Thawj kauj ruam ntawm CAR-T Commercialization

Source: T&L Biotechnology Tso Tawm Sijhawm: 2023-08-31

Raws li ib txoj kev tshiab ntawm kev kho mob qog nqaij hlav ib leeg, CAR-T Kev Kho Mob Cell tau pom muaj peev xwm kho tau zoo. Txawm li cas los xij, kev lag luam kev lag luam txhais tau tias muaj kev cov nyom tshiab. Piv nrog rau cov tshuaj ib txwm muaj, "nyob" biopharmaceuticals muaj ntau dua qhov tsis meej, muaj teeb meem, thiab kev pheej hmoo, cov tuam txhab lag luam yuav tsum xub tsim cov txheej txheem tsim nyog ntawm kev ntsuam xyuas kom ntseeg tau tias muaj kev nyab xeeb thiab ua haujlwm zoo ntawm CAR-T cov khoom.Hnub no, cia peb saib seb yuav ua li cas thiaj li ua tau zoo ntawm CAR-T cov khoom thiab cov txiaj ntsig zoo dua rau cov neeg mob.

1. CAR-T cell amplification peev xwm hauv vitro
CAR-T cell therapy yuav tsum tau ua ntej tau txais T lymphocytes los ntawm tus neeg mob lub cev, thiab tom qab ntawd hloov CAR lub hom phiaj los ntawm kev siv tshuab vitro transgenic. Cov txheej txheem no yuav tsum tau ua kom tag nrho hauv cov kab lis kev cai ntawm tes kom tau txais kev kho mob CAR-T hlwb txaus. Yog li ntawd, lub peev xwm hauv vitro amplification ntawm CAR-T hlwb ncaj qha txiav txim siab seb cov cell puas tuaj yeem tau txais los ua kom tau raws li qhov xav tau ntawm kev kho mob. Peb tuaj yeem ntsuas lub peev xwm hauv vitro amplification ntawm CAR-T cov khoom lag luam ntawm tes los ntawm cov xov tooj ntawm cov xov tooj uas tau txais los ntawm ntau tiam neeg ntawm kab lis kev cai, kev nce ntawm cov xov tooj ntawm tes, thiab lub sij hawm kab lis kev cai yuav tsum tau teeb tsa cov xov tooj ntawm tes [1]. Cov indexes no qhia txog kev loj hlob thiab kev loj hlob ntawm CAR-T hlwb, thiab yog ib qho ntawm cov kev ntsuas tseem ceeb rau kev txhim kho CAR-T cell technology.

Fig1: CAR-T cell amplification txheej txheem hauv vitro

2. Kev pheej hmoo ntawm CAR-T hlwb hauv vivo
Lub sij hawm muaj sia nyob thiab kev pheej hmoo ntawm CAR-T hlwb tom qab infusion kuj tseem ceeb ntawm kev ua haujlwm. CAR-T hlwb nyob ntev tuaj yeem ua rau cov qog tua tau ntev dua. Peb feem ntau tsis tu ncua kuaj pom cov kev hloov pauv ntawm CAR-T hlwb hauv cov ntshav peripheral los ntawm cov cytology ntws los ntsuas lawv qhov kev pheej hmoo hauv vivo. Feem ntau, nws tuaj yeem kuaj pom tsis tu ncua 1-6 lub hlis lossis ntau dua tom qab infusion. Qhov kev tshawb pom siab tshaj plaws feem ntau tshwm sim 1-2 lub lis piam tom qab infusion. Nws yog ib txwm ua rau tus naj npawb ntawm CAR-T hlwb kom txo qis thaum lub sijhawm. Qhov zoo tshaj plaws CAR-T cell formulation yuav tsum muaj lub sij hawm ciaj sia tsawg kawg yog 3-6 lub hlis hauv vivo, tsuas yog hauv txoj kev no tuaj yeem ua kom muaj txiaj ntsig zoo.

Daim duab 2: Kev tshawb nrhiav tsis tu ncua ntawm CAR-T hlwb hauv vivo

3. qog lub hom phiaj kev ua tau zoo ntawm CAR-T hlwb
Cov txheej txheem tseem ceeb ntawm CAR-T cell kho yog tias T lymphocytes tau txais kev sib raug zoo siab rau kev muaj peev xwm txheeb xyuas cov qog nqaij hlav tshwj xeeb antigens tom qab kev hloov kho, yog li CAR-T cov khoom lag luam ntawm tes yuav tsum qhia meej tias muaj peev xwm los tsom cov qog hlwb. Peb tuaj yeem kuaj pom cov nyhuv tua ntawm CAR-T hlwb ntawm cov qog cell kab qhia cov antigens tsom mus rau hauv vitro los txiav txim rau lawv qhov kev ua tau zoo. Tsis tas li ntawd, peb tseem tuaj yeem tshawb xyuas qhov infiltration ntawm CAR-T hlwb hauv cov qog nqaij hlav los ntawm kev ntws cytometry hauv tus neeg mob lub cev kom pom tias nws tuaj yeem nkag mus rau hauv cov qog nqaij hlav kom ua haujlwm tua [3]. Qhov zoo tshaj plaws CAR-T hlwb yuav tsum tau ua kom muaj zog hauv cov qog.

4. Cytotoxic kev ua ntawm CAR-T hlwb
Tom qab CAR-T hlwb paub thiab qhib cov qog, lawv yuav tso ntau yam cytokines thiab cytotoxic hais los tua thiab tua cov qog hlwb. Yog li ntawd, peb tuaj yeem kuaj xyuas cov qib IFN-γ, TNF-α, perforin, granular enzyme thiab lwm cov molecules tso tawm los ntawm CAR-T hlwb los soj ntsuam cov kev ua cytotoxic thiab ua kom cov qog nqaij hlav tua [4]. Hauv vitro, peb tuaj yeem tshawb xyuas cov ntsiab lus ntawm cov cytokines saum toj no thiab cov co toxins los ntawm kev sib koom ua ke CAR-T hlwb thiab lub hom phiaj qog hlwb. Qhov kev sim degranulation tseem tuaj yeem ua rau muaj kev xav txog qib ntawm CAR-T hlwb tso perforin thiab granulase, uas yog cov cim tseem ceeb los ntsuas kev tua cov khoom ntawm CAR-T cell.

Fig4: Kev kuaj xyuas lub peev xwm ntawm CAR-T hlwb los tua cov phiaj hlwb

5. Lub peev xwm nco tau ntawm CAR-T hlwb
Zoo tagnrho CAR-T hlwb yuav tsum muaj lub cim xeeb ua haujlwm, uas txhais tau hais tias lawv tuaj yeem ua tiav cov haujlwm muaj zog tom qab rov ua kom rov ua haujlwm thiab teb rau cov qog nqaij hlav sai dua [5]. Peb tuaj yeem tshawb xyuas qhov cuam tshuam ntawm lub cim xeeb ntawm CAR-T hlwb los ntawm kev txhawb nqa lawv ntau zaus hauv vitro, xws li nce qib ntawm cytokine tso tawm thiab txhim kho kev tua neeg. Tom qab no CAR-T cell nrog lub peev xwm nco tau nkag mus rau hauv lub cev, nws tuaj yeem ua tiav ntev-ntev thiab muaj zog tua cov nyhuv ntawm cov qog.

Daim duab 5: Kev tshawb nrhiav ntev ntev ntawm CAR-T hlwb

6. Kev soj ntsuam kev nyab xeeb ntawm CAR-T cell therapy

Qhov feem ntau pheej hmoo ntawm CAR-T cell therapy yog qhov uas yuav ua rau mob hnyav cytokine tso tawm. Yog li peb yuav tsum kuaj xyuas cov qib ntawm CRS-txog cytokines xws li IL-6, IL-10 thiab IFN-γ uas tsim los ntawm CAR-T hlwb, thiab ntsuas qhov kev pheej hmoo tias CAR-T cell kho yuav ua rau CRS. Tsis tas li ntawd, nws yog ib qho tsim nyog los saib xyuas lwm yam kev mob tshwm sim muaj kuab lom.
Cov ntsuas no tuaj yeem cuam tshuam tag nrho cov kev ua haujlwm tseem ceeb ntawm CAR-T hlwb, suav nrog kev muaj peev xwm nthuav dav, qog lub hom phiaj, kev ua haujlwm cytotoxic, kev pheej hmoo thiab kev nyab xeeb. Tsuas yog CAR-T cov khoom lag luam ntawm tes uas ua tau raws li cov kev cai saum toj no thiab cov cim qhia ib txhij tuaj yeem ua rau muaj txiaj ntsig los tiv thaiv qog noj ntshav hauv kev kho mob. Yog li ntawd, nws yog ib qho tsim nyog yuav tsum tsim kom muaj kev soj ntsuam zoo thiab tsim nyog thiab tshem tawm cov teeb meem ntawm kev tsim cov khoom npaj siv rau kev tsim cov khoom siv tes ua haujlwm siab thiab cov khoom zoo CAR-T cell, thiaj li ua tiav lub hom phiaj ntev uas txo cov nqi thiab txhim kho kev kho mob yav tom ntej, thiab muaj txiaj ntsig zoo rau cov neeg mob xav tau kev kho mob ntau dua.

Lub hnub qub khoom pom zoo
Raws li kev kho lub hnub qub nrov tshaj plaws nyob rau tam sim no, CAR-T txoj kev kho tau raug pom zoo rau npe nrog CAR-T thib peb cov khoom hauv Suav teb. CAR-T cov tuam txhab lag luam thiab cov platforms tau nrawm nrawm ntawm kev tshawb fawb thiab kev tsim kho thiab nquag tsom mus rau qhov sib txawv ntawm cov txheej txheem. Qee lub lag luam ib sab sib tw rau cov khoom lag luam kev nyab xeeb, nws yog ib qho tseem ceeb rau cov tuam txhab lag luam kom txo cov nqi thiab nce kev ua tau zoo, thiab kev hloov pauv hauv tsev kuj yuav dhau los ua txoj hauv kev loj rau kev tsim kho. Tiv thaiv kab mob Magnetic Beads yog cov ntaub ntawv tseem ceeb rau kev npaj CAR-T hlwb, thiab ua lub luag haujlwm tseem ceeb hauv kev sib cais thiab ua kom cov txheej txheem ntawm T cell. Tonglihaiyuan GMP qib khoom ActSep ® CD3 / CD28 Kev Sib cais & Ua kom muaj hlau nplaum nplaum (cov khoom naj npawb: GMP-TL603) integrates kev sib cais thiab ua kom muaj zog kom ua tiav kev sib cais, ua kom muaj zog thiab ua kom muaj zog ntawm T hlwb zoo. Nws yog qhov tsim nyog rau kev siv tib neeg T hlwb, CAR-T thiab lwm yam kab lis kev cai T-cell. Ntxiv mus, thiab cov khoom lag luam tau ua tiav DMF Hom II ua ntaub ntawv nrog US FDA (tus naj npawb: 038124), txhawb kev sau npe thiab tshaj tawm cov tshuaj cellular.

ActSep® CD3 / CD28 Sib cais & Ua kom muaj hlau nplaum sib nqus

1.T-cell qaug zog theem

Kev qhia theem ntawm LAG3 thiab PD1 raug kuaj pom tom qab T-cell ua kom kab lis kev cai 14 hnub nrog sib txawv sib nqus hlaws ntxiv piv. ActSep® yog qhov pib zoo ib yam li cov neeg sib tw. Qhov kev qhia ntawm ActSep ® qaug zog Performance index yog qis dua nyob rau hauv qhov piv ntawm 3: 1 sib nqus hlaws rau ntawm tes. Tsis tas li ntawd, tshem tawm cov hlaws sib nqus rau Hnub 5 yuav txo qis qis ntawm T hlwb ntxiv.

2. T-cell subtype tsom xam

Tshawb xyuas cov kev hloov pauv ntawm T-cell subtypes ntawm cov kab lis kev cai sib txawv tom qab ActSep® kev ua kom sib cais. Qhov kev faib ua feem ntawm Tcm nce thaum lub sij hawm cog qoob loo, thiab qhov piv ntawm Teff rau Tem nce nrog rau ncua sij hawm cog qoob loo.

Hais txog T&L
T&L Biotechnology Ltd., nrhiav tau nyob rau hauv 2011, tsom rau kev tshawb fawb thiab kev loj hlob ntawm upstream GMP qib raw cov ntaub ntawv thiab reagents ntawm cell thiab noob therapy (CGT). Peb cog lus los muab cov khoom lag luam txhim khu kev qha thiab cov kev pabcuam rau kev ua neej nyob