Plaub lub ntsiab lus tseem ceeb thiab kev loj hlob ntawm ADC kev txhim kho tshuaj

ADCs (antibody-drugconjugates) thev naus laus zis yog txuas cov tshuaj monoclonal cov tshuaj tiv thaiv thiab cov tshuaj lwg tshuaj ua ke sib txuas los ntawm cov txuas txuas, siv cov phiaj xwm tshwj xeeb ntawm cov tshuaj tiv thaiv los thauj tshuaj lwg me me mus rau cov nqaij mos, txo cov kev phiv tshuaj lom rau cov tshuaj, txhim kho lub qhov rais kho tshuaj kom nthuav tawm lub peev xwm ntawm cov tshuaj tiv thaiv kho [1]. Tom qab ADC nthuav tawm hauv cov ntshav khi rau lub hom phiaj antigen, nws nyob sab hauv los ntawm clathrin-mediated endocytosis. Lub sab hauv ua txoj hauv kev dhau los ces nkag mus rau txoj kev kawg-lysosome txoj kev, thiab feem ntau, yog thawj thauj mus rau qhov kev ua tiav thaum ntxov, thiab tom qab ntawd mus rau lysosomes. Qhov chaw acidic thiab enzymes proteolytic ua rau kev txo qis ntawm lysosomes muaj ADCs, yog li tso cov tshuaj cytotoxic rau hauv cytoplasm. Cov tshuaj cytotoxic tso tawm tom qab ntawd ntws tawm mus rau hauv cytoplasm thiab induces apoptosis los ntawm kev tso DNA lossis kev cuam tshuam ntawm microtubule synthesis. Yog li, cov phiaj xwm tseeb, tshuaj tiv thaiv kab mob sib txuas, qhov sib txuas thiab cytotoxic payloads tau dhau los ua plaub yam tseem ceeb uas cuam tshuam rau ADCs tshuaj.

1. Lub hauv paus tseem ceeb plaub ntawm tshuaj ADC

1.1 Xaiv lub hom phiaj raug

Qhov ua tiav tau zoo ntawm ADC nyob ntawm cov kev khi ntawm cov tshuaj tiv thaiv mus rau lub phiaj antigen. ADC lub hom phiaj zoo yog kev qhia siab nyob rau ntawm cov qog nqaij hlav, tsis tshua hais tawm lossis tsis hais tawm nyob rau hauv cov ntaub so ntswg ib txwm muaj, lossis tsawg kawg yog txwv rau cov ntaub so ntswg tshwj xeeb, xws li CD138, 5T4, mesothelin, leukemia thiab CD37. Lub hom phiaj qhia nyob rau hauv cov ntaub so ntswg ib txwm yuav noj ADC tshuaj, uas tsis tsuas yog ua rau" tshem tawm-phiaj" ua rau muaj kev phom sij, tab sis kuj txo ADC ntau ntxiv hauv cov nqaij mob cancer thiab txo qhov ADC tshuaj kho qhov rai.

ADC muaj txiaj ntsig zoo cuam tshuam nrog tus naj npawb ntawm antigens ntawm lub ntsej muag ntawm tes. Cov kev tshawb fawb pom tau tias kom ua tiav cov haujlwm ADC zoo, tsawg kawg yog 104 antigens xav tau ntawm lub ntsej muag ntawm tes kom paub meej tias cov tshuaj cytotoxic ua kom tuag rau hauv lub cell. Vim tias muaj pes tsawg tus antigens nyob rau ntawm cov qog hlwb (qhov nruab nrab ntawm cov tshuaj tiv thaiv kab mob hauv ib puag ncig ntawm lub cev yog li 5,000 txog 106), thiab feem ntau cov chaw kho mob ADC tshuaj muaj qhov nruab nrab DAR ntawm 3.5 mus rau 4, yog li cov tshuaj ADC xa mus rau mob hlwb. Tsawg heev. Qhov no tseem tau suav tias yog ib qho tseem ceeb ntawm qhov kev tsis pom kev soj ntsuam ntawm ADC ua ke nrog cov tshuaj cytotoxic xws li methotrexate, paclitaxel thiab tshuaj tua kab mob anthracycline.

Ntxiv nrog rau qhov tshwj xeeb thiab kev hais tawm txaus, qhov zoo tshaj plaws phiaj antigen yuav tsum tseem ua rau muaj kev ua haujlwm zoo ADC. Cov ntawv cog lus ntawm cov tshuaj tiv thaiv mus rau saum npoo antigen ntawm lub hom phiaj cell tuaj yeem cuam tshuam txoj kev ua haujlwm sab hauv ntawm cov tshuaj tiv thaiv-antigen ua rau hauv lub cell, yog li ua tiav cov tshuaj xa mus rau sab hauv.

Tam sim no, leukocyte nto sib txawv antigen yog thawj qhov dav siv ADC phiaj. Tam sim no, 20 ADC tshuaj hauv kev kho mob hauv qib kho tau muaj 10 lub hom phiaj (CD33, CD30, CD79b, CD22, CD19, CD56, CD138, CD74) nyob rau ntawm leukocyte antigen. Ntau cov tshuaj ADC tsom lub hom phiaj leukocyte nto antigens ntau vim tias cov tshuaj tiv thaiv kab mob no muaj txiaj ntsig hauv cov qog nqaij hlav, tsis hais nyob rau hauv cov ntaub so ntswg ib txwm muaj, lossis qhia nyob rau qib qis.

Tsis tas li ntawd, qee qhov khoom qog pob qog ua kom zoo dua cov tshuaj lwg me me tau maj mam pom tias tsim nyog ADC cov hom phiaj, xws li PSMA rau mob qog nqaij hlav prostate, kab mob kev loj hlob receptor EGFR thiab zes qe menyuam mob qog nqaij hlav nectin 4 thiab lwm yam tshuaj ADC tau nkag mus rau hauv chaw kho mob Theem II. Kadcyla pom zoo los ntawm FDA xyoo 2013 nrog lub hom phiaj HER2. Hauv xyoo 2019, Padcev pom zoo los ntawm FDA nrog lub hom phiaj ntawm NECTIN4 yog qhov tshuaj tiv thaiv ADC thib ob uas tau pom zoo rau kev kho cov mob qog.

1.2 Xaiv cov tshuaj tiv thaiv

Lub siab tshwj xeeb ntawm cov tshuaj tiv thaiv ua kom lub zog yog qhov yuav tsum tau ua kom tiav cov txiaj ntsig ntawm ADC tshuaj, kom thiaj li mloog zoo cytotoxic tus neeg sawv cev ntawm cov qog nqaij hlav. Kev tsub siab rau qhov muaj txiaj ntsig zoo ntawm cov tshuaj tua kab mob, ntxiv rau kom tsis txhob muaj tshuaj lom rau cov hlwb noj qab haus huv, cov tshuaj tiv thaiv tsis muaj cov qog ntshav yuav raug tshem tawm los ntawm cov kab mob ntshav, ua rau ADC tshuaj mus rau" ua ntej ncav cov qog nqaij hlav. Vim li no, cov tshuaj cytotoxic feem ntau txuas rau Fc feem lossis thaj av tsis tu ncua ntawm mAb los tiv thaiv qhov kev ntes thiab khi ntawm antigen.

Vim tias cov 150kDa antibody lwg me me no tsis tsuas yog muaj ntau qhov chaw tsim rau kev sib txuas, tab sis kuj tuaj yeem hloov kho rau lwm qhov chaw tawm tsam, tag nrho ADC cov tshuaj tiv thaiv tam sim no yog IgG lwg me me. Qhov zoo ntawm IgG lwg me me yog nws qhov kev xav tau zoo rau lub hom phiaj antigen thiab lub neej ntev dua ib nrab nyob rau hauv cov ntshav, uas ua rau kom nce tsub zuj zuj ntawm cov qog nqaij hlav. Piv nrog rau lwm cov IgG lwg me me, IgG1 thiab IgG3 muaj ntau cov tshuaj tiv thaiv zoo-kev tiv thaiv cytotoxicity (ADCC) thiab ntxiv cov tshuaj tiv thaiv cytotoxicity (CDC), tab sis vim tias IgG3 muaj luv luv ib nrab-lub neej, nws tsis yog qhov kev xaiv zoo rau ADC tshuaj. Ib qho ntxiv, piv nrog IgG2 thiab IgG4, lub pob khawm tsim los ntawm IgG1 hauv lub cell yog yooj yim txo, yog li nws nyuaj rau kev tsim cov tshuaj ADC raws li cysteine ​​ntau lawm. Yog li, vim tias IgG1 muaj cov ADCC thiab CDC muaj zog heev, ntev ib nrab-lub neej, thiab kev tsim khoom yooj yim, cov tshuaj ADC feem ntau tam sim no tsim siv siv IgG1 scaffolds [3].

Qhov tshuaj tiv thaiv kab mob ntawm ADC yog ib qho kev txiav txim siab tseem ceeb ntawm kev mus ncig ib nrab ntawm lub neej. Thaum Ntxov ADCs tau siv cov tshuaj monoclonal nas ua rau muaj zog, ua kom muaj kev tiv thaiv kab mob (HAMA) hauv tib neeg lub cev. Tam sim no, ADC feem ntau siv cov tshuaj tiv thaiv tib neeg lossis tshuaj tiv thaiv txhua tus neeg.

Feem ntau, qhov zoo tshaj plaws mAb rau ADC architecture yuav tsum yog tus qauv ua tib neeg lossis tag nrho los ntawm IgG1 qauv uas tuaj yeem xaiv khi rau cov qog hlwb tsis muaj qhov cuam tshuam nrog cov hlwb zoo. Ib qho ntxiv, ADC kev kho nyob sab hauv yuav yog qhov tseem ceeb tshaj dua li qhov cuam tshuam rau kev kho kom zoo.

1.3 Kev xaiv ntawm cov tshuaj lom molecule (Payload)

Toxin lwg me me yog qhov tseem ceeb hauv qhov ua tiav ntawm ADC tshuaj txhim kho. Tsuas yog ib feem me me ntawm cov tshuaj tua kab mob txhaj rau hauv lub cev tsim hauv cov qog ua cov nqaij hlav, yog li thawj zaug muaj sub-nanomolar lom cov lwg me me (IC50 tus nqi ntawm 0.01-0.1nM). Cov nqi tsim nyog. Tsis tas li ntawd, cov pa roj carbon monoxide lom yuav tsum muaj cov pab pawg tsim nyog uas tuaj yeem txuas tau, muaj cov cytotoxicity, yog hydrophobic, thiab zoo heev nyob rau hauv lub cev kev mob.

Cov pa roj carbon monoxide lom rau tam sim no siv rau ADC kev tsim kho yeeb tshuaj tuaj yeem muab faib ua ob pawg: microtubule inhibitors thiab DNA ua rau cov kab mob ua kom tsis haum, thiab lwm cov roj me me xws li α-amanitin (xaiv RNA polymerase II inhibitors) kuj tseem nyob hauv kev kawm [12]. Cov qub tau sawv cev los ntawm MMAE thiab MMAF (tshuaj pub dawb IC50: 10-11-10-9M) ntawm Seattle's Genetics thiab DM1 thiab DM4 (tshuaj dawb IC50: 10-11-10-9M) tsim los ntawm ImmunoGen's. Qhov kawg yog sawv cev los ntawm Calichemicin, duocarmycins, thiab Spirogen's PBD (tshuaj dawb IC50< 10-9m).="" cov="" co="" toxins="" tau="" sib="" thooj="" adc="" tshuaj="" yuav="" tshawb="" thiab="" tsim="" hauv="" qhov="" chaw="" kuaj="" mob.="" ntau="" lub="" tuam="" txhab="" tseem="" tab="" tom="" txhim="" kho="" lawv="" tus="" kheej="" them="" nyiaj,="" xws="" li="" nerviano="" medical="" sciences,="" mersanatherapeutics="" thiab="" lwm="" lub="" tuam="">

1.4 Xaiv Txuas Txuas

Txawm hais tias nws yog ib qho tseem ceeb kom xaiv cov tshuaj tiv thaiv tshwj xeeb thiab kev them nyiaj raws li hom qog hlwb, hais txog pharmacokinetics, pharmacology, thiab kho lub qhov rais, kev xaiv cov txuas txuas tsim nyog los txwv cov tshuaj tiv thaiv thiab payloads yog tus yuam sij rau kev ua tiav ADC kev tsim kho. Qhov zoo tshaj plaws linker Cov xwm txheej hauv qab no yuav tsum tau ntsib: (1) Tus sib kis yuav tsum ruaj khov nyob rau hauv cov ntshav ncig cov ntshav, thiab nws tuaj yeem tso tawm sai sai thaum nws nyob hauv lossis ze rau cov qog nqaij hlav. Qhov tsis khov ntawm cov kab txuas yuav ua rau tso tawm ntxov ntawm kev xa nyiaj, ua rau cov ntaub so ntswg zoo li qub. Kev puas tsuaj ntawm tes. Kuj tseem muaj qhov chaw kuaj mob qhia tau tias ADC kev nyab xeeb ntawm velvet alkaloids yog qhov cuam tshuam txog qhov tshwm sim tsis zoo. Yog li ntawd, rau kev sib xyaw ua ke ntawm cov tshuaj tiv thaiv, qog nqaij hlav thiab them nyiaj, nws yog ib qho tseem ceeb heev los txiav txim siab qhov linker nrog qhov zoo tshaj plaws ruaj khov. (2) Thaum ADC yog sab hauv rau lub hom phiaj nqaij hlav, qhov sib txuas yuav tsum muaj lub peev xwm ua kom nrawm nrawm thiab tso cov tshuaj lom cov lwg me me. (3) Hydrophobicity kuj tseem yog qhov tseem ceeb uas txiav txim siab los ntawm linker. Hydrophobic sib txuas rau pawg thiab hydrophobic payloads feem ntau txhawb nqa kev sib sau ntawm ADC lwg me me, yog li ua rau cov tshuaj tiv thaiv kab mob.

Cov Txuas Txuas tam sim no tau muab faib ua ob pawg: ib qho yog cov txuas txuas tau yooj yim (cov kab mob sib txuas-acid labile, protease cleavable linkers, disulfide linkers), lub ntsiab ntawm ADC tshuaj siv; lwm qhov tsis yog qhov txuas tsis txuas, thiab qhov sib txawv yog seb nws yuav nyob rau hauv Nws yog qhov chaw sab hauv ntawm tes.

Qhov txuas txav tau tsim los kom tau txais txiaj ntsig qhov sib txawv ntawm ib puag ncig ntawm cov ntshav thiab cov qog ntshav. Piv txwv li, cov kab txuas kua qaub-acid feem ntau yog ruaj khov hauv cov ntshav, tab sis tsis khov kho nyob rau hauv lysosomes nrog qis pH thiab sai sai, tso tawm dawb Active cov tshuaj lom molecule (Mylotarg (gemtuzumab ozogamicin)). Zoo ib yam li ntawd, protease cleavable linkers rhiab rau cov proteases yuav ruaj khov nyob rau hauv cov ntshav, tab sis nyob rau hauv lysosomes nplua nuj nyob rau hauv proteases (paub txog lawv cov protein tshwj xeeb ua ntu zus), lawv tau nrawm nrawm mus tso cov pa tshuaj lom neeg nquag, ib yam li Val-Cit Cov kev sib txuas yog sai hydrolyzed los ntawm intracellular cathepsins (Adcetris (brentuximab vedotin)). Tus qauv tsim disulfide cross-sib txuas ua ke siv cov lus qhia siab ntawm cov khoom tso kua mis txo qis glutathione, thiab qhov txo disulfide daim ntawv cog lus tso tawm cov tshuaj lom muaj lwg me me (IMGN-901 (anti-CD56-maytansine)) hauv lub xov tooj ntawm tes.

Qhov txuas tsis sib txuas yog tsim los ntawm cov ntawv pov thawj ruaj khov tiv taus cov kab mob protease kev tiv thaiv thiab zoo heev hauv cov ntshav. Nws cia siab rau ADC cov tshuaj tiv thaiv ua kom muaj kev puas tsuaj tag nrho los ntawm cytoplasm thiab lysosomal proteases, thiab thaum kawg tso tawm payload txuas rau cov amino acid seem los ntawm kev tso tshuaj tiv thaiv kom tua Cancer Cancer (piv txwv li ado-trastuzumab emtansine, T-DM1, lossis Kadcyla). Nyob rau tib lub sijhawm, ADC tshuaj uas tsis tuaj yeem pov tseg qhov txuas tsis tuaj yeem tso tawm tsis tau, thiab tua tsis tau cov qog nqaij hlav nyob ze los ntawm" bystander effect" ;.

Yog lawm, qhov xaiv ntawm hom linker yog ze rau cov hom phiaj xaiv. Ntawm cov tshuaj ADC nrog qhov txuas yooj yim, cov phiaj yog B cell antigens (CD19, CD20, CD21, CD22, CD79B, CD180), uas tau ua pov thawj pom tias muaj txiaj ntsig zoo hauv vivo. Hauv kev sib piv, hauv cov tshuaj ADC nrog uncleavable linkers, lub hom phiaj uas tau lees paub tias yuav endocytosed hauv vivo thiab sai thauj mus rau lysosomes suav nrog CD22 thiab CD79b.

Nws yog lub hom phiaj kawg ntawm Linker los xyuas kom meej tshwj xeeb kev tso tawm tshuaj pub dawb hauv cov qog hlwb, thiab kev tswj hwm ntawm kev haus tshuaj phem kuj tseem ceeb heev. Thaum kawg, qhov teeb meem yuav tsum tau txiav txim siab yuav ua li cas thiaj li xaiv qhov zoo tsim nyog txuas, lub hom phiaj, thiab cov tshuaj lom molecule kom sib txig sib luag thiab cov tshuaj lom ntawm ADC tshuaj.

2. Keeb kwm ntawm ADC kev txhim kho tshuaj pom cov kev hloov pauv ntawm plaub yam tseem ceeb

Kev txhim kho ntawm oncology tshuaj tuaj yeem ua rau taug txoj hauv kev rov qab mus rau ib nrab xyoo pua. Nws tau tshawb pom tias nitrogen mustards ua kom rhuav tshem cov leeg pob txha thiab cov nqaij mos lymphoid los ntawm kev tsom mus rau cov faib cov qog nqaij hlav sai. Cov tshuaj no suav nrog folic acid thiab purine analogues (methotrexate thiab 6-mercaptopurine), microtubule polymerization inhibitors / cov neeg txhawb nqa (vinca alkaloids thiab taxanes) thiab DNA rhuav tshem (anthracyclines thiab nitrogen) Mustard) [2]. Txij li thaum ntxov kho cov tshuaj tua kab mob tsis tsuas yog tsom lub hlwb mob qog noj ntshav tab sis kuj muaj qhov ua rau tua txhua lub hlwb hauv lub cev, ua rau muaj kev mob tshwm sim loj hauv cov neeg mob, qhov no tau txwv ntau qhov ntau ntawm cov tshuaj thiab cov tshuaj kho tau zoo (siab tshaj plaws zam koob tshuaj / qis kawg Cov koob tshuaj) muaj qis heev, kho qhov rai yog nqaim. Cov tshuaj ADC yuav pab tau kom muaj cov tshuaj lom rau cov kab mob cancer tshwj xeeb.

2.1 Xyoo ADC thawj zaug siv yeeb siv tshuaj

Ntawm cov thawj ADC tshuaj, antitumor tshuaj xws li mitomycin C, idarubicin, anthracyclines, N-acetyl melphalan, doxorubicin, vinca alkaloids, thiab methotrexate feem ntau dhau los ntawm qhov tsis muaj qhov sib txuas Qhov linker (amide lossis succinimide) yog txuas nrog cov nas monoclonal. tshuaj tiv thaiv.

Xyoo 2000, Asmeskas FDA pom zoo thawj cov tshuaj tiv thaiv kab mob sib txuas ua ke Gemtuzumab Ozogamicin (npe lag luam Mylotarg, Wyeth, lub chaw muag khoom ntawm Pfizer). Lub hom phiaj yog CD33. Gemtuzumab Ozogamicin muaj peb ntu: 1) Recombinant humanized IgG4 kappa monoclonal antibody Gemtuzumab; 2) Cytotoxic N-acetyl gamma calicheamicin; 3) Acid-tshem tawm hom muaj 4- (4-acetylphenoxy) -butanoic acid (AcBut) thiab 3-methyl-3-mercaptobutane hydrazide (dimethylhydrazide) Functional Linker molecule. Lub Linker cov roj ntsha covalently txuas calicheamicin rau monoclonal tiv thaiv kab mob, thiab cov tshuaj tiv thaiv tshuaj tiv thaiv-sib piv ADR nruab nrab 2 txog 3. Tom qab txiav tawm los ntawm lub hom phiaj hlwb, cov tshuaj tawm calicheamicin los ntawm hydrolyzing linker, inhibition ntawm ob txoj kev sib kis ntawm DNA tawg, uas ua rau lub voj voos ntawm tes raug ntes. thiab apoptosis. Cov tshuaj no yog siv los kho CD33-positive acute myeloid leukemia.

Tom qab ntawd, nws tau pom tias Gemtuzumab Ozogamicin tsis muaj qhov tseem ceeb hauv tsev kho mob piv nrog lwm cov tshuaj los tiv thaiv tus mob cancer, thiab muaj lub siab ua kom mob siab. Hauv xyoo 2010, 10 xyoo tom qab kev teev npe ntawm Gemtuzumab Ozogamicin, nws tau coj txoj hauv kev thim rov qab los ntawm kev ua lag luam. Cov teeb meem kev kho mob uas tsis muaj peev xwm ntawm Gemtuzumab Ozogamicin suav nrog kev tsis sib haum ntawm qhov txuas, tso 50% ntawm cov tshuaj rau hauv kwv yees li 48 teev; calicheamicin nyob rau hauv cov tshuaj muaj siab heev hydrophobic, qhov khi khi nrog monoclonal antibody yog 50%, cov tshuaj lom yog siab, CMC Tsis Zoo. Tsis tas li ntawd, muaj kev tshawb fawb qhia pom tias monoclonal antibody Gemtuzumab tuaj yeem tshem tawm cov hlwb los ntawm efflux cov twj (MDR1 thiab MRP1), thiab tsis muaj kev kho mob tseem ceeb piv nrog lwm cov tshuaj tiv thaiv qog noj ntshav.

2.2 Cov tshuaj ADC thib ob

Tom qab ze li ntawm 10 xyoo ntawm kev txhim kho sai ntawm cov tshuaj monoclonal antibody, thiab ntau cov tshuaj tiv thaiv qog noj ntshav me me cov tshuaj molecule tau pom (100-1000 zaug). Qhov tshuaj ADC tiam thib ob muaj cov zoo CMC dua li cov tshuaj ADC thawj. Cov sawv cev ntawm cov tshuaj thib ob suav nrog Brentuximab vedotin, Ado-trastuzumab emtansine, Inotuzumab Ozogamicin.

Txawm li cas los xij, cov tshuaj thib ob txuas muaj lub qhov rai nqaim kho. Qhov laj thawj loj tshaj plaws yog tias lawv muaj cov tshuaj tua kab mob tsis zoo thiab sib tw nrog cov tshuaj tiv thaiv kab mob me me tshuaj tiv thaiv kab mob rau cov qog hom phiaj. Lub cim thib ob muaj cov tshuaj sib txawv ntawm cov tshuaj sib txawv (DAR) 0-8. Feem ntau DAR ntau tshaj li 4, nws yuav ua kom pom qis qis, siab plasma tshem tawm qhov kev ua haujlwm thiab qhov ua tau zoo tsawg ntawm vivo [3]. Piv txwv, Brentuximab vedotin yog 4, Ado-trastuzumab emtansine yog 3.5, thiab Inotuzumab Ozogamicin yog 6.

1) Cov neeg Adcetris

Brentuximab vedotin (npe lag luam Adcetris) tau sib koom tsim los ntawm Seattle Genetics thiab Millennium (lub chaw tsim khoom ntawm Takeda Pharmaceuticals), thiab tau pom zoo los ntawm Asmeskas FDA thaum Lub Yim Hli 2011. Lub hom phiaj yog CD30, uas muaj peb ntu: 1) CD30 tsom teeb meem chimerism Hom IgG1 kappa monoclonal antibody Brentuximab; 2) microtubule inhibitor MMAE (monomethyl auristatin E); 3) protease cleavage yam linker molecule maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC). Linker covalently khub niam txiv MMAE rau cov tshuaj tua kab mob monoclonal los ntawm cysteine ​​residues, thiab cov tshuaj tiv thaiv-rau-cov tshuaj tiv thaiv sib piv DAR nruab nrab 3 txog 5. Tom qab Brentuximab vedotin yog sab hauv los ntawm lub hom phiaj cell, MMAE cleaved los ntawm protease tuaj yeem khi rau tubulin thiab rhuav tshem lub cell' s microtubule network, ua rau lub voj voog ntawm tes raug ntes thiab apoptosis. Cov cim yog Hodgkin' s lymphoma, cov kab ke hauv lub cev loj heev, cov kab mob ntawm cov leeg ua ntshav tawm thiab cov kab mob mycosis fungoides.

2) Kadcyla

Ado-trastuzumab emtansine (npe hu ua Kadcyla) tau tsim los ntawm Genentech (cov neeg koom nrog Roche), thiab tau pom zoo los ntawm Asmeskas FDA rau Lub Ob Hlis 2013. Lub hom phiaj yog HER2, uas muaj peb ntu: 1) Trastuzumab tsom HER2 Anti; 2) Lub luag haujlwm ruaj khov thi linker MCC (4- [N-maleimidomethyl] cyclohexane-1-carboxylate); 3) Microtubule inhibitor DM1 ntawm hom maytansine derivative. MCC-DM1 complex yog hu ua emtansine. Qhov nruab nrab ntawm cov tshuaj tiv thaiv kab mob sib piv DAR yog 3.5. Ado-trastuzumab emtansine induces cell voj voog ntes thiab apoptosis los ntawm HER2 kev taw qhia txoj hauv kev thiab rhuav tshem cov microtubule network. Qhov taw qhia yog metastatic mob cancer mis yog HER2-zoo thiab tau txais tsawg kawg yog trastuzumab thiab taxane ib leeg lossis hauv kev sib xyaw.

3) Besponsa

Inotuzumab Ozogamicin (npe hu ua Besponsa) tau sib koom tsim los ntawm Pfizer thiab USB. Nws tau pom zoo los ntawm European Medicines Agency (EMA) thaum Lub Rau Hli 2017 thiab tau pom zoo los ntawm Asmeskas FDA thaum Lub Yim Hli 2017. Lub hom phiaj yog CD22, uas muaj peb ntu Cov Txheem: 1) Recombinant humanized IgG4 kappa monoclonal antibody Inotuzumab; 2) N-acetyl-gamma-calicheamicin uas tuaj yeem ua rau kom muaj kev sib tsoo ntawm ob-txoj kev sib tsoo ntawm DNA; 3) Acid Tsis khov kho tsis tuaj yeem txuas cov kab txuas, uas yog cov hws tsim los ntawm 4- (4-acetylphenoxy) -butanoic acid (AcBut) thiab 3-methyl-3-mercaptobutanehydrazide (tseem hu ua dimethylhydrazide). Cov kab txuas txuas molecule khub thauj cov N-acetyl-γ-calicheamicin rau monoclonal antibody. Qhov nruab nrab them nyiaj ntawm txhua qhov kev tiv thaiv monoclonal yog 6 thiab qhov faib tawm ntau yog 2 txog 8. Thaum Inotuzumab Ozogamicin khi rau CD22 antigen ntawm B hlwb, nws yog sab hauv rau cov hlwb, thiab tus neeg sawv cev cytotoxic tso tawm kom rhuav tshem cov cell. Qhov taw qhia yog monotherapy rau kev kho mob ntawm cov neeg laus rov qab lossis rov qab kho mob CD22-zoo B-cell tus kab mob rau cov mob lymphoblastic leukemia (TXHUA), tsim nyog rau cov neeg mob uas tau txais tsawg kawg yog ib qho mob tyrosine kinase inhibitor (TKI) kev kho mob tsis ua hauj lwm Cov neeg laus uas muaj mob rov qab los yog refractory B -rau cov mob ua ntej mob ntshav thiav ntshav (TXHUA) leej twg yog Philadelphia chromosome zoo (Ph +).

2.3 Lub Cim Thib Peb ntawm ADC cov tshuaj

Tus yuam sij rau cov tshuaj thib peb yog kev sib txuas ntawm thaj chaw, uas tuaj yeem ua kom cov tshuaj tiv thaiv zoo-sib xyaw nrog cov tshuaj DAR tseeb. Ntxiv rau, tshuaj tiv thaiv kev ua kom zoo dua, txuas txuas, thiab cov tshuaj molecule me me tuaj yeem txhim kho txoj kev kho tshuaj ntawm ADC tshuaj. Cov tshuaj sawv cev yog Polatuzumab vedotin, Enfortumab vedotin, Fam-trastuzumab deruxtecan. Los ntawm qhov tshwj xeeb khi ntawm cov tshuaj molecule me rau monoclonal cov tshuaj tiv thaiv kab mob, kev txhim kho cov tshuaj tiv thaiv kab mob sib txuas nrog cov tshuaj DAR nqi ntawm 2 lossis 4 tsis tau nce ntxiv tshuaj lom neeg thiab tsis muaj tshuaj tua kab mob monoclonal, txhim kho tshuaj ruaj khov thiab pharmacokinetics kev ua yeeb tshuaj thiab kev ua yeeb yam rau cov hlwb nrog qis dua antigen theem.

1) Polivy

Polatuzumab vedotin (npe lag luam, Polivy) tau pom zoo los ntawm Asmeskas FDA thaum Lub Rau Hli 2019. Nws tau tsim thaum xub thawj los ua ke los ntawm Genentech (ib qho chaw muag khoom ntawm Roche) thiab Seattle Genetics. Tom qab ntawd, Sinochem Pharmaceuticals (Roche Holdings) tau tso cai tshawb nrhiav tshuaj thiab kev txhim kho. Lub hom phiaj yog CD79b, uas muaj peb ntu: 1) recombinant humanized IgG1 kapppa monoclonal antibody Polatuzumab phiaj CD79b; 2) cleavable mc-val-cit-PABC (maleimidocaproyl-valyl-citrullinyl-paminobenzyloxycarbonyl) Linker; 3) Cov tshuaj me me molecule MMAE (monomethyl auristatin E). Cov tshuaj tiv thaiv thiab MMAE tau sib xyaw nrog cysteine ​​ntawm Linker. Qhov nruab nrab ntawm DAR yog 3 ~ 4. Nws raug pom zoo kom siv los ua ke nrog bendamustine thiab rituximab rau kev kho mob ntawm refractory diffuse. Cov neeg laus mob siab nrog B-cell lymphoma.

2) Padcev

Enfortumab vedotin (npe lag luam, Padcev) tau koom ua ke los ntawm Agensys (ib qho khoom lag luam ntawm Astellas) thiab Seattle Genetics, thiab tau pom zoo los ntawm Asmeskas FDA rau lub Kaum Ob Hlis 2019 rau kev tso npe. Lub hom phiaj yog NECTIN4, Enfortumab vedotin yog tsim ntawm peb ntu: 1) Recombinant tag nrho tib neeg IgG1 kappa monoclonal antibody enfortumab; 2) Qhov yooj yim mc-val-cit-PABC Linker qauv, uas yog txiv neej menididocaproyl-valyl -citrullinyl-p-aminobenzyloxycarbonyl; 3) Cov tshuaj me me ntawm cov tshuaj molecule MMAE, monomethyl auristatin E. MMAE yog piv rau cov cysteine ​​ntawm monoclonal antibody los ntawm Linker, thiab qhov piv nruab nrab ntawm cov tshuaj rau monoclonal antibody DAR yog 3.8: 1. Nws tau pom zoo rau cov neeg mob laus uas tau txais PD- 1 lossis PD-L1 inhibitors thiab platinum-uas muaj cov tshuaj tua kab mob rau hauv zos cov qib siab lossis metastatic urothelial carcinoma.

3) Cov Enhertu

Fam-trastuzumab deruxtecan (npe lag luam, Enhertu) tau pom zoo los ntawm Asmeskas FDA rau thaum Lub Kaum Ob Hlis 2019 thiab raug tsim los ntawm Daiichi Sankyo. Fam-trastuzumab deruxtecan yog tshuaj tiv thaiv tshuaj tua kabmob ua kom haum HER2 thiab muaj peb ntu: 1) pom zoo ua rau tib neeg IgG1 kappa hom tshuaj tiv thaiv HER2 monoclonal antibody trastuzumab; 2) Cathepsin B cleavable tetrapeptide GGFG qauv molecule Hom Txuas; 3) Camptothecin derivatives nrog kev them nyiaj ntawm topoisomerase I inhibition. Qhov them nyiaj tau txuas nrog lub cysteine ​​ntawm monoclonal tiv thaiv kab mob los ntawm qhov txuas txuas, nrog qhov nruab nrab DAR tus nqi ntawm 8. Pom zoo rau kev kho mob rau cov neeg mob laus uas tsis muaj kev tiv thaiv lossis metastatic HER2-zoo mob cancer mis uas yav tas los tau txais tsawg kawg yog ob qho kev tiv thaiv HER2 kev kho mob Cov.