Antibody-Drug conjugates (ADCs) ua los ntawm tshwj xeeb rau cov qog cell nto antigens los ntawm monoclonal antibodies (mAbs). Cov tshuaj tiv thaiv kab mob ua kom yooj yim xaiv cov qog cell lees paub, thiab los ntawm receptor- kho endocytosis, ua rau ADCs nkag mus rau cov qog hlwb. Sab hauv, me me - cov tshuaj molecule raug tso tawm los ntawm hydrolysis lossis enzymatic cleavage los tua cov qog hlwb. Nws yog ib qho tseem ceeb rau kev tshawb fawb pharmacodynamics thiab kev soj ntsuam raws li cov qauv tsim thiab kev ua haujlwm ntawm ADCs.
Prisys Biotech tshwj xeeb hauv kev tshawb fawb tshuaj preclinical siv cov crab- noj macaques ua qauv. Peb muab cov kev tshawb fawb loj - tsiaj txhu uas muab cov ntaub ntawv tseem ceeb ntawm kev coj cwj pwm thiab kev ua tau zoo. Siv cov thev naus laus zis thiab kev txawj ntse hauv cov tshuaj tiv thaiv kab mob -Drug conjugate (ADC)Pharmacokinetics (PK)thiabpharmacodynamics (PD), Prisys Biotech txhawb txoj kev txhim kho tshuaj. Peb cov kev tshawb fawb ua kom muaj kev ntsuam xyuas tseeb ntawm kev faib tshuaj, cov metabolism, thiab tshem tawm, ua kom yooj yim rau kev hloov pauv ntawm kev tshawb fawb preclinical mus rau kev sim tshuaj.
1. Kev soj ntsuam ntawm ADC Lub Hom Phiaj Ua Tau Zoo
Covkev ua tau zoontawm ADCs tso siab rau ntau lub hom phiaj xa khoom ntawm mAb tivthaiv. Kev sib txuas nrog cov txuas txuas thiab cov tshuaj molecules tuaj yeem hloov kho mAb qhov kev sib raug zoo rau cov chaw phiaj xwm, ua rau tag nrho cov phiaj xwm kev ua tau zoo tseem ceeb hauv ADC txoj kev loj hlob. Kev ntsuam xyuas tag nrho siv ob qho tib si hauv vitro thiab hauv vivo txoj kev raug pom zoo. Hauv vitro, txoj hauv kev zoo li Biacore, kev sib tw ELISA, thiab ntws cytometry tuaj yeem ntsuas ADC binding affinity rau lub hom phiaj antigens. Hauv vivo, cov qauv qog qhia txog qib siab ntawm lub hom phiaj antigen tuaj yeem ntsuas ADC kev faib tawm hauv cov ntaub so ntswg, thiab lwm txoj hauv kev (xws li, radiolabeled immunoassays) yuav raug siv yog tias tus qauv ELISA tsis ua tau. Tswj pawg nrog antigen-cov hlwb tsis zoo lossis tsis yog- ADCs tshwj xeeb, nrog rau kev suav nrog cov pab pawg me me - cov tshuaj molecule, ntxiv validate ADC hom phiaj.
2. Kev ntsuam xyuas ntawm ADC-Mediated Tumor Cell Endocytosis
Rau qee qhov ADCs, kev ua tau zoo ntawm qhov cuam tshuam ntawm qhov induced endocytosis ntawm lub conjugate, ib tug txheej txheem zoo li los ntawm tej yam xws li antigen epitope selectivity, binding affinity, thiab intracellular thauj txoj kev. Thaum ntxov - kev txhim kho tshuaj yuav tsum txheeb xyuas qhov ADCs tsim nyog tshaj plaws rau endocytosis. Endocytosis kinetics yuav tsum tau soj ntsuam siv txoj kev xws li ntws cytometry los yog confocal immunofluorescence microscopy. Tsis tas li ntawd, cov tshuaj pharmacokinetics ntawm tes, sib piv me me - qib tshuaj molecule ntawm antigen-positive thiab antigen-cov hlwb tsis zoo, pab txiav txim siab endocytosis efficiency. Rau ADCs siv tau yam tsis muaj endocytosis, cov kauj ruam ntsuas no yuav raug tshem tawm.
3. Kev tshuaj xyuas ntawm ADC Antitumor Effects
ADC antitumor kev ua tau zoo ua raws li hauv vitro thiab hauv vivo txoj kev rau lwm cov tshuaj tiv thaiv kab mob. Kev sim tsim, tshwj xeeb yog pawg tswj hwm, yog qhov tseem ceeb. Cov kev tswj hwm tau pom zoo suav nrog mAb- tsuas yog pab pawg los tshuaj xyuas yog ADC muaj cov txiaj ntsig zoo tshaj plaws ntawm cov tshuaj tiv thaiv kab mob, ib pawg ADC tsis cuam tshuam los ntsuas lub hom phiaj tshwj xeeb, thiab cov pab pawg me me - tswj cov molar nrog molar sib npaug rau lub hom phiaj ADC. Kev sim ua ntej dav dav tau qhia kom paub tseeb tias kev tshawb fawb tsim tau zoo rau hauv vivo thiab hauv vitro antitumor kuaj.
4. Kev soj ntsuam ntawm Antibody-Mediated Effector Functions of ADCs
Txawv IgG subtypes muaj ntau yam kev ua haujlwm, nrog IgG1 paub txog cov tshuaj tiv thaiv zoo dua -nyob ntawm tes-mediated cytotoxicity (ADCC) thiab ntxiv -dependent cytotoxicity (CDC) cuam tshuam, thaum IgG2 thiab IgG4 tsis muaj zog. ADCs uas yuav tsum tau txhim kho cov nyhuv antitumor los ntawm effector functions, los yog cov uas xav tau kom tsis txhob muaj peev xwm tawm ntawm -lub hom phiaj toxicity, yuav tsum muaj lawv cov Fc- kho kom haum xeeb kev soj ntsuam, tshwj xeeb tshaj yog tias conjugation yuav hloov cov dej num no. Kev ntsuam xyuas cov haujlwm ua haujlwm yog qhov tseem ceeb hauv cov xwm txheej uas liab qab mAbs nthuav tawm Fc kev ua haujlwm, txawm hais tias cov haujlwm ua haujlwm feem ntau tsis tsav ADC kev ua tau zoo.
5. Kev ntsuam xyuas ntawm ADCs Targeting Tumor-Associated Antigens in Non-Tumor Cells
Qee ADCs lub hom phiaj qog-cov tshuaj tiv thaiv kab mob sib txuas tsis tau hais tawm ntawm cov qog nqaij hlav tab sis ntawm cov vasculature los yog stroma, yuav tsum tau muaj kev ntsuam xyuas tshwj xeeb. Tus qauv hauv vitro cell proliferation inhibition kev soj ntsuam yuav tsis haum. Hloov chaw, kev soj ntsuam raws li cov tshuaj cov txheej txheem, xws li HUVEC proliferation inhibition lossis chorioallantoic membrane angiogenesis tests, raug pom zoo rau kev soj ntsuam los tiv thaiv -angiogenesis ADCs. Qhov twg lub hom phiaj antigens yog tib neeg- tshwj xeeb, lwm txoj hauv kev, xws li surrogate molecules lossis humanized tsiaj qauv, yuav tsum tau siv rau kev soj ntsuam pharmacodynamic.
Prisys Biotech tuav lub siab - cov chaw zoo thiab ntiav ib pab neeg ua haujlwm hauv -tsiaj tshuaj kho mob loj, muab tso rau peb ua tus muab kev pabcuam tshawb fawb txog kev kho mob. Peb cov kev tshawb fawb PK thiab PD, tshwj xeeb yog cov uas tau ua nrogtsis yog - tib neeg primates, muab lub platform muaj txiaj ntsig rau kev txhim kho ADCs thiab lwm yam tshuaj lom neeg. Peb txhawb kom koj tshawb nrhiav peb lub peev xwm thiab tshawb nrhiav seb peb tuaj yeem pab txhawb koj li kev txhim kho tshuaj li cas nrog cov ntaub ntawv muaj zog, cov ntaub ntawv - tsav kev nkag siab.
