1. Taw qhia
Antibody-drug conjugates (ADC) yog tsim los ntawm peb yam tseem ceeb: cov tshuaj tiv thaiv kab mob, tshuaj (feem ntau hu ua payload los yog me me - cov tshuaj molecule toxin), thiab cov linker. ADCs ua haujlwm los ntawm kev siv cov tshuaj tiv thaiv kab mob tshwj xeeb rau lub hom phiaj antigen kom xa cov ADC mus rau lub hom phiaj. Thaum khi rau cov antigen, ADC yog sab hauv los ntawm lub hom phiaj ntawm tes, qhov chaw them nyiaj raug tso tawm kom siv nws cov teebmeem cytotoxic, tshem tawm lub hom phiaj ntawm tes.
Prisys Biotech tshwj xeeb hauv kev tshawb fawb tshuaj preclinical nrog Cynomolgus macaques, muab cov kev tshawb fawb loj- tsiaj txhu uas muab kev nkag siab tseem ceeb rau kev coj cwj pwm thiab kev ua tau zoo. Kev siv thev naus laus zis thiab kev txawj ntse hauv ADCPharmacokinetics (PK)thiabpharmacodynamics (PD), Prisys Biotech txhawb txoj kev txhim kho tshuaj los ntawm kev ua kom muaj kev ntsuam xyuas meej ntawm kev faib tshuaj, cov metabolism, thiab tshem tawm, pab txhawb kev hloov pauv los ntawm kev tshawb pom preclinical mus rau kev kho mob kom zoo.
Txij li cov tshuaj ADC txawv ntawm cov tshuaj tiv thaiv kab mob monoclonal (mAbs) thiab feem ntau yog siv rau hauv cov hlab ntsha (IV), cov ntaub ntawv no tsis tham txog cov yam ntxwv ntawm kev nqus thiab es tsis txhob tsom mus rau kev faib tawm thiab tshem tawm ntawm ADCs.
2. Kev faib cov tshuaj ADC
Raws li ADCs feem ntau muaj cov qauv tshuaj tiv thaiv kab mob, lawv cov yam ntxwv faib khoom feem ntau zoo ib yam li cov tshuaj tiv thaiv liab qab. Peb lub ntsiab tseem ceeb cuam tshuam rau ADC kev faib tawm: lub hom phiaj- kho qhov kev faib tawm tshwj xeeb, cov kua dej ntws tawm ntawm cov ntshav, cov kua dej hauv cov ntaub so ntswg, thiab cov qog ntshav, thiab cov khoom siv ntawm ADC nws tus kheej.
Hom phiaj -Mediated Distribution: Cov txheej txheem no feem ntau cuam tshuam los ntawm kev qhia ntawm lub hom phiaj antigens thiab tus nqi ntawm endocytosis. Qhov zoo tshaj plaws, lub hom phiaj antigen yuav tsum sib txawv ntawm cov qog thiab cov ntaub so ntswg ib txwm los txhim kho kev ua tau zoo thiab txo cov tshuaj toxicity.
Convective Fluid Flow: Vim lawv qhov hnyav molecular loj (~150 kDa), ADCs tseem nyob hauv vasculature sai tom qab kev tswj hwm, mus txog qhov ruaj khov- lub xeev ntim ntawm kev faib (Vss) nyob ib ncig ntawm 0.2 L / kg.
Intrinsic Properties ntawm ADC: Molecular loj, nqi, thiab hydrophobicity tag nrho cov cuam tshuam rau ADC lub peev xwm mus hla capillary pores. Siab DAR (tshuaj-rau-antibody piv) qhov tseem ceeb, feem ntau siab dua 4, tuaj yeem ua rau nce ntshav plasma clearance tus nqi thiab cov kab mob siab.
3. Kev tshem tawm cov tshuaj ADC
Kev tshem tawm ADC yog qhov nyuaj, muab nws cov qauv tsim ntawm cov tshuaj tiv thaiv kab mob, txuas txuas, thiab them nyiaj. Cov txheej txheem tseem ceeb muaj xws li:
3.1 Hom phiaj -Kev tshem tawm qhov nruab nrab: Ua raws li kev khi nrog daim nyias nyias ntawm cov tshuaj tiv thaiv kab mob, ADCs tau txais receptor-mediated endocytosis thiab lysosomal degradation. Cov nqi endocytic siab dua pab txhawb kev siv tshuaj zoo los ntawm kev ua kom ADC sab hauv thiab tso nyiaj tso tawm.
3.2 FcRn Receptor Kev Sib Tham: FcRn receptor tiv thaiv ADC los ntawm degradation nyob rau hauv cov hlwb, txuas plasma ib nrab-lub neej thiab muaj peev xwm pab tau ADC-mediated antibody-dependent cellular cytotoxicity (ADCC) los.
3.3 Linker Stability: Linkers raug cais raws li cleavable los yog tsis yog -cleavable, cuam tshuam rau payload tso mechanisms thiab cuam tshuam rau kev ua tau zoo thiab toxicity. Cleavable linkers vam khom pH qhov sib txawv los yog cov enzymes tshwj xeeb, thaum tsis yog -cleavable linkers tso payloads tsuas yog thaum cov tshuaj tiv thaiv tawg.
3.4 Kev them nyiaj yug Dynamics: Thaum tso tawm, payloads tuaj yeem nthuav tawm dawb lossis nyob twj ywm hauv zos. Payloads uas yog substrates ntawm efflux transporters, xws li P-glycoprotein, yuav xav tau kev hloov kho kom ceev ceev nyob rau hauv lub hom phiaj.
4. Cov lus xaus
Kab lus no tau piav qhia txog ADME cov txheej txheem thiab muaj feem cuam tshuam rau ADC cov tshuaj, lees paub tias yuav tsum muaj kev tshawb fawb ntxiv kom nkag siab txog cov txheej txheem no vim qhov txawv ntawm cov tshuaj ADC piv rau cov tshuaj me me - cov tshuaj molecule.
Nrog kev txiav- cov chaw ntug thiab ib pab neeg tau ntsib hauvloj- tsiaj tshuaj, Prisys Biotech tseem nyob ntawm qhov ua ntej ntawm cov kev pabcuam tshawb fawb ua ntej. Peb cov kev tshawb fawb PK thiab PD, tshwj xeeb nrog cov tsis yog - tib neeg primates, muab lub platform uas muaj nuj nqis rau kev nce qib ADC thiab lwm yam tshuaj lom neeg. Peb caw koj los kawm paub ntxiv txog peb lub peev xwm thiab peb tuaj yeem pab txhawb rau koj li kev txhim kho tshuaj li cas nrog kev ntseeg siab, cov ntaub ntawv - tau tsav kev nkag siab.
