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Peptide and linker chemistry can constrain a dual-payload ADC program, alongside antibody production, payload supply, njikọ, analytics and formulation. D…
Kedu ihe na-agbanwe na teknụzụ mgbe ADC na-ebu ụgwọ abụọ kama ibu otu
M Peptides soplaya Megharịa Peptides Ibu ụgwọ abụọ apụtaghị njikọ abụọ nọọrọ onwe ha. N'ime nrụnye ịkwụ ụgwọ abụọ, parampat enwere ike ịchịkwa bụ ebe ọgwụ ọ bụla jikọtara ya, otu esi ahapụ nke ọ bụla, nkezi mkpokọta DAR na A:Oke ịkwụ ụgwọ B, so DAR_total = DAR_A + BUT_B, ya na A:Ọnụọgụ B dịka oke njikwa dị iche (Wen et al., mAbs, 2025). Ihe nrụpụta nwere ike ijide DAR mkpokọta ma ka bụrụ ihe dị iche.
Ihe owuwu njikọ na-ebu ibu ahụ. Njikọ ndị nwere ngalaba nwere aka orthogonal reactive, dịka ọmụmaatụ otu thiol-reactive na otu aka-reactive ogwe aka, kwe ka ntinye usoro nke ibu ọrụ na-ekwekọghị na kemịkalụ (Wen et al., mAbs, 2025). Nrụpụta e bipụtara na-egosi etu oghere imewe si agbasa: a 2026 nyocha nke ibu abuo na-ewulite tabulates DAR ụzọ abụọ sitere na nnukwu ibu mgbochi CD30 MMAE/MMAF jikọtara ọnụ ruo obere ibu MMAF/SN38 ụzọ abụọ. (Ọgwụ ọgwụ 19:860, 2026).
Ratio na-emetụta onwe ya. A 2025 Ntụleghachi nke otu ụzọ njikọkọ abụọ-akwụ ụgwọ na-akọ a 4+2 MMAE/MMAF na-arụ ọrụ nke ọma na DAR6 MMAE ADC na DAR4 otu ADC na-akwụ ụgwọ., n'ụdị preclinical sitere na otu ndị na-ere ikpo okwu abụọ akwụ ụgwọ (Wen et al., mAbs, 2025). Mesoo nke ahụ dị ka echiche atụmatụ, ọbụghị nha akwadoro. Nsonaazụ bara uru maka kemịkalụ ADC linker-payload bụ na a ga-akọwapụtarịrị peptide na njikọ n'otu aka., ọ bụghị kwa molekul.
Ebe peptide dabara, na ihe kpatara njikọ-peptide ji bụrụ akụkụ siri ike
Nkọwapụta otu ogwe aka ahụ na-agbada na peptide, nke a ga-ahazi na nkọwapụta tupu njikọ ọ bụla emee ma bụrụ ebe usoro ọdịda ọdịda usoro n'elu.. Ezinụlọ njikọ Val-Cit-PABC na-adabere na mgbawa enzyme lysosomal sochiri onye oghere PABC na-eme onwe ya nke na-ewepụta ụgwọ ọrụ site na 1,4/1,6-mwepu. (Guo et al., Oke na Immunology, 2026). A na-eji otu ụzọ lysosomal kewaa GGFG tetrapeptide linker eji na DXd conjugates., Ya mere, usoro peptide na-eme ntọhapụ kemịkalụ, ọ bụghị naanị oghere.
Ụlọ ọrụ na-akwụ ụgwọ abụọ na-eme ka peptide na-aga n'ihu. SPARC's multipayload architecture architecture na-ewulite modul sitere na dipeptide VA linker gbakwunyere polysarcosine-PAB spacer na-eme onwe ya., CuAAC gbakọtara ma tinye ya na saịtị VA (Sun et al., Bioconjugate Chemistry, 2025). Nke ahụ bụ peptide nwere ntụpọ alaka akọwapụtara, ihe ntọhapụ akọwapụtara na saịtị mgbakwunye nke abụọ akọwapụtara, niile n'otu usoro.
Njirimara ndị ahụ bụkwa ihe egwu njikọ. Usoro na-ebu cysteine abụọ echedoro iche iche, nnukwu ụgwọ ọrụ hydrophobic dị n'akụkụ yana oghere na-ekpochapụ onwe ya na-elekwasị anya na ihe isi ike nke oge ochie.: Epimerization na njikọ nke ọ bụla, nguzobe aspartimide ebe Asp-Gly motifs pụtara, na mkpokọta resin site na ịgba ọsọ hydrophobic. Usoro cysteine orthogonal nke Seattle Genetics na-egosi kemịkalụ nwere ike nweta na protein apịaji. (Levengood et al., Angew Chem Int Ed, 2017); ma onye na-ebubata ya nwere ike megharịa ya n'ọtụtụ gị bụ ajụjụ dị iche, na onye na-ekpebi usoro iheomume gị.
Kedu ka njikọ-peptide na-arụkọ ọrụ aka abụọ na-echekwa ya n'ụzọ ọ bụla?
Nchedo orthogonal na-enyere aka ịrụ ọrụ nke ọma mgbe ọ bụla reagent na etiti na-anabata usoro na-esote. The zoro aka 2017 kemistri bụ ihe atụ akụkọ ihe mere eme, ọ bụghị naanị ụzọ a na-arụ ọrụ; họrọ a scalable usoro na ịchịkwa reagent residues, gụnyere ọla ebe ọ dị mkpa.
Nhọrọ nhọrọ bụ isi ihe. Chebe otu cysteine dị ka disulfide reducible na nke ọzọ dị ka Acm na-ahapụ ka etinyere ụgwọ ọrụ otu mgbe nke ọzọ. (Levengood et al., Angew Chem Int Ed, 2017). Acm kwụsiri ike na TCEP mana aqueous mercury acetate wepụrụ ya, nke bụ ihe na-eme ka usoro ahụ kwe omume (Levengood et al., Angew Chem Int Ed, 2017). Otu akwụkwọ akụkọ na-akọ na-ewu na 16 mkpokọta ọgwụ, Kewaa 8+8, na 98% monomer nwere mgbochi antigen, nke mere na usoro nchebe bụ ihe mgbochi imewe karịa nkọwa nchacha.
Sortase A na-amatakarị motif LPXTG, nke LETG bụ ihe atụ, ma nwee ike ịbanye na oligoglycine nucleophile kwesịrị ekwesị. Motif na mkpụrụ chọrọ dabere na enzyme na ịrụ ya.
Otu anyị si etinye nke a na MOL Changes, onye bipụtara akwụkwọ ntuziaka a. Anyị na-emepụta peptides omenala na usoro gị akọwapụtara, ruo 200 amino asịd, Ya mere enwere ike wuo njikọ-peptide na nkọwapụta otu ogwe aka ị debere tupu njikọ. Anyị anaghị arụ ọrụ nchebe cysteine orthogonal ma ọ bụ usoro njikọ ọ bụla, ma anyị anaghị akwụ ụgwọ njikọ njikọ abụọ; atụmatụ nchebe, ụzọ njikọ na njikwa DAR ka bụ nke gị iji chepụta na nyochaa.
Kedu ka njikọta saịtị kpọmkwem si egbochi imewe peptide?
Ụzọ njikọ ga-ekpebi nke ejiri peptide gị ga-ebu yana nke ga-echekwa ya. Stochastic lysine ma ọ bụ interchain-cysteine conjugation na-enye DAR dị iche iche., mgbe a na-emepụta cysteine , Amino acid na-abụghị nke canonical na ụzọ na-emegharị glycan na-enye njikwa DAR siri ike karị, ya na nhazigharị glycan na Fc Asn297 na-eji saịtị dịpụrụ adịpụ nke na-emebi obere njikọ antigen. (Ocana et al., Ntugharị mgbaàmà na ọgwụgwọ ezubere iche, 2026). Ụzọ ọ bụla na-atụgharị gaa na nkọwapụta peptide dị iche.
Ọnụọgụ pipeline e bipụtara bụ ụbọchị- na nkọwa-adabere na iche n'etiti reviews. Ntinye n'ime ọmụmụ ụlọ ọgwụ n'oge abụghị ihe akaebe Onye na-ebu polypeptide nke uru ahụike. Edemede a anaghị ewepụta ọnụọgụ ugbu a zuru oke ma ọ bụ arụmọrụ klaasị ma ọ bụ nkwubi okwu nchekwa.
Isi mmalite ndị ahụ ekwenyeghị na ole nzụta bioconjugation akọwapụtara saịtị. Otu 2026 Ntụleghachi na-ekwu n'ụzọ doro anya na ọ ka edoghị anya n'ọtụtụ nkwalite ịdị n'otu na-enye aka na nsonaazụ ụlọ ọgwụ, na-achọpụta na trastuzumab emtansine, trastuzumab deruxtecan na sacituzumab govitecan niile na-eji conjugation oge na-egosi uru ụlọ ọgwụ. (Kumari et al., Ọrịa cancer, 2026). Ụzọ ọzọ akọwapụtara saịtị dị ka ịme ka njikwa DAR siri ike ka ọ na-echekwa usoro mgbochi mmadụ yana njikọ antigen. (Ocana et al., Ntugharị mgbaàmà na ọgwụgwọ ezubere iche, 2026). Ha abụọ nwere ike ịbụ eziokwu: tighter akara bụ àgwà àgwà, na ntụgharị asụsụ ụlọ ọgwụ akwadobeghị. Ọ nweghị ebe na-akọwapụta òkè nke pipeline na-eji saịtị akọwapụtara na njikọ na-enweghị usoro, ya mere na-emeso ụdị ọ bụla dị otú ahụ na-enyo enyo.
Kedu ka esi akọwapụta ịdị ọcha: peptide dị ọcha, conjugate ịdị ọcha, Nkesa DAR?
Otu pasent HPLC abụghị nkọwapụta ịdị ọcha. Ntuziaka EMA synthetic-peptide nke malitere na June 2026 na-ahazi Ph. Euro. ọnụ ụzọ maka adịghị ọcha metụtara peptide na akụkọ dị n'elu 0.1%, mata n'elu 0.5% ma tozuo oke 1.0%, chọrọ usoro adịghị ọcha ọ bụla ma ọ dịkarịa ala izute 0.1% ngafe akuko, ma ọ naghị akwado ịchịkọta ihe ndị na-adịghị ọcha (EMA/CHMP/CVMP/QWP/367182/2025, dị ka a pụrụ isi kwuo ya 2026-06-01). Ọ na-ejikwa ịdị ọcha dị ka otu n'ime CQA kachasị mkpa maka peptides sịntetik ma chọọ nkọwapụta ihe na-arụ ọrụ iji kwupụta mkpokọta na adịghị ọcha nke onye ọ bụla megide ọnụ ụzọ ndị ahụ..
Usoro n'azụ ọnụ ọgụgụ ahụ nwere ihe ọ chọrọ. I Q2(R2) Atụmanya nkwado chọrọ ka a gosipụta ịdị ọcha na usoro adịghị ọcha ka a ga-egosipụta megide ụdị spiked ma ọ bụ nrụgide siri ike yana site na usoro orthogonal ebe enweghị ike ikewapụ adịghị ọcha. (I Q2(R2), 2023). Otu usoro HPLC, Otú ọ dị nke ọma ọ na-agba ọsọ, abụghị nkwupụta ịdị ọcha kwadoro.
Klas adịghị ọcha dị adị, ọbụlagodi ebe anaghị ebipụta ugboro ole. A 2026 Achọpụtara nyocha adịghị ọcha nke semaglutide sịntetik na-esochi 57 adịghị ọcha n'elu a 0.02% ebipụ n'ofe ọgwụ itoolu, na nhichapụ nke Thr, Ya na Gly n'etiti umu amata (Kop et al., Nnyocha ọgwụ, 2026). Nke ahụ na-akwado "ihichapụ na-eme na a ga-achọrịrị"; ọ naghị akwado ọnụego ihichapụ.
Oke oke dị mkpa. Ntuziaka EMA na-ekwu maka otu njikọ na njikọ dị ka isiokwu CMC, gụnyere akwụkwọ ndị na-ebubata ihe na ntule adịghị ọcha mutagenic, na ekwughị ihe ọ bụla gbasara ADC, ụgwọ abụọ ma ọ bụ DAR. Jiri ya maka peptide, ọ bụghị maka conjugate.
Kọwaa peptide na njirimara njikọ, mkpa adịghị, conjugate umu, ngụkọta na kwa-ụgwọ ibu ibu, free ugwo na nkwụsi ike maka n'ezie ewu. SEC naanị anaghị ewepụta ịdị ọcha nke njikọta ọnụ; jikọta ụzọ na mkpuchi egosipụtara. Ọnụ ụzọ sịntetik-peptide abụghị oke nnabata ADC-linker ozugbo.
Kedu ihe dị na ngwungwu handoff nyocha site na nchọpụta ruo na mmepe?
Ihe ngwungwu handoff ga-ahapụrịrị ka ndị otu na-anata mepụtaghachi nọmba gị na-enweghị ịmaliteghachi nyocha ahụ. Maka ọtụtụ ADC na-akwụ ụgwọ, atụmatụ bioanalytical ga-agbatịrịrị n'ofe ọgwụ mgbochi na nyocha njikọ-antibody., LC-MS na-arụkọ ọrụ ọnụ na-adịghị arụ ọrụ, na nyocha etiti ala maka nkesa ibu ọgwụ pụtara (Riccardi Sirtori et al., Bioanalysis, 2025). Nyocha n'etiti ala maka nkesa ibu ọgwụ pụtara bụ nke na-efukarị site na ngwungwu nchọpụta.
Ntụnye nke ndị na-eweta peptide dị warara ma ọ bụ ihe siri ike. Otu onye na-eweta njikọ-peptide si akọwa dabara maka ebumnuche QC bụ HPLC ma ọ bụ ịdị ọcha UPLC gbakwunyere njirimara LC-MS, na nhọrọ pre- na nkwenye mgbawa nke post-akpalite (Bio-Synthesis, peptide njikọ cleavable, ewepụtara 2026-10). Rịọ maka ọtụtụ chromatograms na spectra mass, ọ bụghị nchịkọta akwụkwọ.
Oghere abụọ n'eziokwu. Ọ nweghị ebe na-akọwa usoro iwu kwadoro maka ịlele DAR nke ọ bụla na-akwụ ụgwọ na nlele ụlọ ọgwụ., na mbelata RPLC-UV n'ozuzu enweghị ike idozi ụkpụrụ DAR nke ọ bụla maka ụgwọ a na-akwụ ụgwọ ọ bụla n'ihi na agbụ dị arọ nwere otu mkpokọta DAR mana nhazi ụgwọ ọrụ dị iche iche co-elute. (Ọgwụ ọgwụ 19:860, 2026). Usoro nkọwapụta nke ICH Q6B na-enye ụkpụrụ izugbe maka ịtọ na izi ezi nkọwa maka ngwaahịa ndu (FDA, Q6B, 1999), mana usoro ahụ anaghị agwa gị nyocha nke na-edozi ibu ọrụ abụọ gị.
Ndepụta aka aka: usoro na otutu nọmba; Atụmatụ nchekwa-otu na usoro nchebe; Usoro HPLC/UPLC nwere kọlụm, gradient na wavelength; LC-MS njirimara na hụrụ n'ihu na usoro iwu uka; okpokoro adịghị ọcha megide 0.1/0.5/1.0%; nkwenye nkwụsịtụ ma ọ bụrụ na onye na-ejikọta ya bụ enzyme-cleavable; yana usoro ekwuputara maka DAR kwa-akwụ ụgwọ, ma ọ bụ ndetu doro anya na edozibeghị ya.
Kedu otu ị ga-esi họrọ n'etiti ọkachamara na-agbanwe agbanwe na onye na-eweta ọrụ zuru oke?
Nhọrọ ahụ na-agbanye ebe mmachi gị nọ n'ezie. Onye na-eweta agbakwunyere na-enye otu nkwekọrịta n'ofe mgbochi, njikọ, ugwo na njuputa-emecha; Ihe nrụpụta ADC agbakwunyere nke Lonza na-akọwa mmepụta gram-ụgwọ na ike ọtụtụ kilogram na Visp yana onyinye agbakwunyere n'ofe ọgwụ mgbochi., njikọ, ibu ibu, bioconjugation na sterile ndochi-emecha (Lonza, Peptides dị ọcha ewepụtara 2026-10). Nlereanya Advanced Synthesis nke dabara adaba na nkebi ya na-ewepụta ike n'ofe nchọpụta, mmepe na akụrụngwa ụlọ ọgwụ karịa inye ihe niile n'oge ọ bụla (Ndụmọdụ mgbasa ozi Lonza, 2026). Ụlọ ọrụ mmepụta ihe Peptide
Onye ọkachamara na-etinye uche na otu oyi akwa. Nke ahụ bụ uru mgbe nsogbu siri ike bụ usoro: Cysteine dị iche iche na-echebe, polysarcosine spacer, mkpado LETG ma ọ bụ ọsọ hydrophobic nke na-agbakọta na resin. Ọ bụ mwepu mgbe ịchọrọ otu usoro dị mma iji kpuchie njikọ na mejupụta.
|
Usoro |
Ọkachamara mgbanwe |
Onye na-eweta agbakwunyere n'ụzọ zuru ezu |
|---|---|---|
|
Kacha mma dabara |
Mgbagwoju anya ma ọ bụ alaka peptide, atụmatụ nchebe na-adịghị ahụkebe, ngwa ngwa usoro iteration |
Mmemme chọrọ otu sistemu dị mma site na njikọ njikọ ruo imecha |
|
omimi nyocha Mmepụta Peptides |
Ọtụtụ HPLC/MS na nkwenye nbibi, mmepe nke usoro maka peptide |
Nnwale ikpo okwu gafee conjugate, ugwo na-emebibeghị oke |
|
Ihe ize ndụ dị elu |
Nyefee gaa na saịtị nke abụọ maka njikọ na nnyefe ụlọ ọgwụ |
Nyefe otu saịtị, obere mfu aka |
|
Ebe a ga-enyocha |
Ahụmahụ nchedo orthogonal, usoro DAR kwa-akwụ ụgwọ, akụkọ adịghị ọcha megide 0.1% |
Ma oyi akwa peptide na-enweta mmepe usoro raara onwe ya nye ma ọ bụ ndabara ikpo okwu |
Ntụnyere bụ echiche nchịkọta akụkọ, ọ bụghị ọkwa sitere n'ike; ọnweghị ebe m nyochara akara nrịbama ụdị abụọ ahụ n'isi n'isi. Jiri ya hazie ajụjụ, mgbe ahụ, ka azịza kpebie.
Akaụntụ
Usoro chemistry abụọ. Ọnọdụ cysteine orthogonal sitere na 2017 ma gosi ya na ihe mgbochi ihe atụ, ya mere ha bụ ntụnye aka imewe, ọ bụghị usoro kwadoro (Levengood et al., Angew Chem Int Ed, 2017). Na nkwupụta na DAR dị elu na-akpata mkpokọta nwere ihe ewepụrụ akwụkwọ: nke 8+8 ịrụ ruru 98% monomer nwere ihe ndọtị PEG24, ya mere hydrophobicity masking, ọ bụghị DAR naanị, bụ mgbanwe. Ọ nweghị ebe ọ bụla na-enye mpụtara a tụrụ atụ ma ọ bụ mfu ịdị ọcha maka iweta peptide gbagwojuru anya site na milligram ruo kilogram; ihe ize ndụ ahụ na-anọgide qualitative.
Ajụjụ a na-ajụkarị
DAR dị elu ọ na-ebute mkpokọta na mkpochapụ ngwa ngwa?
Mba. Ejikọtara DAR dị elu na mkpokọta yana mkpochapụ ngwa ngwa maka ibu ọrụ hydrophobic, ma njikọ ahụ na-agbanwe site na njikọ hydrophobicity (Ocana et al., Ntugharị mgbaàmà na ọgwụgwọ ezubere iche, 2026). Ihe nrụpụta dual-auristatin nwere ihe ndọtị PEG24 ruru 98% monomer (Levengood et al., Angew Chem Int Ed, 2017).
Ntuziaka EMA sịntetik-peptide na-ekpuchi ADC abụọ akwụ ụgwọ?
Mba. Ọ na-ekpuchi peptides sịntetik ma na-emeso akụkụ njikọ na njikọ dị ka isiokwu CMC.; ọ naghị ekwu ihe ọ bụla gbasara ADC, ụgwọ abụọ ma ọ bụ DAR (EMA/CHMP/CVMP/QWP/367182/2025, dị ka a pụrụ isi kwuo ya 2026-06-01).
Ọkachamara peptide nwere ike inyefe onye na-eweta ọkwa ụlọ ọgwụ?
Ee, ọ bụrụ na ngwungwu handoff na-ebu data HPLC na LC-MS akọwapụtara, atụmatụ nchekwa na usoro nchekwa, yana usoro ekwuputara maka DAR kwa-akwụ ụgwọ. Ọdịiche a ga-eme atụmatụ maka ya bụ na ọ nweghị usoro iwu kwadoro maka DAR ọ bụla a na-akwụ ụgwọ na nlele ụlọ ọgwụ ka akọwara na isi mmalite ndị a nyochara. (Ọgwụ ọgwụ 19:860, 2026).
Mmechi
Iwu mkpebi maka onye mmekọ nkwado na-esite na nke ahụ. Dakọtara onye mmekọ gị na mmachi gị n'ezie. Ọ bụrụ na mmachi a bụ alaka ma ọ bụ usoro echedoro iche, ọkachamara nwere ahụmahụ nchebe orthogonal egosipụtara na nyocha ọkwa ọkwa dị mma ka mma. Ọ bụrụ na mmachi bụ otu mma usoro gafee conjugation na ụlọ ọgwụ ọkọnọ, onye na-eweta agbakwunyere na-enweta mmeri n'ihe egwu mbufe. N'okwu abụọ ahụ, rịọ maka ngwugwu nyocha tupu nhota ahụ, ma na-emeso onye na-ebubata ihe na-enweghị ike ịkọwa DAR onye ọ bụla na-akwụ ụgwọ dị ka onye na-ebubata nke na-edozighị ọkara nyocha nke nsogbu ahụ..
Nzọụkwụ ọzọ bụ nyocha teknụzụ nke usoro na nkọwapụta gị: atụmatụ nchekwa otu, usoro nchebe, ọnụ ụzọ adịghị ọcha na usoro DAR, mapụtara megide ihe onye nkwado nwere ike depụta nza site n'ife nza.
Nkpughe nke onye mbipụta: MOL Mgbanwe na-enye ọrụ peptide ma nwee mmasị azụmahịa na isiokwu a. Ogo ọrụ na nkwupụta ikike bụ nkwupụta ndị na-ebubata ya; nnweta na ịrụ ọrụ maka otu ihe owuwu chọrọ ihe akaebe akọwapụtara nke ọma.
