Antibodies nyinshi zimaze gukoreshwa cyangwa zirimo gutezwa imbere nkubuvuzi bwo kuvura COVID-19.Mugihe hagaragaye uburyo bushya bwa syndrome ikaze yubuhumekero coronavirus 2 (SARS-CoV-2), ni ngombwa guhanura niba bazakomeza kwandura antibody.Inyenyeri n'abandi.Isomero ry'umusemburo ryakoreshejwe, rikubiyemo ihinduka ryimiterere yose muri SARS-CoV-2 reseptor ihuza indangarugero itazahungabanya cyane guhuza reseptor yakira (ACE2), ikanashushanya uburyo iyi ihinduka rigira kuri bitatu nyamukuru birwanya SARS-CoV -2 antibody ihuza.Iyi mibare igaragaza ihinduka ryimiterere ihinduka rya antibody, harimo ihinduka ryimiterere imwe ihunga antibodi ebyiri zivanze na antibody ya Regeneron.Guhinduka kwinshi guhunga antibody imwe ikwirakwira mu bantu.
Antibodies nubuvuzi bushobora kuvura syndrome ikaze yubuhumekero bukabije coronavirus 2 (SARS-CoV-2), ariko ntibisobanutse ko virusi ikura kugirango ihunge ibyago byabo.Hano, turashushanya uburyo ihinduka ryose muri SARS-CoV-2 reseptor ihuza indangarubuga (RBD) bigira ingaruka ku guhuza cocktail ya REGN-COV2 na antibody LY-CoV016.Aya makarita yuzuye yerekanye ihinduka rya aside amine yirinze burundu imvange ya REGN-COV2, igizwe na antibodi ebyiri REGN10933 na REGN10987 yibasira epitopi zitandukanye.Iyi mibare irerekana kandi ihinduka rya virusi ryatoranijwe mu barwayi bakomeje kwandura bavuwe na REGN-COV2 ndetse no mu gihe cyo gutoranya virusi ya vitro.Hanyuma, iyi mibare irerekana ko ihinduka ryirinda antibody imwe isanzwe igaragara mukuzenguruka SARS-CoV-2.Ikarita yuzuye yo guhunga irashobora gusobanura ingaruka ziterwa na mutation zagaragaye mugihe cyo gukurikirana virusi.
Antibodies zirimo gutegurwa kuvura syndrome ikabije yubuhumekero coronavirus 2 (SARS-CoV-2) (1).Antibodiyite zirwanya izindi virusi zimwe na zimwe zirashobora gutangwa nta ngaruka zatewe n’imihindagurikire ya virusi yatoranijwe mu gihe cyo kuvura abarwayi banduye (2, 3) cyangwa ihindagurika rya virusi ryakwirakwiriye ku isi hose kugira ngo ritange virusi yose.Kubwibyo rero, kumenya ihinduka rya SARS-CoV-2 rishobora guhunga antibodi zingenzi ni ngombwa gusuzuma uburyo ihinduka ry’imihindagurikire y'ikirere mu gihe cyo kugenzura virusi rigira ingaruka ku miti ivura antibody.
Antibodiyite nyinshi zirwanya anti-SARS-CoV-2 zireba virusi ya virusi ihuza virusi (RBD), ihuza guhuza na angiotensin ihindura enzyme 2 (ACE2) reseptor (5, 6).Vuba aha, twashyizeho uburyo bwimbitse bwo gusikana mutation kugirango dushushanye uburyo ihinduka ryimiterere ya RBD rigira ingaruka kumikorere no kumenyekana na antibodiyite zirwanya virusi (7, 8).Uburyo bukubiyemo gukora isomero ryimiterere ya RBD, kubigaragaza hejuru yumusemburo, no gukoresha selile ya fluorescence itondekanya ingirabuzimafatizo hamwe nuburyo bwimbitse kugirango hamenyekane uburyo buri mutation igira ingaruka kumuzingo wa RBD, isano ya ACE2 (bipimirwa murukurikirane rwa titre), hamwe no guhuza antibody (Igicapo S1A).Muri ubu bushakashatsi, twifashishije isomero rya mutant risubiramo ryasobanuwe muri (7), rigizwe na barcode ya RBD, ikubiyemo 3804 muri 3819 ishobora guhinduka.Isomero ryacu ryateguwe duhereye kuri genetike ya RBD ya Wuhan-Hu-1.Nubwo inshuro nyinshi za mutant zigenda ziyongera, ziracyerekana urutonde RBD rusanzwe (9, 10).Twashushanyijeho bibiri muri 2034 mutation idahungabanya cyane ububiko bwa RBD hamwe na ACE guhuza (7) uburyo bwo kunyura cocktail ya REGN-COV2 (REGN10933 na REGN10987) (11, 12) na LY-CoV016 ya Eli Lilly. antibody igira ingaruka muburyo bwo guhuza antibody (nanone yitwa CB6 cyangwa JS016) (13) (Igicapo S1B).REGN-COV2 iherutse guhabwa uruhushya rwo gukoresha byihutirwa kuri COVID-19 (14), mugihe LY-CoV016 kuri ubu iri mu cyiciro cya 3 cyamavuriro (15).
[Glu406 → Trp (E406W)] yarokotse cyane ivangwa rya antibodi ebyiri (Ishusho 1A).Ikarita yo guhunga ya LY-CoV016 yanagaragaje ihinduka ryinshi ry’imihindagurikire ku mbuga zitandukanye muri RBD (Ishusho 1B).Nubwo ihinduka ry’imihindagurikire rishobora guhungabanya ubushobozi bwa RBD guhuza ACE2 cyangwa kwerekana mu buryo bukwiye, ukurikije ibipimo byabanjirije ibipimo bya mutation byimbitse ukoresheje umusemburo werekanwe na RBD, ihinduka ryinshi ryimikorere ntirishobora kugira ingaruka kuri iyi mikorere (7) ) (Igicapo 1, A na B byerekana igihombo cya ACE2, mugihe Ishusho S2 yerekana kugabanuka kwimvugo ya RBD.
(A) Gushushanya antibody muri REGN-COV2.Igishushanyo cyumurongo ibumoso cyerekana guhunga kuri buri rubuga muri RBD (igiteranyo cya mutation zose kuri buri rubuga).Ishusho yikirango iburyo yerekana ahantu hakomeye ho guhungira (umurongo wijimye).Uburebure bwa buri nyuguti buragereranywa nimbaraga zo guhunga zahujwe na mutation ya aside amine, kandi "amanota yo guhunga" ya 1 kuri buri mutation bihuye no guhunga burundu.Igipimo cya y-axis kiratandukanye kuri buri murongo, bityo, kurugero, E406W ihunga antibodi zose za REGN, ariko biragaragara cyane kuri cocktail kuko irengerwa nizindi mbuga zahunze za antibodi kugiti cye.Kuri verisiyo nini, S2, A na B, zikoreshwa muguhindura ikarita nukuntu ihinduka rigira ingaruka kumvugo ya RBD ikubye.S2, C na D bikoreshwa mugukwirakwiza ingaruka kuri ACE2 no kwerekana imvugo ya RBD mubihinduka byose byagaragaye mugukwirakwiza virusi.(B) Nkuko bigaragara muri (A), shushanya LY-CoV016.(C) Koresha spike-pseudotyped lentiviral ibice kugirango ugenzure ihinduka ryingenzi muburyo bwo kutabogama.Twahisemo kugenzura ihinduka ryimiterere yahanuwe ko izagira ingaruka zikomeye cyangwa kubaho kumurongo mwinshi muri SARS-CoV-2 yihariye (nka N439K) mukuzenguruka.Buri ngingo yerekana ubwiyongere bwikubye hagati ya median inhibitory concentration (IC50) ya mutation ugereranije nimpinga yubwoko bwimisozi idahinduwe (WT) irimo D614G.Umurongo ucagaguye wubururu 1 ugereranya ingaruka zidafite aho zibogamiye zisa na WT, kandi agaciro> 1 kagereranya kwiyongera kutabogamye.Ibara ry'akadomo ryerekana niba ushaka guhunga ikarita.Utudomo twerekana ko kuva IC50 iri hanze yuruhererekane rwa dilution yakoreshejwe, impinduka nyinshi zirasuzumwa (imipaka yo hejuru cyangwa munsi).Mutants nyinshi zapimwe muburyo bubiri, nuko hariho ingingo ebyiri.Kutabogama kwuzuye kwerekanwe mubishusho 2. S3.Amagambo amwe ahinnye y'ibisigisigi bya aside amine ni ibi bikurikira: A, Ala;C, Cysteine;D, Asp;E, Glu;F, Phe;G, Gly;H, ibye;I, Ile;K, lysine;L, Liu;Metropolis N, Assen;P, Pro;Ikibazo, Gln;R, Arg;S, Ser;T, Thr;V, Val;W, tryptophan;na Y, Tyr.
Kugirango tumenye ingaruka za antigenic ziterwa n’imihindagurikire y’ingenzi, twakoze ubushakashatsi bwo kutabogama dukoresheje uduce duto twa lentiviral panicle pseudotyped, dusanga ko hari isano iri hagati yikarita yo guhunga antibody hamwe nigitekerezo cyo kutabogama (Ishusho 1C nishusho S3).Nkuko byari byitezwe ku ikarita ya antibody ya REGN-COV2, ihinduka ry’umwanya wa 486 ntirishobora guteshwa agaciro na REGN10933, mu gihe ihinduka ry’imyanya 439 na 444 ridafite aho ribogamiye na REGN10987, bityo rero ihinduka ntirishobora guhunga.Ariko E406W yarokotse antibodi ebyiri za REGN-COV2, nuko nayo irokoka imvange ikomeye.Binyuze mu isesengura ry’imiterere no guhitamo virusi, Regeneron yizera ko nta muti wa aside amine ushobora guhunga antibodi ebyiri ziri muri cocktail (11, 12), ariko ikarita yacu yuzuye igaragaza E406W ko ihinduka rya cocktail ihinduka.E. S3F).
Kugirango tumenye niba ikarita yacu yo guhunga ijyanye n’ihindagurika rya virusi mu guhitamo antibody, twabanje gusuzuma amakuru y’ubushakashatsi bwatoranijwe bwo guhunga virusi ya Regeneron, aho imvugo y’imvugo yakuriye mu muco w’akagari imbere ya REGN10933. virusi ya stomatitis (VSV), REGN10987 cyangwa REKN-COV2 cocktail (12).Uyu murimo wagaragaje ihinduka ry’imihindagurikire itanu kuva REGN10933, ihinduka ry’imihindagurikire ibiri ya REGN10987, kandi nta ihinduka ryaturutse kuri cocktail (Ishusho 2A).Ihinduka ryatoranijwe n'imico irindwi yose y'utugari ryerekanwe ku ikarita yacu yo guhunga, kandi impinduka imwe-nucleotide ya codon yo mu bwoko bwa codon yo mu bwoko bwa Wuhan-Hu-1 RBD nayo iraboneka (Ishusho 2B), byerekana itandukaniro riri hagati yo guhunga Concordance igishushanyo na virusi ihindagurika munsi ya antibody mumico ya selile.Birakwiye ko tumenya ko E406W idashobora kugerwaho nimpinduka imwe ya nucleotide, ishobora gusobanura impamvu guhitamo cocktail ya Regeneron idashobora kubimenya nubwo bihanganira kwihanganira ububiko bwa RBD hamwe na ACE2.
(A) Imbere ya antibodies, Regeneron akoresha panicle pseudotype VSV kugirango ahitemo ihinduka ryimiterere ya virusi mumico y'utugari (12).(B) Igishushanyo cyo guhunga, nkuko bigaragara ku gishushanyo 1A, ariko cyerekana gusa ihinduka ryagerwaho nimpinduka ya nucleotide imwe murwego rwa Wuhan-Hu-1.Ibara ritari imvi ryerekana ihinduka ryumuco wumudugudu (umutuku), nabarwayi banduye (ubururu)), cyangwa byombi (ibara ry'umuyugubwe).Igicapo S5 cerekana ibishushanyo, bigira amabara nuburyo ihinduka rigira ingaruka kuri ACE2 cyangwa imvugo ya RBD.(C) Ibikorwa bya mutation ya RBD kubarwayi bavuwe na REGN-COV2 kumunsi wa 145 wanduye (umurongo wumukara utudomo).Inshuro yo guhuza hagati ya E484A na F486I yariyongereye, ariko kubera ko E484A atari ihinduka ryimihindagurikire yimiterere yacu, ntabwo ryerekanwa mubindi bice.Reba kandi ishusho.S4..Buri ngingo ni ihinduka, kandi imiterere n'amabara byerekana niba bishobora kugerwaho no guhitamo mugihe cyo gukura kwa virusi.Iburyo bwiburyo bwiburyo kuri x-axis byerekana antibody ikomeye ihuza guhunga;ingingo zo hejuru kuri y-axis zerekana isano iri hejuru ya ACE2.
Kugirango tumenye niba Escape Atlas ishobora gusesengura ubwihindurize bwa virusi yanduza abantu, twasuzumye amakuru yimbitse yakurikiranye n’umurwayi udafite ubudahangarwa wanduye wakiriye REGN-COV2 ku munsi wa 145 nyuma yo gusuzuma indwara ya COVID-19 (16).Kuvura bitinze bituma virusi y’umurwayi yegeranya amoko atandukanye, amwe muri yo akaba ashobora guterwa n’ubudahangarwa bw'umubiri, kubera ko umurwayi afite intege nke za antibody mbere yo kuvurwa (16).Nyuma yubuyobozi bwa REGN-COV2, inshuro eshanu ihindagurika rya aside amine muri RBD yahindutse vuba (Ishusho 2C nishusho S4).Ikarita yacu yo guhunga yerekanaga ko bitatu muri byo byahindutse byarokotse REGN10933 naho umwe aratoroka REGN10987 (Ishusho 2B).Birakwiye ko tumenya ko nyuma yo kuvura antibody, ntabwo ihinduka ryose ryimuriwe kurubuga rwagenwe.Ibinyuranye, hariho kuzamuka no kugwa kw'irushanwa (Ishusho 2C).Ubu buryo bwagaragaye mu bwihindurize bw’imbere bw’imihindagurikire y’izindi virusi (17, 18), bishoboka ko biterwa no guhatana hagati y’imiterere y’imiterere y’imiterere y’imiterere ya virusi.Izi mbaraga zombi zisa nkizifite uruhare mubarwayi bafite ubwandu buhoraho (Igicapo 2C nishusho S4C): E484A (ntabwo ihinduka ryimiterere yo guhunga ku gishushanyo cyacu) na F486I (guhunga REGN10933) kugendera kubuntu nyuma yo kuvurwa, hamwe numurongo wa virusi utwara N440D Kandi Q493K (guhunga REGN10987 na REGN10933,) yabanje guhatana na REGN10933 guhunga mutant Y489H, hanyuma irushanwa numurongo utwaye E484A na F486I na Q493K.
Batatu muri bane bahinduye ihinduka ry’abarwayi bavuwe na REGN-COV2 ntibamenyekanye mu gutoranya umuco wa virusi ya Regeneron (Ishusho 2B), byerekana ibyiza by'ikarita yuzuye.Guhitamo virusi ntabwo byuzuye kuko birashobora gusa kumenya ihinduka ryimiterere ryatoranijwe muri ubwo bushakashatsi bwihariye bwumuco.Ibinyuranye nibyo, ikarita yuzuye isobanura ihinduka ryimiterere yose, ishobora kuba irimo ihinduka ryatewe nimpamvu zidafitanye isano no kuvurwa, ariko kubwimpanuka bigira ingaruka kubihuza antibody.
Birumvikana ko ubwihindurize bwa virusi buterwa nimbogamizi zakazi hamwe nigitutu cyo kwirinda antibodi.Ihinduka ry’abarwayi n’abarwayi batoranijwe mu muco w’akagari bahora bujuje ibi bikurikira: bahunga guhuza antibody, barashobora kwinjira binyuze mu mpinduka imwe ya nucleotide, kandi bakagira amafaranga make cyangwa nta kiguzi cyo guhuza ACE2 [binyuze mu ihinduka ryimbitse ryerekanwe hakoreshejwe umusemburo Scanning gupima RBD (7) )] (Ishusho 2D n'ishusho S5).Kubwibyo, ikarita yuzuye yukuntu ihinduka ryimiterere yibintu byingenzi bya biohimiki ya RBD (nka ACE na antibody bihuza) bishobora gukoreshwa mugusuzuma inzira zishoboka ziterwa na virusi.Icyifuzo kimwe ni uko mugihe kirekire cyubwihindurize, nkuko bigaragara mubudahangarwa bwa virusi no guhunga ibiyobyabwenge, kubera imikoranire yibiza, umwanya wo kwihanganira ihinduka ry’imihindagurikire ushobora guhinduka (19-21).
Ikarita yuzuye iradufasha gusuzuma ihinduka ryimiterere ihari mukuzenguruka SARS-CoV-2.Twagenzuye ibintu byose biboneka bikomoka ku bantu SARS-CoV-2 kugeza ku ya 11 Mutarama 2021 dusanga umubare munini w'imihindagurikire ya RBD warokotse antibodi imwe cyangwa nyinshi (Ishusho 3).Nyamara, guhunga mutation yonyine igaragara muri> 0.1% byurukurikirane ni REGN10933 guhunga mutant Y453F [0.3% byurukurikirane;reba (12)], REGN10987 guhunga mutant N439K [1.7% byurukurikirane;reba Ishusho 1C na (22)], Na LY-CoV016 guhunga mutation K417N (0.1% bikurikiranye; reba na 1C).Y453F ifitanye isano n’ibyorezo byigenga bijyanye n’imirima ya mink mu Buholandi na Danemarke (23, 24);birakwiye ko tumenya ko urutonde rwa mink ubwabwo rimwe na rimwe rurimo izindi mutation zo guhunga, nka F486L (24).N439K irazwi cyane mu Burayi, kandi igize igice kinini cyurukurikirane ruva muri Scotland na Irlande mu Burayi (22, 25).K417N ibaho mumirongo ya B.1.351 yavumbuwe bwa mbere muri Afrika yepfo (10).Indi mutation yibibazo byubu ni N501Y, iboneka muri B.1.351 ndetse no mumirongo ya B.1.1.7 yagaragaye mbere mubwongereza (9).Ikarita yacu yerekana ko N501Y nta ngaruka igira kuri antibody ya REGN-COV2, ariko ingaruka zoroheje kuri LY-CoV016 (Ishusho 3).
Kuri buri antibody cyangwa antibody ihuriweho, guhera ku ya 11 Mutarama 2021, muri 317.866 yo mu rwego rwo hejuru ikomoka ku bantu ikomoka kuri SARS-CoV-2 ikurikirana kuri GISAID (26), isano iri hagati y’amanota yo guhunga kuri buri mutation ninshuro zayo.Ikimenyetso.REGN-COV2 cocktail guhunga mutation E406W isaba impinduka nyinshi za nucleotide muburyo bwa Wuhan-Hu-1 RBD, kandi ntibigaragara muburyo bwa GISAID.Izindi ihinduka ry’ibisigisigi E406 (E406Q na E406D) byagaragaye hamwe no kubara inshuro nke, ariko izo aside amine acide ntabwo ari ihinduka rya nucleotide imwe kure ya W.
Nkuko byari byitezwe, guhunga ihinduka mubisanzwe muri antibody-RBD.Nyamara, imiterere yonyine ntabwo ihagije guhanura ihinduka ryimiterere ihuza guhunga.Kurugero, LY-CoV016 ikoresha iminyururu iremereye kandi yoroheje kugirango ihuze na epitope yagutse irenga ACE2 ihuza ubuso, ariko inzira yo guhunga ikubiyemo ihinduka ryimiterere yibisigisigi bya RBD murwego rwuzuzanya rwerekana akarere (Ishusho 4A nishusho S6, E kugeza G).Ibinyuranye, guhunga kuva REGN10933 na REGN10987 byabereye cyane cyane kubisigisigi bya RBD byashyizwe kumurongo wiminyururu iremereye kandi yoroheje (Ishusho 4A nishusho S6, A kugeza D).Ihinduka rya E406W ryarokotse imvange ya REGN-COV2 ryabereye ku bisigazwa bitajyanye na antibody (Ishusho 4, A na B).Nubwo E406 yegeranye muburyo bwa LY-CoV016 (Igicapo 4B nishusho ya S6H), ihinduka rya E406W rifite ingaruka ntoya kuri antibody (Ishusho 1, B na C), byerekana ko uburyo bwihariye bwimiterere ndende irwanya REGN - Antibody ya COV2 (Igicapo S6I).Muncamake, ihinduka ryibisigisigi bya RBD bihura na antibodi ntabwo buri gihe bihuza guhunga, kandi ihinduka ryingenzi ryo guhunga ribaho kubisigisigi bidahuye na antibodies (Igicapo 4B nishusho S6, D na G).
(A) Igishushanyo cyo guhunga giteganijwe kumiterere ya RBD ihujwe na antibody.[REGN10933 na REGN10987: Ububiko bwa poroteyine (PDB) ID 6XDG (11);LY-CoV016: PDB ID 7C01 (13)].Imiterere ihindagurika yiminyururu iremereye kandi yoroheje ya antibody yerekanwa nkikarito yubururu, naho ibara hejuru ya RBD ryerekana imbaraga zo guhunga kwa mutation-medrated kuri uru rubuga (umweru werekana ko nta gutoroka, naho umutuku ugaragaza imbaraga zikomeye guhunga urubuga rwa antibody cyangwa imvange).Imbuga zidahinduwe neza zirashaje..Buri ngingo igereranya urubuga, rugabanijwemo guhunga (umutuku) cyangwa kudahunga (umukara).Umurongo wijimye wijimye werekana agaciro gakomeye gakoreshwa mugushira urubuga nkuguhunga cyangwa kudahunga (kubisobanuro birambuye, reba Ibikoresho nuburyo).Imibare itukura numukara yerekana umubare wimbuga muri buri cyiciro zacitse cyangwa zidacunzwe.
Muri ubu bushakashatsi, twashushanyije rwose ihinduka ryirinda antibodi eshatu zikomeye zirwanya SARS-CoV-2.Aya makarita yerekana ko ibiranga ubanza kuranga ihinduka ryuzuye bituzuye.Nta ihindagurika rimwe rya aside amine rishobora guhunga antibodi ebyiri muri cocktail ya REGN-COV2, nta nubwo ryagaragaje umubare munini w'abarwayi banduye bakomeje kuvurwa na cocktail.mutation.Birumvikana ko ikarita yacu itarasubiza ikibazo cyingutu: SARS-CoV-2 izatera imbaraga zo kurwanya antibodi?Ariko ikidashidikanywaho ni uko biteye impungenge ko ihinduka ryinshi ry’imihindagurikire ridafite ingaruka nke ku gufunga kwa RBD cyangwa kwakirwa, kandi hari hasanzwe hari ihinduka rito ryo mu rwego rwo gukwirakwiza virusi.Mu kurangiza, birakenewe gutegereza no kureba ihinduka rya SARS-CoV-2 ryanduza iyo rimaze gukwirakwira mu baturage.Akazi kacu kazafasha "kwitegereza" duhita dusobanura ingaruka za mutation zashyizwe mubikorwa na virusi ya genome.
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Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
Ikarita yuzuye ya mutation ya SARS-CoV-2 ihunga antibody ya Regeneron monoclonal ivanze ifasha gusobanura ihindagurika rya virusi mu kuvura abarwayi.
Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
Ikarita yuzuye ya mutation ya SARS-CoV-2 ihunga antibody ya Regeneron monoclonal ivanze ifasha gusobanura ihindagurika rya virusi mu kuvura abarwayi.
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Igihe cyo kohereza: Gashyantare-24-2021