Gawo Loyamba la CAR-T Commerceization

Gwero: T&L Biotechnology yotulutsidwa nthawi: 2023-08-31

Monga njira yatsopano ya munthu payekha chotupa immunotherapy, CAR-T Chithandizo cha Ma cell wasonyeza mphamvu zazikulu zochiritsira. Komabe, ntchito zamalonda zimatanthauza zovuta zatsopano. Poyerekeza ndi mankhwala achikhalidwe, "amoyo" biopharmaceuticals ali ndi kusatsimikizika kwakukulu, mavuto omwe angakhalepo, ndi zoopsa, makampani opanga mankhwala ayenera choyamba kupanga ndondomeko yoyenera yoyesera kuti atsimikizire chitetezo ndi mphamvu ya mankhwala a CAR-T.

1. Kutha kwa ma cell a CAR-T mu vitro
CAR-T cell therapy imafuna kupeza kaye ma T lymphocyte kuchokera m'thupi la wodwalayo, kenako kutulutsa madera omwe akukhudzidwa ndi CAR kudzera muukadaulo wa in vitro transgenic. Njirayi iyenera kukulitsidwa mokwanira mu dongosolo la chikhalidwe cha maselo kuti mupeze maselo ochiritsira okwanira a CAR-T. Choncho, mphamvu ya in vitro amplification ya maselo a CAR-T imatsimikizira mwachindunji ngati chiwerengero cha maselo chingapezeke kuti chikwaniritse zosowa za chithandizo. Titha kuwunika kuthekera kwa in vitro kukulitsa kwazinthu zama cell a CAR-T kudzera pakuchulukirachulukira kwa ma cell omwe amapezedwa kudzera m'mibadwo ingapo yachikhalidwe, kuchuluka kwa ma cell, komanso nthawi yachikhalidwe yofunikira kukhazikitsa kuchuluka kwa ma cell [1]. Ma index awa akuwonetsa kuchulukana komanso nyonga ya ma cell a CAR-T, ndipo ndi imodzi mwazofunikira kwambiri pakupanga ukadaulo wa cell wa CAR-T.

Chithunzi 1: CAR-T cell amplification process in vitro

2. Kulimbikira kwa maselo a CAR-T mu vivo
Nthawi yopulumuka ndi kulimbikira kwa maselo a CAR-T pambuyo pa kulowetsedwa ndi zizindikiro zofunika kwambiri za ntchito. Ma cell a CAR-T omwe amakhala nthawi yayitali amatha kusewera chotupa chokhalitsa. Nthawi zambiri timawona kusintha kwa chiwerengero cha maselo a CAR-T m'magazi ozungulira kudzera mu cytology yothamanga kuti tiwone kulimbikira kwawo mu vivo. Nthawi zambiri, imatha kudziwika mosalekeza pakatha miyezi 1-6 kapena kupitilira apo. Kuzindikira kwakukulu kumachitika pakatha milungu 1-2 kulowetsedwa. Ndi zachilendo kuti chiwerengero cha maselo a CAR-T chichepe pakapita nthawi. Maselo abwino a CAR-T ayenera kukhala ndi nthawi yopulumuka ya miyezi 3-6 mu vivo, mwa njira iyi yokha ndi yomwe ingatsimikizire kuti chithandizo chamankhwala chikhale chokwanira.

Chithunzi 2: Kuzindikira kokhudzana ndi kulimbikira kwa ma cell a CAR-T mu vivo

3. Kugwira ntchito kwa chotupa kumaselo a CAR-T
Makina ofunikira a CAR-T cell therapy ndikuti ma T lymphocyte adapezedwa kuyanjana kwakukulu kuti athe kuzindikira ma antigen enieni amtundu wa chotupa pambuyo posinthidwa, chifukwa chake ma cell a CAR-T ayenera kukhala omveka bwino kuti athe kulunjika ma cell chotupa. Titha kuwona kupha kwa ma cell a CAR-T pamizere yama cell chotupa omwe amawonetsa ma antigen omwe akulunjika kudzera mu vitro kuti aweruze momwe akulunjika. Kuphatikiza apo, titha kuzindikiranso kulowetsedwa kwa ma cell a CAR-T mu minofu yotupa kudzera mu cytometry yamagazi m'thupi la wodwalayo kuti tiwone ngati angalowe bwino pamalo otupa kuti agwire ntchito yopha [3]. Maselo abwino a CAR-T ayenera kulemeretsedwa kwambiri mu chotupacho.

4. Ntchito ya Cytotoxic ya maselo a CAR-T
Ma cell a CAR-T akazindikira ndikuyambitsa zotupa, amamasula ma cytokines ndi tinthu ta cytotoxic kuti tiwukire ndikupha ma cell chotupa. Choncho, tikhoza kuzindikira milingo ya IFN-γ, TNF-α, perforin, enzyme granular ndi mamolekyu ena otulutsidwa ndi maselo a CAR-T kuti ayese ntchito ya cytotoxic ndi kuyambitsa kupha zotupa [4]. Mu vitro, timatha kuzindikira zomwe zili pamwambazi ndi ma cytokines ndi ma cell a CAR-T omwe amapangidwa ndi ma cell a chotupa. Kuyesa kwa degranulation kumatha kuwonetsanso mwachilengedwe kuchuluka kwa maselo a CAR-T omwe amatulutsa perforin ndi granulase, zomwe ndizizindikiro zofunika kuyesa ntchito yopha ma cell a CAR-T.

Chithunzi cha 4: Kuzindikira kuthekera kwa ma cell a CAR-T kupha ma cell omwe akufuna

5. Kukhoza kukumbukira ma cell a CAR-T
Maselo abwino a CAR-T amayeneranso kukumbukira kukumbukira, zomwe zikutanthauza kuti amatha kuchita zinthu zamphamvu pambuyo poyatsa mobwerezabwereza ndikuyankha zotupa zotupa mwachangu [5]. Titha kuzindikira zomwe zimachitika pamaselo a CAR-T powalimbikitsa kangapo mu vitro, monga kuchulukitsa kwa cytokine kumasulidwa ndikuwonjezera kupha. Selo la CAR-T ili lokhala ndi luso lokumbukira litalowetsedwa m'thupi, limatha kupha zotupa zokhalitsa komanso zamphamvu.

Chithunzi 5: Kuzindikira kwanthawi yayitali kwa ma cell a CAR-T

6. Kuwunika kwa chitetezo cha CAR-T cell therapy

Chiwopsezo chachikulu cha chithandizo cha ma cell a CAR-T ndikuti chingayambitse matenda oopsa a cytokine. Chifukwa chake tiyenera kuzindikira milingo ya ma cytokines okhudzana ndi CRS monga IL-6, IL-10 ndi IFN-γ opangidwa ndi ma cell a CAR-T, ndikuwunika kuopsa kwakuti chithandizo cha cell cha CAR-T chingayambitse CRS. Komanso, m`pofunika kuwunika zina zotheka poizoni mavuto.
Zizindikirozi zimatha kuwonetsa bwino ntchito yayikulu ya maselo a CAR-T, kuphatikiza kuthekera kochulukira, chotupa cholunjika, zochita za cytotoxic, kulimbikira ndi chitetezo. Ma cell a CAR-T okha omwe amakwaniritsa zofunikira pamwambapa ndi zisonyezo panthawi imodzi amatha kusewera zenizeni zotsutsana ndi chotupa pazachipatala. Chifukwa chake, ndikofunikira kukhazikitsa njira yowunikira yasayansi komanso yololera ndikuchotsa zolepheretsa kupanga zinthu zokonzeka kugwiritsidwa ntchito popanga zinthu zama cell apamwamba kwambiri komanso apamwamba kwambiri a CAR-T, kuti mukwaniritse cholinga chanthawi yayitali chochepetsera ndalama ndikuwongolera chithandizo chamankhwala m'tsogolo, komanso kupindulitsa odwala ambiri omwe akufunika chithandizo.

Nyenyezi zopangira
Monga chithandizo chodziwika bwino cha nyenyezi pakali pano, chithandizo cha CAR-T chavomerezedwa kuti chisatchulidwe ndi chachitatu cha CAR-T ku China. Mabizinesi oyenerera a CAR-T ndi nsanja zathandizira mayendedwe a kafukufuku ndi chitukuko ndipo amayang'ana kwambiri masanjidwe osiyanasiyana. Mabizinesi ena pambali pawo amapikisana pachitetezo chazinthu, ndikofunikira kuti mabizinesi oyenerera achepetse ndalama ndikuwonjezera magwiridwe antchito, komanso kulowetsa m'malo mwanyumba kudzakhalanso njira yayikulu yotukula mafakitale. Chitetezo cha mthupi Magnetic Beads ndi zida zofunika zopangira ma cell a CAR-T, ndipo zimagwira ntchito yofunika kwambiri pakulekanitsa ndi kuyambitsa ma T cell. Tonglihaiyuan GMP level product ActSep ® CD3/CD28 Kupatukana & Activation Maginito Mikanda (chinthu nambala: GMP-TL603) imagwirizanitsa ntchito zolekanitsa ndi kuyambitsa kuti akwaniritse kulekanitsa, kutsegula ndi kukulitsa kwa maselo a T bwino. Ndizoyenera kugwiritsa ntchito ma cell a T aumunthu, CAR-T ndi chikhalidwe china cha T-cell. Kuphatikiza apo, ndipo malondawo amaliza kulemba kwa DMF Type II ndi US FDA (nambala yolemba: 038124), kuthandizira kulembetsa ndi kulengeza kwamankhwala am'manja.

Kupatukana kwa ActSep® CD3/CD28 & Activation Magnetic Bead

1.T-cell kutopa mlingo

Miyezo ya mawu a LAG3 ndi PD1 imadziwika pambuyo pa chikhalidwe cha T-cell activation masiku 14 ndi maginito owonjezera a maginito. ActSep® kwenikweni ndi yofanana ndi ya opikisana nawo. Mawu a ActSep ® etoustion index ndi otsika pansi pa chiŵerengero cha 3: 1 mikanda ya maginito ku selo. Kuphatikiza apo, kuchotsa mikanda ya maginito pa Tsiku 5 kudzachepetsanso kutopa kwa ma T cell.

2. T-cell subtype kusanthula

Dziwani zosintha za T-cell subtypes pazikhalidwe zosiyanasiyana pambuyo poyambitsa kupatukana kwa ActSep®. Gawo la Tcm limawonjezeka panthawi yolima, ndipo chiŵerengero cha Teff mpaka Tem chimawonjezeka ndi nthawi yolima.

Za T&L
T&L Biotechnology Ltd., yomwe idakhazikitsidwa mchaka cha 2011, imayang'ana kwambiri kafukufuku ndi chitukuko cha zida za GMP zopangira ma cell and gene therapy (CGT). Timadzipereka kupereka zinthu zodalirika ndi ntchito za sayansi ya moyo