov neeg nqa khoom tau daws qhov teeb meem no zoo heev, thiab cov neeg nqa khoom xa tuaj tuaj yeem nqa cov lus teb tiv thaiv kab mob sib txawv los ntawm ob qhov kev txiav txim loj thiab tuaj yeem ua los ntawm ntau yam txheej txheem. Cov neeg nqa khoom sib txawv xa cov siRNA molecules hla cov cell membranes hauv txoj kev tshwj xeeb (Daim duab 2), nthuav tawm siRNA rau ntau qhov sib txawv thiab hom qauv lees paub receptors (PRRs), ua rau lawv muaj kev cuam tshuam ntau rau innate tiv thaiv kab mob. Tsis tas li ntawd, txoj kev xa khoom tam sim no ntawm GalNAc (N-acetylated galactosamine) conjugation thiab lipid nanoparticle (LNP) cov neeg nqa khoom feem ntau yog txhaj tshuaj hauv cov hlab ntsha thiab subcutaneous, uas muaj kev pheej hmoo siab dua ntawm kev tiv thaiv kab mob. Nyob rau hauv xyoo tas los no, tshiab oligonucleotide xa cov tshuaj xws li endogenous vesicles, spherical nucleic acids, thiab nanotechnology daim ntaub ntawv kuj tau nce, uas tseem yuav coj cov teeb meem tshiab rau kev kuaj immunogenicity.
Analysis Strategy for Immunogenicity of Oligonucleotide Drugs
Xav tias immunogenicity muaj feem cuam tshuam nrog kev ua tau zoo thiab kev nyab xeeb ntawm cov tshuaj, kev tshuaj xyuas immunogenicity yog xav tau rau cov tshuaj oligonucleotide los txhawb lawv txoj kev loj hlob thiab kev sim tshuaj. Ntau lub hauv paus ntsiab lus ntawm bioanalytical siv rau cov tshuaj protein kuj tseem siv tau rau cov tshuaj oligonucleotide, feem ntau yog ua raws li hierarchical immunogenicity tsom xam cov tswv yim, tab sis peb kuj yuav tsum xav txog cov txheej txheem tshwj xeeb ntawm cov tshuaj oligonucleotide, txoj hauv kev ntawm kev tswj hwm thiab qhov chaw ntawm kev nqis tes ua uas ua rau kom nyuaj ntawm kev tiv thaiv kab mob thiab cov txheej txheem bioanalytical.
Raws li cov yam ntxwv ntawm cov tshuaj oligonucleotide, qee qhov kev saib xyuas yuav tsum tau them thaum kuaj lawv cov tshuaj tiv thaiv kab mob: 1)Anti- tshuaj tiv thaiv kab mob (ADAs)uas tej zaum yuav raug tsim los ntawm kev hloov tshuaj, cov khoom xa tuaj thiab cov khoom xa tuaj yuav tsum tau soj ntsuam tag nrho; 2) Cov tshuaj Oligonucleotide muaj ntau txoj hauv kev ntawm kev tswj hwm, peb yuav tsum tau them sai sai rau kev kuaj pom ntawm ntau hom immunoglobulin antibodies hauv ntau hom qauv; 3) Raws li cov kev paub tam sim no, piv nrog cov tshuaj ib txwm siv, ADA cov lus teb cuam tshuam los ntawm cov tshuaj oligonucleotide qee zaum maj mam, tej zaum tau ntau lub hlis. Yog li ntawd, thaum ua kev ntsuam xyuas kev pheej hmoo ntawm immunogenicity nyob rau theem pib ntawm txoj kev loj hlob, nws raug nquahu kom khaws cov qauv ntawm theem no thiab tshawb xyuas lawv cov kev tiv thaiv kab mob raws li cov ntaub ntawv tshiab nthuav tawm hauv tsev kho mob, muab cov ntaub ntawv rau tom qab thiab cov kev tshawb fawb tseem ceeb.
Txhawm rau txhawb txoj kev loj hlob thiab kev sim tshuaj ntawm siRNA tshuaj, Pharmaron tau tsim ib txoj hauv kev tshawb nrhiav rau ADAs uas tsim los ntawm siRNA, thiab muaj qee qhov kev txiav txim siab thiab cov lus pom zoo hauv cov txheej txheem tsim:
Vim yog cov qauv sib txawv los ntawm cov tshuaj tiv thaiv kab mob protein, cov txheej txheem kev sau cov protein ib txwm siv tsis tau rau siRNA cov ntawv sau tshuaj, thiab ib txoj kev sau npe tshiab ua ke nrog biotin thiab digoxin tau ua tiav;
Vim yog qhov tsis muaj zog immunogenicity ntawm siRNA, qhov kev sib raug zoo ntawm kev npaj cov tshuaj tiv thaiv zoo yog qhov tsis zoo. Los ntawm tsis tu ncua optimizing cov kauj ruam nrhiav kom tau, txoj kev rhiab heev tau ua raws li cov cai tam sim no.
