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Market Trend and Current Status of the Research and Development of Antibody-Drug Conjugates
Biomed Sci Letters 2021;27:121-133
Published online September 30, 2021;  https://doi.org/10.15616/BSL.2021.27.3.121
© 2021 The Korean Society For Biomedical Laboratory Sciences.

Sun-Il Kwon†,*

Department of Biomedical Laboratory Science, Deagu Health Science University, Daegu 41453, Korea
Correspondence to: Sun-Il Kwon. Department of Biomedical Laboratory Science, DeaguHealth Science University, Youngsong-ro 15 (Taejeon-dong), Buk-ku, Daegu 41453, Korea.
Tel: +82-53-320-1302, Fax: +82-53-320-1450, e-mail: psikwon@dhc.ac.kr
*Professor.
Received August 18, 2021; Revised September 17, 2021; Accepted September 27, 2021.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Antibody-drug conjugates (ADCs) are drawing much interest due to its great potential to be one of the important options in cancer treatments. ADCs are acting like a magic bullet which delivers cytotoxic drugs specifically to cancerous cells throughout the body, thus attacks these cells, while not harming healthy cells. ADCs are complex molecules that are composed of an antibody having targeting capability and linked-payload or cytotoxic drug killing cancerous cells. The key factors of the success in the development of ADC are selection of appropriate antibody, cytotoxic payload and linker for conjugation. Recently there was considerable progress in ADCs development, and a large number of ADCs gained US FDA approval. About 80 new ADCs are under active clinical studies. In this review we present a brief introduction of the US-FDA approved ADCs and global situation in the clinical studies of ADC pipelines. We address an overview on each component of an ADC design such as target antigens, payloads, linkers, conjugation methods, drug antibody ratio. In addition, we discuss on the trend of ADC market where global big pharmas and domestic biopharmaceutical companies are competing to develop safer and more effective ADCs.
Keywords : ADC, Antibody, Drug, Conjugate, Linker, Payload, Anti-cancer, Clinical
1. 꽌濡

쓽빟뭹 떆옣뿉꽌뒗 빀꽦쓽빟뭹怨 諛붿씠삤쓽빟뭹씠 몢 異뺤쓣 씠猷щ떎. 怨쇨굅뿉뒗 빀꽦쓽빟뭹씠 二쇰쪟瑜 씠猷⑥뿀쑝굹 씠젣 諛붿씠삤쓽빟뭹씠 꽭씠떎. 諛붿씠삤쓽빟뭹 洹 鍮꾩쨷씠 利앷븯뒗 異붿꽭씤뜲 2017뀈뿉뒗 꽭怨 10 釉붾줉踰꾩뒪꽣 以 8媛쒕 李⑥븯寃 릺뿀떎(Urquhart, 2018). 2019뀈뿉뒗 留ㅼ텧븸 꽭怨 긽쐞 100 쓽빟뭹 以 諛붿씠삤쓽빟뭹쓽 鍮꾩쨷씠 71%瑜 꽆뼱꽌 빀꽦쓽빟뭹 留ㅼ텧븸쓽 몢 諛곕 꽆뿀떎(KoBIA, 2021). 珥덉갹湲곗뿉 긽슜솕맂 諛붿씠삤쓽빟뭹 빆泥댁쓽빟뭹쑝濡 떒씪겢濡좏빆泥(monoclonal antibody; mAb)媛 二쇰 씠猷⑥뿀떎. 湲곗〈 빆泥댁쓽빟뭹뿉꽌 븞쟾꽦怨 쑀슚꽦쓣 媛쒖꽑븳 쁺떊 빆泥댁쓽빟뭹씠 留롮씠 뿰援щ릺怨 엳떎. 쁺떊 빆泥댁쓽빟뭹쑝濡쒕뒗 떒씪겢濡좏빆泥대 媛쒖꽑븳 諛붿씠삤踰좏꽣(biobetter), 빆泥대 옉寃 留뚮뱺 빆泥 젅렪(antibody fragment), 몢 媛吏 빆썝怨 룞떆뿉 寃고빀븯뒗 씠以 빆泥(bispecific antibody), 빟臾쇨낵 빆泥대 寃고빀떆궓 빆泥-빟臾 젒빀泥(antibody-drug conjugate; ADC, 씠븯 ADC) 벑씠 엳떎.

씠以 ADC뒗 꽭룷룆꽦빟臾쇱쓽 슚젰쓣 떒룆 빟臾쇰줈 궗슜븷 븣蹂대떎 븞쟾븯寃 뼢긽떆궗 닔 엳뒗 옞옱젰쑝濡 二쇰ぉ 諛쏄퀬 엳떎. ADC뒗 빆泥댁뿉 빟臾쇱쓣 떖븘꽌 빆泥닿 듅씠쟻쑝濡 蹂묒냼遺쐞留 寃잜똿븯룄濡 븯뿬 빟臾쇱씠 젙긽議곗쭅뿉뒗 쟾떖릺吏 븡怨 蹂묒냼遺쐞뿉留 쟾떖릺룄濡 븳떎. 븫꽭룷쓽 寃쎌슦 븫꽭룷 몴硫댁뿉 諛쒗쁽맂 듅젙 빆썝뿉 듅씠쟻쑝濡 寃고빀븯뒗 빆泥대 궗슜븯뿬 룆꽦씠 媛뺥븳 빟臾쇱쓣 븫꽭룷뿉 듅씠쟻쑝濡 쟾떖븯뿬 븫꽭룷留 궗硫몄떆궎寃 븳떎. 洹몃룞븞 룆꽦씠 넂怨 洹몄뿉 뵲씪 移섎즺뿭씠 醫곸 寃껋씠 臾몄젣젏쑝濡 吏쟻릺뼱 솕쑝굹 理쒓렐뿉뒗 룆꽦쓣 以꾩씤 李⑥꽭 ADC媛 벑옣븯뿬 ADC뒗 諛붿씠삤쓽빟뭹 떆옣쓽 二쇰쪟 듃젋뱶媛 릺怨 엳떎.

2000뀈룄뿉 誘멸뎅 Wyeth(쁽 솕씠옄(Pfizer)濡 빀蹂)궗뿉꽌 留덉씪濡쒗洹(Mylotarg®)濡 理쒖큹쓽 ADC瑜 뿀媛瑜 諛쏆 씠옒濡 11媛쒖쓽 ADC媛 誘멸뎅 떇뭹쓽빟援(U.S. Food and Drug Administration, US FDA)뿉꽌 듅씤쓣 諛쏆븯뒗뜲, 洹쇰옒뿉 뱾뼱꽌 2019뀈뿉뒗 뙣뱶꽭釉(Padcev®), 뤃씪씠鍮(Polivy®), 뿏뿀닾(Enhertu®)媛 2020뀈뿉뒗 듃濡쒕뜽鍮(Trodelvy®), 釉붾젋젟(Blenrep®)씠 2021뀈뿉뒗 吏꾨줎(Zylonta®)媛 뿰씠뼱 듅씤쓣 諛쏆븘꽌 ADC 엫긽뿰援ъ뿉꽌 겙 寃곗떎쓣 留브퀬 엳떎. 삉븳 湲濡쒕쾶 鍮낇뙆留 媛꾩쓽 怨좉쓽 뵜씠 ADC 뙆씠봽씪씤뿉꽌 굹삤怨 엳떎. 쁽옱 ADC뒗 꽭怨꾩쟻쑝濡 빟 80뿬媛 뭹紐⑹뿉 300嫄댁씠 꽆뒗 엫긽떆뿕씠 吏꾪뻾릺怨 엳뼱꽌 諛앹 誘몃옒媛 湲곕릺怨 엳떎. 諛붿씠삤쓽빟뭹 떆옣뿉꽌 ADC媛 李⑥븯뒗 鍮꾩쨷룄 뜑슧 而ㅼ쭏 寃껋쑝濡 깮媛곷맂떎. 蹂멸퀬뿉꽌뒗 ADC 移섎즺젣 뿰援 媛쒕컻쓽 쁽솴怨 떆옣 룞뼢뿉 븯뿬 怨좎같빐蹂닿퀬옄 븳떎.

2. ADC쓽 벑옣 諛곌꼍

븫쓽 移섎즺뿉뒗 硫댁뿭빆븫젣媛 留롮씠 벐씠怨 엳吏留 븘吏곷룄 쟾넻쟻씤 솕븰슂踰뺤젣媛 以묒슂븳 뿭븷쓣 븯怨 엳떎. 솕븰슂踰 빆븫젣뒗 二쇰줈 씪諛섏꽭룷 븫꽭룷瑜 援щ텇븯湲 쐞븯뿬 꽭룷二쇨린쓽 李⑥씠瑜 씠슜븳떎. 솕븰슂踰뺤젣뒗 移섎즺슚怨쇰 뼸湲 쐞븯뿬 蹂댄넻 理쒕 뿀슜웾(maximum tolerated dose) 洹쇱쿂뿉꽌 궗슜맂떎. 솕븰슂踰뺤젣뒗 븫꽭룷媛 몴쟻씠吏留, 젙긽꽭룷 븫꽭룷쓽 援щ텇씠 뾾씠 떒吏 鍮좊Ⅴ寃 遺꾩뿴븯뒗 꽭룷瑜 二쎌씪 肉먯씠誘濡 쟾떊룆꽦怨 꽭룷룆꽦쓣 뵾븯湲 뼱졄떎. 뵲씪꽌 솕븰슂踰뺤젣씤 꽭룷룆꽦 빟臾쇱쓣 븫꽭룷뿉留 寃잜똿븯뿬 븫꽭룷留 듅씠쟻쑝濡 궗硫몄떆궎뒗 諛⑸쾿씠 븘슂븯떎.

移섎즺슜 떒씪겢濡좏빆泥대뒗 醫낆뼇꽭룷쓽 몴硫댁뿉 議댁옱븯뒗 빆썝뿉 듅씠쟻쑝濡 寃고빀븯뿬 꽭룷궡긽슚怨쇰 씪쑝궓떎. 醫낆뼇꽭룷뿉留 寃고빀븯誘濡 鍮꾪듅씠쟻씤 쟾떊룆꽦 遺떞쓣 以꾩뿬以떎. 移섎즺슜 빆泥대뒗 솕븰슂踰뺤젣蹂대떎 쑀由ы븳 옣젏씠 엳吏留 醫낆뼇 듅씠 빆泥 以 냼닔쓽 빆泥대쭔 븫移섎즺슜쑝濡 궗슜맂떎. 긽떦닔쓽 醫낆뼇 듅씠 빆泥대뒗 빆泥대쭔쑝濡 븫꽭룷瑜 슚怨쇱쟻쑝濡 二쎌씠吏 紐삵븯湲 븣臾몄씠떎.

媛뺣젰븳 궡긽뒫젰쓣 媛吏 솕븰슂踰뺤젣 븫꽭룷뿉留 寃잜똿쓣 븯뒗 듅씠꽦쓣 媛吏 빆泥대 寃고빀떆궗 寃쎌슦 移섎즺슚怨쇰 넂씪 닔 엳떎. 씠윭븳 湲곕 씗留앹쑝濡 깂깮븳 寃껋씠 빆泥댁 솕븰슂踰뺤젣瑜 寃고빀떆궓 빆泥-빟臾 以묓빀泥(antibody-drug conjugate, ADC)씠떎(Hasan et al., 2018).

3. ADC 옉룞썝由

빆泥대뒗 빆썝뿉 븯뿬 寃고빀 移쒗솕젰怨 寃고빀 듅씠꽦쓣 媛吏怨 엳떎. 씠瑜 씠슜븯뿬 몴쟻쑝濡 젙솗븯寃 븞궡븯뒗 빆泥댁뿉 븫꽭룷 媛숈 몴쟻꽭룷瑜 뙆愿댄븷 닔 엳뒗 꽭룷룆꽦빟臾(cytotoxic drugs, payload)쓣 떒 寃껋씠 ADC씠떎. ADC瑜 留뚮뱾 븣뿉뒗 씠 몢 꽦遺꾩쓣 젒빀(conjugation)떆궎뒗 留곸빱(linker)源뚯 룷븿븯뿬 紐⑤몢 꽭 媛吏 슂냼媛 븘슂븯떎(Fig. 1) (Su and Zhang, 2021).

Fig. 1. The structure of antibody-drug conjugates. n = DAR (drugtoantibody ratio) (modified from Joubert et al., 2020).

ADC媛 옉룞븯젮硫 ADC媛 몴쟻꽭룷 궡濡 吏꾩엯븯뿬빞 븳떎. 븫꽭룷 媛숈 몴쟻꽭룷쓽 몴硫댁뿉 諛쒗쁽맂 듅젙 빆썝뿉 ADC쓽 빆泥닿 듅씠쟻쑝濡 寃고빀맂 떎쓬 꽭룷留됱쓽 겢씪듃由 뵾蹂 냼怨(clathrin-coated pit) 옉룞湲곗쟾쑝濡 몴쟻꽭룷 븞쑝濡 뱾뼱媛꾨떎.

꽭룷 궡濡 븿엯맂 ADC뒗 겢씪듃由곗뿉꽌 遺꾨━릺怨, 꽭룷 궡뿉꽌 떎瑜 냼룷泥(vesicles) 쑖빀맂 떎쓬, 뿏룄醫-由ъ냼醫(endosome-lysosome) 寃쎈줈瑜 뵲씪媛寃 맂떎. 뿏룄醫뿉 룄떖븳 떎쓬 씠怨녹쓽 듅씠쟻씤 醫낆뼇꽭룷 궡遺 솚寃쎌쓽 듅젙 슂냼뿉 쓽빐 빆泥댁뿉꽌 빟臾쇱씠 遺꾨━맂떎. 빆泥댁뿉꽌 뼥뼱졇 룆由쏀븳 옄쑀濡쒖슫 꽭룷룆꽦빟臾쇱 由ъ냼醫 留됱쓣 愿넻븯뿬 꽭룷吏덈줈 媛寃 맂떎. 솢꽦솕맂 빟臾쇱 二쇰뿉 엳뒗 옄湲 옄떊쓽 遺꾩옄 寃잛뿉 寃고빀븿쑝濡쒖뜥 빟由ы슚怨쇰 諛쒗쐶븯뿬 醫낆뼇꽭룷쓽 꽭룷二쇨린瑜 젙吏떆궎怨 꽭룷궗硫몄쓣 쑀룄븯뿬 븫꽭룷瑜 二쎌씠寃 맂떎(Hammood et al., 2021).

씠윭븳 솢룞 媛슫뜲뿉꽌 씪遺쓽 꽭룷룆꽦빟臾쇱 닔룞쟻쑝濡 솗궛릺嫄곕굹, 뒫룞쟻쑝濡 닔넚릺嫄곕굹, 샊 二쎌 꽭룷瑜 넻빐 꽭룷 諛뽰쑝濡 鍮좎졇굹媛寃 맂떎. 씠젃寃 二쇰쑝濡 띁吏 빟臾쇱씠 꽭룷留됱쑝濡 닾怨쇰릺硫 씤젒꽭룷뿉 뱾뼱媛 二쇰꽭룷룄 媛숈씠 二쎌씠뒗 二쇰꽭룷궡긽 옉슜씠 諛쒖깮븯湲곕룄 븳떎. 긽떦닔쓽 븫 듅씠쟻 빆썝 븫꽭룷쓽 몴硫댁뿉 젣븳쟻쑝濡 諛쒗쁽맂떎. 씠윭븳 寃쎌슦 ADC濡 異⑸텇븳 뼇쓽 꽭룷룆꽦빟臾쇱쓣 븫꽭룷 궡濡 쟾떖븯뒗 寃껋씠 돺吏 븡븘꽌 븞쑝濡 룆냼쓽 媛뺣룄瑜 넂씤떎. ADC뿉 寃고빀릺뒗 꽭룷룆꽦빟臾쇰줈뒗 씪諛섏쟻씤 빆븫젣蹂대떎 媛뺥븳 빟臾쇱씠 궗슜릺뿀떎(Kim, 2011; Bae, 2019).

4. US FDA뿉꽌 듅씤맂 ADC

理쒖큹濡 US FDA뿉꽌 듅씤맂 ADC뒗 Wyeth쓽 留덉씪濡쒗洹(Mylotarg®)씤뜲 2000뀈뿉 듅씤릺뿀떎. 留덉씪濡쒗洹몃뒗 2010뀈뿉 븞쟾꽦뿉 븳 슦젮濡 2010뀈 옄諛쒖쟻쑝濡 듅씤 泥좏쉶릺뿀떎媛 2017뀈뿉 옱듅씤 릺뿀떎. 吏궃 20뀈 媛 諛붿씠삤젣빟뾽怨꾧 ADC 媛쒕컻 遺꾩빞뿉 寃쏀뿕怨 湲곗닠쓣 異뺤쟻븯硫댁꽌, 洹 끂젰씠 깉濡쒖슫 ADC 젣뭹쓽 듅씤씠씪뒗 꽦怨쇰줈 굹굹怨 엳떎. 2019뀈 씠썑 떎뼇븳 ADC 移섎즺젣媛 以꾩뼱 誘멸뎅 FDA뿉꽌 듅씤릺怨 엳떎. Table 1 吏湲덇퉴吏 US FDA뿉꽌 떆뙋 듅씤맂 11媛吏 ADC 젣뭹쓣 醫낇빀븯뿬 蹂댁뿬以떎(Table 1). US FDA 듅씤쓣 쉷뱷븳 몴쟻씤 ADC瑜 꽭蹂꾨줈 굹늻뼱 궡렣蹂닿쿋떎.

US FDA-approved ADCs

Drug Maker Condition Trade name Target Approval year
Gemtuzumab ozogamicin Pfizer/Wyeth Relapsed acute myelogenous leukemia (AML) Mylotarg CD33 2017; 2000
Brentuximab vedotin Seattle Genetics, Millennium/Takeda Relapsed HL and relapsed sALCL Adcetris CD30 2011
Trastuzumab emtansine Genentech, Roche HER2-positive metastatic breast cancer (mBC) following treatment with trastuzumab and a maytansinoid Kadcyla HER2 2013
Inotuzumab ozogamicin Pfizer/Wyeth Relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia Besponsa CD22 2017
Moxetumomab pasudotox Astrazeneca Adults with relapsed or refractory hairy cell leukemia (HCL) Lumoxiti CD22 2018
Polatuzumab vedotin-piiq Genentech, Roche Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) Polivy CD79 2019
Enfortumab vedotin Astellas/Seattle Genetics Adult patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor, and a Pt-containing therapy Padcev Nectin-4 2019
Trastuzumab deruxtecan AstraZeneca/Daiichi Sankyo Adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens Enhertu HER2 2019
Sacituzumab govitecan Immunomedics Adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for patients with relapsed or refractory metastatic disease Trodelvy Trop-2 2020
Belantamab mafodotin-blmf GlaxoSmithKline (GSK) Adult patients with relapsed or refractory multiple myeloma Blenrep BCMA 2020
Loncastuximab tesirine-lpyl ADC Therapeutics Large B-cell lymphoma Zynlonta CD19 2021

Source: Biochempeg Worldwide PEG Supplier home page (https://www.biochempeg.com/article/74.html) (Biochempeg, 2021)



4-1. 1꽭 젅떒 留곸빱 ADC; 留덉씪濡쒗洹(Mylotarg®), 踰좎뒪룿궗(Besponsa®)

留덉씪濡쒗洹몃뒗 2000뀈뿉 湲됱꽦怨⑥닔援ъ꽦諛깊삁蹂(acute myeloid leukemia, AML)쓣 쟻쓳利앹쑝濡 듅씤릺뿀떎. 留덉씪濡쒗洹몃뒗 媛뺣젰븳 DNA 젅떒 빟臾쇱씤 calicheamicin쓣 룎뿰蹂씠 빆-CD33 떒씪겢濡좏빆泥댁씤 gemtuzumab뿉 븯씠뱶씪議 寃고빀(hydrazone bond)쓣 룷븿븯뒗 젅떒삎 留곸빱濡 寃고빀떆궓 寃껋씠떎. 씠 ADC뒗 빟臾 빆泥 鍮꾩쑉(drug-to-antibody ratio, DAR) 媛믪씠 룊洹 1.5씠硫, 50% 젙룄쓽 寃고빀릺吏 븡 빆泥댁 꽎씤 샎빀臾쇱씠떎. 꽭룷뿉 뱾뼱媛 썑 븯씠뱶씪議 寃고빀 뿏룄넑쓽 궛꽦 솚寃쎌뿉꽌 媛닔遺꾪빐릺뼱 calicheamicin쓽 쟾援ъ껜媛 諛⑹텧릺뒗뜲 湲猷⑦移섏삩뿉 쓽빐 솚썝릺뼱 옄쑀삎쓽 calicheamicin쑝濡 쟾솚맂떎. Calicheamicin DNA쓽 遺솃(minor groove)뿉 寃고빀븳 썑 怨좊룄쓽 솢꽦 옒뵒移(radical)쓣 留뚮뱺 썑 DNA 씠以묎떏쓣 젅떒븳떎. 씠濡좎쟻쑝濡 븯씠뱶씪議댁 삁瑜섏쓽 깮由ъ쟻 pH뿉꽌 븞젙쟻씠怨 꽭룷 궡옱솕 썑 醫낆뼇꽭룷쓽 궛꽦 솚寃쎌뿉꽌留 꽑깮쟻쑝濡 媛닔遺꾪빐 릺吏留, 떎젣濡쒕뒗 삁옣닚솚 以 誘몃━ 諛⑹텧릺뼱 떖븳 룆꽦쓣 蹂댁떎. 2017뀈뿉 옱듅씤맆 븣뿉뒗 슜웾쓣 궙異붽퀬 닾뿬 媛꾧꺽쓣 議곗젙븯떎(Joubert et al., 2020).

2017뀈뿉 솕씠옄쓽 踰좎뒪룿궗(Besponsa®)媛 湲됱꽦由쇳봽援ъ꽦諛깊삁蹂(Acute lymphocytic leukemia, ALL) 移섎즺 슜룄濡 듅씤릺뿀떎. 뿬湲곗뿉꽌룄 留덉씪濡쒗洹몄뿉꽌 궗슜맂 留곸빱 쑀궗븳 留곸빱媛 calicheamycin쓣 빆-CD22 IgG4, 떒씪겢濡좏빆泥댁뿉 뿰寃고븯뒗 뜲 궗슜릺뿀떎(Jabbour et al., 2021).

4-2. 2꽭 鍮꾩젅떒 留곸빱 ADC; 罹먯떥씪씪(Kadcyla®)

誘멸뎅 씠裕ㅻ끂젨(ImmunoGen)궗뒗 湲猷⑦移섏삩 媛먯쓳꽦 씠솴솕 寃고빀(disulfide bond)쓣 씠슜븯뿬 maytansine 쑀룄泥대 寃고빀떆궎뒗 留곸빱 媛쒕컻뿉 吏묒쨷븯떎. 븫꽭룷쓽 꽭룷吏덉뿉뒗 삁옣蹂대떎 湲猷⑦移섏삩쓽 냽룄媛 1,000諛 媛웾 뜑 넂븘꽌 넻젣맂 諛⑹텧쓣 湲곕븷 닔 엳湲 븣臾몄씠떎. 씠 怨쇱젙뿉꽌 젣꽙뀓(Genentech)怨 濡쒖뒋(Roche)뿉꽌 듅씤諛쏆 罹l떥씪씪쓽 媛쒕컻씠 씠猷⑥뼱議뚮떎. 罹l떥씪씪뿉꽌뒗 빆븫빟臾쇱씤 DM1 (Mertansine; Maytansinoid DM1)쓣 빆-HER2 떒겢濡좏빆泥댁쓽 씪씠떊 옍湲곗뿉 鍮꾩젅떒 留곸빱씤 heterobifunctional thioether 留곸빱濡 寃고빀떆耳곕뒗뜲, 꽭룷 궡옱솕 썑뿉留 빟臾쇱씠 슚냼쟻쑝濡 젅떒릺뿀쑝硫, HER2 뼇꽦 쑀諛⑹븫뿉 媛뺣젰븳 슚怨쇰 굹깉떎(Barginear et al., 2013).

씠 諛⑹떇쓽 ADC뒗 깮由ъ쟻 pH뿉꽌 쟾븯瑜 쓣怨 엳뼱꽌 二쇰꽭룷궡긽 옉슜씠 뾾뿀떎. 씠 鍮꾩젅떒 留곸빱뒗 빆썝쓣 蹂댁쑀븳 몴쟻꽭룷뿉留 꽑깮쟻쑝濡 옉슜븯怨 젙긽꽭룷뿉꽌뒗 룆꽦씠 젣븳쟻씠硫, 삁瑜섏뿉꽌 留곸빱뒗 젅떒릺吏 븡븯떎(Joubert et al., 2020).

4-3. 2꽭 젅떒 留곸빱 ADC: 븷뱶꽭듃由ъ뒪(Adcetris®), 뤃씪씠鍮(Polivy®), 뙣뱶꽭봽(Padcev®)

븳렪 떆뿉젣꽕떛뒪(Seattle Genetics)궗뒗 移섎즺빟臾쇰줈 dolastatin 쑀룄泥댁씤 MMAE (monomethyl auristatin E)瑜 꽑깮븯뿬 빆-CD30 떒씪겢濡좏빆泥댁쓽 떆뒪뀒씤 옍湲곗뿉 뿰寃곗떆궎뒗 留곸빱瑜 꽕怨꾪븯뿬 븷뱶꽭듃由ъ뒪瑜 媛쒕컻븯떎. 빆-CD30 떒겢濡좏빆泥댁쓽 씠솴솕 寃고빀쓣 遺遺꾩쟻쑝濡 솚썝떆궓 썑 젅떒 留곸빱씤 heterobifunctional maleimide 留곸빱(ValCit-PAB linker)뿉 寃고빀떆耳곕떎. 씠 留곸빱뒗 由ъ냼醫쓽 cathepsin B뿉 媛먯쓳꽦씤 valine-citrulline 렔떚뱶瑜 媛吏怨 엳뼱꽌 CD30-뼇꽦 븫꽭룷뿉 궡옱솕맂 썑 MMAE媛 諛⑹텧릺뼱 몴쟻 븫꽭룷瑜 궡긽븯寃 맂떎.

븷뱶꽭듃由ъ뒪뒗 2011뀈 뿭삎꽦꽭룷由쇳봽醫낃낵 샇吏궓由쇳봽醫낆쓣 쟻쓳利앹쑝濡 듅씤릺뿀떎. 留곸빱媛 젅떒맂 썑 諛⑹텧맂 MMAE뒗 몴쟻꽭룷瑜 뙆愿댄븯怨 꽭룷留됱쓣 넻怨쇳븯뿬 二쇰쓽 븫꽭룷룄 궡긽븯誘濡 鍮꾧퇏吏덉꽦 由쇳봽醫낅룄 移섎즺븯뒗 슚怨쇰 蹂댁떎(Katz et al., 2011).

씠 2꽭 留곸빱濡 빆븫빟臾 MMAE瑜 빆-CD79b 빆泥댁뿉 뿰寃고븳 寃껋씠 젣꽙뀓怨 濡쒖뒋뿉꽌 媛쒕컻븳 뤃씪씠鍮꾩씠떎. 뤃씪씠鍮꾨뒗 誘몃쭔꽦 겙 B꽭룷 由쇳봽醫 蹂묒슜移섎즺젣濡 2019뀈뿉 듅씤릺뿀떎. 뵆씪씠鍮꾩쓽 룊洹 DAR 媛믪 3.5씠떎(Deeks, 2019).

떆뿉젣꽕떛뒪 븘뒪뀛씪뒪(Astellas)뿉꽌 媛쒕컻븳 뙣뱶꽭봽뒗 媛숈 留곸빱瑜 궗슜븯뒗뜲, 醫낆쟾뿉 빆-PD1/PDL1 빆泥대줈 移섎즺瑜 諛쏆븯뜕 쟾씠꽦 슂濡쒖긽뵾꽭룷븫 솚옄瑜 쟻쓳긽쑝濡 븯뿬 2019뀈 듅씤릺뿀떎(McGregor and Sonpavde, 2019).

4-4. 3꽭 ADC; 듃濡쒕뜽鍮(Trodelvy®) 뿏뿀닾(Enhertu®), 釉붾젋젟(Blenrep®), 吏꾨줎(Zynlonta®)

理쒓렐 듅씤맂 깉濡쒖슫 3꽭 ADC뿉꽌뒗 媛쒖꽑맂 꽭룷룆꽦빟臾쇨낵 깉濡쒖슫 留곸빱媛 궗슜릺뿀떎.

씠裕ㅻ끂硫붾뵓뒪(Immunomedics)뒗 듃濡쒕뜽鍮(Trodelvy)瑜 媛쒕컻븯뒗뜲 빟媛 怨쇰컻쁽맂 몴쟻쓣 寃잜똿쓣 븯怨, 醫낆쟾쓽 MMAE굹 DM1怨 媛숈 빟臾쇰낫떎 뜑 룆꽦씠 빟븳 빟臾쇱쓣 梨꾪깮븯怨, 빟臾쇱씠 꽭룷 궡遺 諛 꽭룷 쇅遺뿉꽌 紐⑤몢 諛⑹텧씠 릺寃 븯떎. 2020뀈 US FDA뿉꽌 듅씤쓣 諛쏆 듃濡쒕뜽鍮(Trodelvy)뿉꽌뒗 빆-TROP2 떒씪겢濡좏빆泥댁뿉 꽭룷룆꽦빟臾쇰줈꽌 topoisomerase I 뼲젣젣씤 SN-38쓣 polyethylene glycol (PEG)濡 遺숈씤 젅떒삎 maleimide 留곸빱瑜 궗슜븯떎. 듃濡쒕뜽鍮꾨뒗 2踰 씠긽 移섎즺씠젰씠 엳뒗 옱諛쒖꽦, 궃移섏꽦 쟾씠 3以 쓬꽦 쑀諛⑹븫쓣 쟻쓳利앹쑝濡 듅씤릺뿀뒗뜲, 씠 遺꾩빞뒗 湲곗〈 移섎즺젣媛 뾾뒗 誘몄땐議깆쓽猷뚯닔슂 쁺뿭씠떎. 留곸빱뿉 PEG瑜 룄엯븯뿬 DAR쓣 7.6源뚯 삱졇떎(Goldenberg and Sharkey, 2020).

떎씠씠移섏궛荑(Daiichi Sankyo)뒗 뿏뿀닾(Enhertu)쓽 媛쒕컻뿉 SN-38蹂대떎 븫꽭룷뿉꽌 10諛 젙룄 솢꽦씠 넂 꽭룷룆꽦빟臾쇱씤 DXD (exatecan)瑜 궗슜븯떎. DXD뒗 슜빐꽦씠 醫뗪퀬 鍮꾧탳쟻 븞쟾븯硫 二쇰꽭룷궡긽슚怨쇨 넂븘꽌 鍮꾧퇏吏덉쥌뼇쓽 移섎즺뿉 씠젏씠 엳떎. 洹몃윭굹 삤봽寃 슚怨쇰 以꾩씪 닔 엳뒗 쐞븳 諛섍컧湲곕뒗 吏㏓떎. DXD뒗 빆-HER2 빆泥댁쓽 떆뒪뀒씤 옍湲곗뿉 maleimide 留곸빱濡 깮젒빀릺뿀뒗뜲 洹좎쭏 DAR 媛믪씠 8뿉 떖븳떎. 넂 DAR 媛믪뿉룄 遺덇뎄븯怨 DXD媛 삁옣뿉꽌 21씪 룞븞 떒 2.1%留 諛⑹텧릺뿀쓣 젙룄濡 븞젙꽦씠 넂떎(Ogitani et al., 2016). 뿏뿀닾뒗 2019뀈 US FDA뿉꽌 뿀媛瑜 諛쏆븯뒗뜲 긽 솚옄뒗 怨쇨굅 2踰 씠긽 HER2 몴쟻移섎즺瑜 諛쏆 쟾젰씠 엳뒗 젅젣 遺덇뒫븳 쟾씠꽦 Her2 뼇꽦 쑀諛⑹븫 꽦씤 솚옄씠떎(Keam, 2020).

湲씫냼뒪誘몄뒪겢씪씤(GlaxoSmithKline, GSK) 떎諛쒖꽦怨⑥닔醫 ADC 떊빟씤 釉붾젋젟(Blenrep)쓣 2020뀈 듅씤諛쏆븯떎. 釉붾젋젟 빆-B꽭룷꽦닕솕빆썝(B-cell maturation antigen, BCMA, CD38) 떒씪겢濡좏빆泥 ADC濡쒖꽌, 봽濡쒗뀒븘醫 뼲젣젣, 硫댁뿭議곗젅젣瑜 룷븿빐 理쒖냼 꽕 媛吏 씠긽쓽 移섎즺瑜 諛쏆 옱諛쒖꽦 삉뒗 遺덉쓳꽦 떎諛쒖꽦怨⑥닔醫 꽦씤 솚옄쓽 떒룆슂踰뺤쑝濡 듅씤諛쏆븯떎. 釉붾젋젟 쟾 꽭怨꾩뿉꽌 理쒖큹濡 듅씤맂 빆-BCMA 移섎즺젣씠떎. 釉붾옖젟 빟 4媛쒖쓽 MMAF 遺꾩옄瑜 빆-BCMA 떒씪겢濡좏빆泥댁쓽 떆뒪뀒씤 옍湲곗뿉 鍮꾩젅떒 protease-빆꽦 maleimidocaproyl 留곸빱瑜 씠슜븯뿬 젒빀떆耳 넃븯떎(Tai et al., 2014). 釉붾옖젟 뿬윭 媛吏 湲곗쟾쑝濡 븫꽭룷瑜 젣嫄고븯뒗뜲, MMAF쓽 궡긽슚怨쇱뿉 뜑븯뿬 빆泥 쓽議 꽭룷룆꽦, 빆泥 쓽議 떇꽭룷옉슜 벑씠 愿뿬븳떎(Markham, 2020).

誘멸뎅 깮紐낃났븰湲곗뾽 ADC 뀒씪벂떛뒪(ADC Therapeutics)뒗 빆-CD19 떒씪겢濡좏빆泥 ADC씤 吏꾨줎瑜 2021뀈 5썡뿉 듅씤諛쏆븯떎. 吏꾨줎뒗 몢 媛吏 씠긽쓽 쟾떊슂踰뺤쓣 諛쏆 꽦씤쓽 옱諛쒖꽦 삉 遺덉쓳꽦(r/r) 嫄곕 B꽭룷 由쇳봽醫낆쑝濡 쟻쓳利앹쓣 씤젙諛쏆븯떎. 씠 듅씤뿉뒗 떖由 紐낆떆릺吏 븡 誘몃쭔꽦 嫄곕 B꽭룷 由쇳봽醫, 벑湲 由쇳봽醫 諛 怨좊벑湲 B꽭룷 由쇳봽醫낆뿉꽌 諛쒖깮븳 誘몃쭔꽦 嫄곕 B꽭룷 由쇳봽醫낅룄 룷븿맂떎. 吏꾨줎뒗 꽭룷룆꽦빟臾쇰줈 pyrrolobenzodiazepine (PBD) 씠빀泥대 理쒖큹濡 梨꾪깮븯떎. 빟 2.3遺꾩옄쓽 PBD 씠빀泥닿 cathepsin B濡 젅떒릺뒗 諛쒕┛-븣씪땶 留곸빱濡 빆泥댁뿉 寃고빀릺뼱 엳떎. 빟臾쇱씠 諛⑹텧릺硫 DNA 遺솃뿉꽌 몢 媛떏 媛 援먯감寃고빀쓣 삎꽦븯뿬 몴쟻꽭룷瑜 二쎌씤떎(Dean et al., 2021; Mullard, 2021).

5. 꽭怨꾩쟻쑝濡 엫긽떆뿕 以묒씤 ADC 쁽솴

Daen 벑쓽 蹂닿퀬꽌뿉 쓽븯硫, 2021뀈 6썡 留 湲곗쑝濡 US FDA뿉꽌 듅씤맂 11媛 ADC 뭹紐⑹ (Table 1) 紐⑤몢 醫낆뼇怨 愿젴맂 쟻쓳利앹쑝濡 뿀媛릺뿀떎. 媛숈 떆젏뿉꽌 80媛 씠긽쓽 ADC 湲곕컲 移섎즺젣媛 떎뼇븳 醫낆뼇쓣 移섎즺븯湲 쐞븳 紐⑹쟻쑝濡 떒룆 샊 蹂묒슜쑝濡 엫긽떆뿕쓣 吏꾪뻾 以묒씠떎. 엫긽떆뿕 以묒씤 ADC 遺遺꾩 엫긽I긽, 샊 엫긽I/II 긽뿉 엳떎. 빟 80%뒗 怨좏삎醫낆뼇뿉 븯뿬 븞쟾꽦怨 슚젰떆뿕 떒怨꾩뿉 엳쑝硫, 굹癒몄뒗 삁븸븫怨 愿젴씠 엳떎. 洹쇰옒 뙣뱶꽭봽 듃濡쒕뜽鍮꾩 媛숈 ADC쓽 꽦怨듭쟻씤 媛쒕컻뿉 옒엯뼱, 쟾泥 ADC 엫긽떆뿕 以 怨좏삎븫뿉 븳 엫긽떆뿕쓽 鍮꾩쨷씠 젏李 而ㅼ뒗 寃쏀뼢씠 蹂댁씤떎(Dean et al., 2021).

쟾꽭怨꾩뿉꽌 吏꾪뻾릺怨 엳뒗 엫긽떆뿕쓣 珥앸쭩씪븯怨 엳뒗 誘멸뎅 'NIH쓽 ClinicalTrials.gov' site뿉꽌 2021뀈 8썡 15씪옄濡 'antibody drug conjugaté씪뒗 궎썙뱶濡 쁽옱떆젏뿉꽌 ADC 엫긽떆뿕 吏꾪뻾 쁽솴쓣 議곗궗븯떎. 寃깋議곌굔쑝濡쒕뒗 recruitment, eligibility criteria, study type, study results, study phase, fund type, study documents瑜 紐⑤몢 'all'濡 븯떎. 벑濡앸맂 ADC 愿젴 엫긽떆뿕쓽 珥 嫄댁닔뒗 316嫄댁쑝濡 굹궗뒗뜲, 80뿬媛 ADC 뭹紐⑹씠 뿬윭 吏뿭뿉꽌 뿬윭 媛吏 쟻쓳利앹쑝濡 以묐났븯뿬 吏꾪뻾릺怨 엳뒗 寃껋쑝濡 蹂댁씤떎. ADC 엫긽嫄댁닔瑜 'On map'쑝濡 吏뿭蹂꾨줈뒗 遺꾨쪟븯쓣 븣, 誘멸뎅 247嫄, 쑀읇 85嫄, 룞븘떆븘 61嫄, 罹먮굹떎 45嫄, 깭룊뼇 32嫄, 씪蹂 21嫄, 以묐룞 15嫄, 윭떆븘 14嫄 벑쑝濡 굹궗떎. 쟾넻쟻쑝濡 諛붿씠삤젣빟궛뾽씠 媛뺥븳 遺곷몄 쑀읇씠 ADC 엫긽떆뿕뿉꽌 以묒떖쟻씤 쐞移섎 李⑥븯怨 엳뿀떎. Table 2뒗 엫긽떆뿕 쟻쓳利(condition)쓣 以묒떖쑝濡 븯뒗 'topic'쑝濡 遺꾨쪟븯뿬, 吏덊솚 condition蹂 엫긽嫄댁닔뿉꽌 鍮덈룄媛 넂 寃껋쓣 異붿텧븳 寃껋씠떎. 遺遺꾩쓽 엫긽떆뿕 醫낆뼇뿉 븯뿬 떆뻾릺怨 엳쑝硫, 媛옣 몴쟻씤 엫긽 긽 吏덊솚쑝濡쒕뒗 쑀諛⑹떊깮臾 67嫄, 鍮꾨눊깮떇湲곗떊깮臾 48嫄, 샇吏궓蹂 46嫄, 룓떊깮臾 38嫄 벑씠뿀떎(ClinicalTrials.com, 2021).

Numbers of clinical trials of ADCs by clinical conditions (extracted from the data by ClinicalTrial.gov. as of Aug. 15th, 2021) (ClinicalTrial.gov., 2021)

Conditions Studies
Adenocarcinoma 26
Breast Neoplasms 67
Carcinoma Bronchogenic 19
Digestive System Neoplasms 24
Endocrine Gland Neoplasms 24
Gastrointestinal Neoplasms 24
Genital Neoplasms, Female 24
Genital Neoplasms, Male 13
Head and Neck Neoplasms 13
Hodgkin Disease 46
Kidney Neoplasms 14
Leukemia 33
Lung Neoplasms 38
Multiple Myeloma 20
Neuroectodermal Tumors 13
Ovarian Neoplasms 25
Pancreatic Neoplasms 10
Prostatic Neoplasms 15
Stomach Neoplasms 11
Thoracic Neoplasms 25
Urogenital Neoplasms 48

6. ADC 媛쒕컻뿉꽌 怨좊젮빐빞븷 슂냼뱾

ADC瑜 꽕怨꾪븷 븣뿉뒗 寃 醫낆뼇꽭룷뿉 븳 듅씠꽦쓣 媛뺥솕븯怨 삁옣뿉꽌쓽 븞젙꽦쓣 솗蹂댄븯뿬 젙긽꽭룷뿉 븳 룆꽦쓣 以꾩씠硫댁꽌 슚쑉쟻씤 빟臾쇱쓣 梨꾪깮븯뿬 醫낆뼇꽭룷 궡긽슚怨쇰 넂씠뒗 寃껋씠 以묒슂븯떎. 씠瑜 쐞빐꽌뒗 ADC쓽 湲곕낯쟻씤 援ъ“(Fig. 1)瑜 삎꽦븯뒗 빆泥, 꽭룷룆꽦빟臾, 씠瑜 젒빀떆궎뒗 留곸빱, 젒빀 諛⑸쾿 벑씠 紐⑤몢 以묒슂븳 怨좊젮슂냼媛 맂떎.

6-1. 몴쟻 빆썝(target antigens)

ADC뿉꽌 빆泥댁 몴쟻 빆썝쓽 긽샇옉슜 븞쟾꽦쓣 솗蹂댄븯怨 移섎즺슚怨쇰 뼸뒗뜲 以묒슂븯떎. 빆썝꽑깮쓽 몢 蹂닔뒗 醫낆뼇듅씠꽦怨 諛쒗쁽닔以씠떎. 씠긽쟻쑝濡쒕뒗 빆썝씠 醫낆뼇뿉꽌留 듅씠쟻쑝濡 諛쒗쁽릺怨, 젙긽꽭룷뿉꽌뒗 諛쒗쁽씠 뾾嫄곕굹 理쒖냼솕릺뒗 寃껋씠떎. 듅씠꽦 룆꽦쓣 以꾩씠뒗뜲 寃곗젙쟻씠硫 ADC쓽 꽦怨듭쓣 醫뚯슦븳떎. 븫 듅씠 빆썝 醫낆뼇꽭룷쓽 몴硫댁뿉꽌 몴硫 닔슜泥대줈 諛쒗쁽릺嫄곕굹 醫낆뼇삁愿怨꾪넻, 醫낆뼇誘몄꽭솚寃 궡遺뿉꽌 諛쒗쁽맂떎. 洹좎쭏 醫낆뼇뿉꽌泥섎읆 븫 듅씠 빆썝씠 醫낆뼇議곗쭅뿉꽌 洹좎쭏븯寃 諛쒗쁽릺뼱꽌 紐⑤뱺 븫꽭룷媛 빟臾쇱뿉 諛섏쓳븯硫 븫쓽 移섎즺媛 돩썙吏꾨떎. 鍮꾧퇏吏 醫낆뼇쓽 寃쎌슦 諛섏쓳쓣 븯吏 븡뒗 븫꽭룷媛 꽎뿬 엳뼱꽌 ADC 移섎즺 썑뿉룄 궡븘궓뒗 븫꽭룷媛 議댁옱븷 닔 엳떎. ADC媛 二쇰꽭룷궡긽슚怨쇰 媛吏怨 엳떎硫 씠윭븳 鍮꾧퇏吏 醫낆뼇쓽 臾몄젣瑜 洹밸났븷 닔 엳떎(Damelin et al., 2015).

ADC뿉 궗슜릺뒗 떒씪겢濡좏빆泥대줈뒗 IgG1, IgG2, IgG4媛 궗슜릺뒗뜲 씠以 IgG1씠 媛옣 留롮씠 궗슜맂떎. 쟾넻쟻씤 ADC뿉꽌뒗 삩쟾븳 쟾泥 겕湲곗쓽(full length) 빆썝씠 궗슜릺뿀떎. 씉닔 닾怨쇰 利앹쭊떆궎湲 쐞븳 쟾왂쑝濡 蹂대떎 옉 Fab, scFv, diabody瑜 떒씪겢濡좏빆泥 떊 궗슜븯뒗 寃껋씠 떆룄릺怨 엳吏留 븘吏곸 寃利앷낵 媛쒖꽑씠 븘슂븯떎(Li et al., 2019).

쁽옱 엫긽떆뿕 以묒씤 ADC 以묒뿉꽌 쎇뼱궃 떆옣꽦쑝濡 씤빐 留ㅻ젰쟻쑝濡 궗슜릺뒗 몴쟻 빆썝 HER2濡 븣젮졇 엳쑝硫 3媛쒖쓽 HER2 몴쟻 ADC媛 엫긽3긽 떒怨꾩뿉 엳떎(Dean et al., 2021).

醫낆뼇꽭룷뿉 궡遺솕맂 빆썝쓣 몴쟻쑝濡 궪뒗 寃껋 꽭룷 궡 湲곗쭏씠 뭾遺븳 怨좏삎醫낆뼇뿉꽌 돺吏 븡 씪씠떎. 씠윭븳 寃쎌슦 븫꽭룷蹂대떎 醫낆뼇誘몄꽭솚寃쎌쓣 몴쟻쑝濡 궪븘 젒洹쇳븳떎. 꽭룷 쇅 떒諛깆쭏씠굹 꽭룷 쇅 湲곗쭏쓽 궛꽦臾쇱쭏씠굹 湲猷⑦移섏삩怨 媛숈 꽦遺꾩쓣 씠슜븯뿬 꽭룷룆꽦빟臾쇱쓣 꽭룷 쇅뿉꽌 諛⑹텧븳떎(Joubert et al., 2020).

6-2. 꽭룷룆꽦빟臾(cytotoxic drugs, payloads)

빆泥대뒗 ADC쓽 슚怨쇰 寃곗젙븯뒗뜲 엳뼱꽌 以묒슂븳 援ъ꽦臾쇰줈 뿬寃⑥吏留 醫낆뼇꽭룷궡긽쓣 吏묓뻾븯뒗 寃껋 諛붾줈 꽭룷룆꽦빟臾쇱씠떎. 꽭룷룆꽦빟臾쇱 醫낆뼇꽭룷쓽 궡긽쓣 쑀룄븯뒗 遺꾩옄 빟臾(small molecule drugs)씠떎. ADC뿉 궗슜릺뒗 꽭룷룆꽦빟臾쇱 誘몄꽭냼愿 뙆愿 빟臾쇨낵 DNA 蹂삎 빟臾쇱씠 二쇱쥌쓣 씠猷щ떎. 誘몄꽭 냼愿씠 뙆愿대릺硫 꽭룷 遺꾩뿴 떒怨꾩뿉 엳뒗 꽭룷媛 궗硫명븳떎. DNA 蹂삎 젣젣뒗 꽭룷二쇨린 긽愿뾾씠 꽭룷瑜 二쎌씪 닔 엳떎. 洹쇰옒뿉 씠 떎瑜 媛쒕뀗쓽 꽭룷룆꽦빟臾쇰뱾룄 媛쒕컻릺뼱 궗슜릺怨 엳떎(Shin et al., 2018).

6-2-1. 誘몄꽭냼愿 뙆愿 빟臾(tubulin disrupter)

媛옣 留롮씠 궗슜릺뒗 誘몄꽭냼愿 뙆愿 빟臾(tubulin disrupter, antimitotic) auristatin 怨꾩뿴씠떎. Monomethyl auristatin E (MMAE, 씪紐 vedotin)씠씪 遺덈━뒗 꽭룷룆꽦빟臾쇱 媛뺣젰븳 誘몄꽭냼愿 以묓빀 뼲젣젣씠떎. 씠 빟臾쇱 븷뱶꽭듃由ъ뒪 뤃씪씠鍮꾧컳 ADC뿉꽌 dipeptide 留곸빱뿉 뿰寃곕릺뼱 cathepsin B 슚냼뿉 쓽빐 빆泥댁뿉꽌 젅떒릺뼱 諛⑹텧릺룄濡 怨좎븞릺뿀떎. 떎瑜 쑀룄泥댁씤 monomethyl auristatin F (MMAF)룄 誘몄꽭냼愿쓽 以묓빀쓣 뼲젣븯硫, 鍮꾨텇빐꽦 留곸빱뿉 寃고빀릺뼱 꽭룷 諛⑹텧씠 젣븳맂 삎깭濡 媛쒕컻릺뿀떎. MMAF뒗 釉붾젋젟뿉꽌 궗슜릺뿀떎. 떎瑜 誘몄꽭냼愿 뼲젣젣濡 maitansine씠 엳뒗뜲 뒠遺덈┛뿉 遺숈뼱꽌 誘몄꽭냼愿쓽 議곕┰쓣 뼲젣븳떎. Maitansine쓽 쑀룄泥대뒗 maytansinoid씪 遺덈━硫 DM1, DM2, DM4 벑씠 엳뒗뜲, 罹l떥씪씪뿉꽌뒗 DM1씠 궗슜릺뿀떎. 떎瑜 誘몄꽭냼愿 뼲젣젣濡쒕뒗 tubulysins, cryptomycins, antimitotic EG45 뼲젣젣 벑씠 뿰援щ릺怨 엳떎(Kostova et al., 2021).

6-2-2. DNA 蹂삎(DNA damaging) 빟臾

븫꽭룷뒗 鍮좊Ⅴ寃 遺꾩뿴븯誘濡 DNA 蹂삎(DNA damaging) 빟臾쇰룄 븫꽭룷 젣嫄곗뿉 슚怨쇱쟻씠떎. DNA 蹂삎 젣젣뒗 媛뺣젰븳 슚젰쓣 媛吏誘濡 ADC뿉 쟻슜븯硫 빟臾쇱쓽 遺옉슜쓣 以꾩씠怨 슚젰 넂씪 닔 엳떎. DNA 蹂삎 젣젣濡쒕뒗 calicheamicin, pyrrolobenzodiazepine (PBD), SN-38, DXD (exatecan 쑀룄泥), camptothecin (CPT)怨 洹 쑀룄泥 벑씠 엳떎.

Calicheamicin DNA 遺솃뿉 寃고빀븳 떎쓬 DNA 씠以묎떏쓣 옒씪궦떎. Calicheamicin 留덉씪濡쒗洹몄뿉꽌 궗슜릺뿀떎. PBD 씠웾泥대뒗 DNA 遺솃뿉 寃고빀븯뿬 援먯감 怨듭쑀寃고빀쓣 留뚮뱾뼱 DNA쓽 蹂듭젣瑜 뼲젣븯뿬 븫꽭룷瑜 궗硫몄떆궓떎. PDB뒗 쁽옱 엫긽떆뿕뿉 留롮씠 쟻슜릺怨 엳쑝硫, 2021뀈뿉 듅씤맂 吏꾨줎뿉 궗슜릺뿀떎.

6-2-3. 湲고 꽭룷룆꽦(cytotoxic) 빟臾

SN-38 DNA 씠냼癒몃씪젣 I (DNA topoisomerase I)쓣 빐븯뿬 꽭룷遺꾩뿴쓣 留됰뒗떎. 湲곗〈뿉 궗슜맂 빟臾쇱뿉 鍮꾪븯뿬 슚젰씠 궙븘꽌 遺옉슜씠 쟻쑝硫 DAR쓣 넂뿬꽌 ADC쓽 遺옉슜 鍮 슚젰쓣 넂씠뒗뜲 궗슜맆 닔 엳떎. SN-38 듃濡쒕뜽鍮꾩뿉 궗슜릺뿀떎. DXD뒗 SN-38蹂대떎 븫꽭룷뿉꽌 10諛 젙룄 솢꽦씠 넂 DNA 씠냼癒몃씪젣 I 뼲젣젣濡쒖꽌 뿏뿀닾뿉 궗슜릺뿀떎(Kostova et al., 2021).

쁽옱 엫긽떆뿕 以묒씤 씪遺 ADC뒗 꽭룷룆꽦빟臾쇰줈 toll-like receptor 7/8 (TLR 7/8) 옉슜빟(agonist)쓣 궗슜븳떎. TLR 7/8씠 옄洹밸릺硫 씤꽣럹濡좉낵 떎瑜 궗씠넗移댁씤씠 留롮씠 깮궛릺뼱꽌, 寃곌낵쟻쑝濡 옄뿰궡긽꽭룷 꽭룷룆꽦T꽭룷媛 솢꽦솕릺뼱 븫꽭룷瑜 뙆愿댄븳떎(Frega et al., 2020).

떎瑜 꽭룷룆꽦빟臾쇰줈뒗 RNA polymerase II 뼲젣젣씤 amatoxin 쑀룄泥댁씤 amanitin 醫낅쪟媛 엳떎. 쁽옱 엫긽떆뿕 以묒씤 ADC뿉꽌 궗슜릺怨 엳뒗뜲, 씠 빟臾쇱 쟾궗怨쇱젙쓣 뼲젣븯뿬 떒諛깆쭏 빀꽦쓣 留됯퀬 꽭룷궗硫몄쓣 쑀룄븳떎(Figueroa-Vazquez et al., 2021).

꽭룷옄硫몄궗(apoptsis) 寃쎈줈瑜 寃잜똿븯뿬 꽭룷궗硫몄쓣 쑀룄븯뒗 寃껊룄 醫뗭 븫移섎즺踰뺤씠 맂떎. BCL-2 뙣諛由 떒諛깆쭏 誘명넗肄섎뱶由ъ븘 以묒옱꽦 꽭룷옄硫몄궗뿉 以묒떖쟻씤 뿭븷쓣 븳떎. 씠以 anti-apoptotic 떒諛깆쭏씤 BCL-2, BCL-XL, MCL-1 옒 븣젮吏 빆븫 寃잛씠떎. BCL-XL쓣 寃잛쑝濡 븯뒗 빟臾쇱씠 ADC뿉 쟻슜릺뼱 엫긽떆뿕씠 吏꾪뻾 以묒씠떎(Zhang et al., 2020).

6-3. 留곸빱(linkers)

留곸빱뒗 ADC뿉꽌 빆泥댁 빟臾쇱쓣 寃고빀떆궓떎. 諛붾엺吏곹븳 留곸빱뒗 삁瑜섏뿉꽌뒗 븞젙쟻硫댁꽌 몴쟻 븫꽭룷뿉꽌뒗 빟臾쇱쓣 쟻젅엳 諛⑹텧븯뿬 빟臾쇱쓣 몴쟻뿉 븞쟾븯寃 쟾떖븯뒗 寃껋씠떎. ADC 뵆옯뤌쓽 媛쒕컻뿉꽌 留곸빱뒗 以묒슂븳 뿭븷쓣 븳떎. 留곸빱濡 빟臾쇱쓣 빆泥댁뿉 寃고빀븷 븣, 빟臾쇱씠 빆泥댁쓽 援ъ“쟻 븞젙꽦怨 湲곗쭏 寃고빀듅꽦怨 빟臾쇰룞깭뿉 쁺뼢쓣 二쇱 븡븘빞 븳떎. 珥덉갹湲 ADC 빟臾쇱씠 떎뙣븳 썝씤 以묒쓽 븯굹뒗 빟臾쇱쓽 議곌린 諛⑹텧濡 븣젮졇 엳떎. 깉濡쒖슫 留곸빱뱾씠 媛쒕컻릺硫댁꽌 떊洹 ADC 젣젣뒗 怨쇨굅뿉 鍮꾪빐 븞쟾븯怨 빟슚룄 넂떎.

쁽옱 엫긽떆뿕 以묒씤 긽떦닔쓽 ADC뒗 hydrazone, disulfide, peptide 삉뒗 thioether 寃고빀 벑 솕븰쟻 留곸빱瑜 梨꾪깮븯怨 엳떎. 留곸빱뿉꽌 빟臾쇱쓣 諛⑹텧븯뒗 怨쇱젙 븫꽭룷 궡쓽 듅젙븳 pH굹 슚냼 냽룄 벑쓽 李⑥씠瑜 씠슜븳떎. 蹂댄넻 hydrazone怨 disulfide 留곸빱뒗 삁옣 궡뿉꽌 븞젙꽦씠 젣븳릺뼱 엳떎. 諛섎㈃ 렔씠뱶 湲곕컲쓽 留곸빱뒗 삁옣 궡 븞젙꽦씠 슦닔븯怨 빟臾 諛⑹텧 議곗젅룄 슜씠븯떎(Shin et al., 2018).

씪遺 솕븰쟻 留곸빱뒗 빆泥댁 빟臾쇱쓽 냼닔꽦(hydrophobicity)쓽 洹좏삎쓣 議곗젅븯뿬 移쒖닔꽦 솚寃쎌씤 삁瑜 궡뿉꽌 ADC쓽 쓳吏묒쓣 諛⑹븳떎. 移쒖닔꽦 留곸빱 뒪럹씠꽌(spacer)뿉뒗 cyclodextrin, polyethylene glycol (PEG) 삉뒗 떎瑜 以묓빀泥닿 엳뒗뜲, 삁瑜 궡쓽 븞젙꽦怨 빟臾쇰룞젰븰쟻 듅꽦뿉 뿭븷쓣 븳떎.

ADC뿉 궗슜맂 留곸빱뒗 젅떒뒫젰뿉 뵲씪 鍮꾩젅떒꽦怨 젅떒꽦쑝濡 굹늻뼱吏꾨떎.

6-3-1. 鍮꾩젅떒삎 留곸빱(non-cleavable linkers)

鍮꾩젅떒꽦 留곸빱뒗 긽쟻쑝濡 넂 삁옣 븞젙꽦쓣 媛吏怨 엳쑝硫 떒諛깆쭏遺꾪빐뿉 빆쟻씠떎. 꽭룷 궡뿉 룄엯맂 썑 빆泥닿 遺꾪빐릺뼱빞 빟臾쇱씠 留곸빱 蹂듯빀泥 삎깭濡 諛⑹텧릺뒗뜲 씠 蹂듯빀泥닿 빟臾쇳솢꽦쓣 媛吏꾨떎. Thioether 留곸빱뒗 몴쟻씤 鍮꾩젅떒삎 留곸빱씤뜲, 떒씪겢濡좏빆泥닿 꽭룷 궡뿉꽌 鍮꾩꽑깮쟻쑝濡 遺꾪빐맂 썑뿉 빟臾쇱씠 씠깉븯뿬 諛⑹텧릺룄濡 븳떎. 罹먯떥씪씪(Kadcyla®)媛 鍮꾩젅떒삎 諛⑹떇쓣 梨꾪깮븯怨 엳떎.

6-3-2. 젅떒삎 留곸빱(cleavable linkers)

젅떒삎 留곸빱뒗 듅젙 솚寃쎌슂냼뿉 諛섏쓳븯뿬 젅떒릺뼱 빟臾쇱쓣 꽭룷吏덈줈 諛⑹텧븳떎. 젅떒삎뿉뒗 슚냼 젅떒삎怨 鍮꾪슚냼 젅떒삎씠 엳떎.

슚냼 젅떒삎 cathepsin B, β-glucuronidase, phosphatase, pyrophosphatase, sulfatase 媛숈 슚냼뿉 쓽빐 젅떒맂떎. Peptide 留곸빱뒗 떒諛깆쭏 遺꾪빐슚냼뿉 쓽빐 遺꾪빐릺硫, 삁옣 궡뿉꽌뒗 떒諛깆쭏 遺꾪빐슚냼 뼲젣젣媛 議댁옱븯뿬 삁옣 븞젙꽦씠 넂떎. ADC뿉 씠슜릺뒗 떒諛깆쭏 遺꾪빐슚냼濡쒕뒗 cathepsin B媛 몴쟻씠떎. Cathepsin B뒗 醫낆뼇議곗쭅뿉꽌 넂 닔以쑝濡 議댁옱븯뿬 ADC뿉寃 醫낆뼇 꽑깮꽦쓣 以떎. Peptide 留곸빱뒗 二쇰줈 븘誘몃끂궛 몢 媛쒕 遺숈씤 dipeptide濡 媛쒕컻릺怨 엳쑝硫 븷뱶꽭듃由ъ뒪(Adcetris®)뿉 쟻슜릺뿀떎. β-glucuronide 留곸빱뒗 由ъ냼醫 궡뿉 議댁옱븯뒗 떦遺꾪빐슚냼씤 β-glucuronidase뿉 쓽빐 遺꾪빐맂떎. β-glucuronidase뒗 씪遺 醫낆뼇꽭룷뿉꽌 怨쇰컻쁽릺뼱 醫낆뼇 듅씠꽦쓣 以떎.

鍮꾪슚냼 젅떒삎뿉뒗 궛 遺덉븞젙 留곸빱(acid-labile linker) 궛솕솚썝諛섏쓳 留곸빱(oxidation-reduction reaction linker)媛 엳떎. 궛 遺덉븞젙 留곸빱뒗 珥덉갹湲곗뿉 媛쒕컻맂 븞젙꽦씠 鍮꾧탳쟻 궙 留곸빱씠吏留 븘吏곷룄 궗슜릺怨 엳떎. 몴쟻씤 寃껋씠 hydrazone 留곸빱濡 醫낆뼇꽭룷뿉 궡옱솕 맂 썑 뿏룄醫, 由ъ냼醫쓽 빟궛꽦 솚寃쎌뿉꽌 媛닔遺꾪빐 릺뼱 빟臾쇱쓣 諛⑹텧븳떎. 궛솕솕썝諛섏쓳 留곸빱뒗 disulfide 留곸빱媛 몴쟻씠떎. 궡옱솕 맂 썑 씠솴솕 援먰솚씠굹 glutathione怨 媛숈 솚썝젣뿉 쓽빐 留곸빱媛 遺꾪빐릺硫댁꽌 꽭룷룆꽦빟臾쇱쓣 諛⑹텧븳떎. Glutathione 궛냼긽깭씤 醫낆뼇꽭룷뿉꽌뒗 젙긽꽭룷蹂대떎 빟 1,000諛 젙룄 냽룄媛 넂븘꽌 ADC뿉 醫낆뼇꽭룷 꽑깮꽦쓣 遺뿬븳떎(Hong et al., 2021; Kostova et al., 2021).

6-4. 젒빀 諛⑸쾿(conjugation methods)

吏湲덇퉴吏 異쒖떆맂 ADC뱾 遺덇퇏吏덊븳 샎빀臾쇰뱾濡쒖꽌 빆泥 쐞뿉꽌 빟臾쇱쓽 寃고빀쐞移섍 뿬윭 援곕뜲씠怨 寃고빀맂 빟臾쇱쓽 닔룄 遺덇퇋移숉븯떎. 빟臾-留곸빱 蹂듯빀泥닿 빆泥댁뿉 젒빀릺뒗 쐞移섎뒗 빟臾쇱쓽 븞젙꽦怨 빟臾쇰룞깭븰-빟臾쇰룞젰븰쟻 듅꽦뿉 쁺빆쓣 以떎. ADC 젣議곌낵젙뿉꽌 빟臾쇱씠 빆泥댁뿉 遺숇뒗 鍮꾩쑉씤 DAR쓣 넻젣븯湲 뼱젮썱뿀떎. DAR씠 넂쑝硫 삁옣뿉꽌 泥냼(clearance)媛 鍮⑤씪吏怨, DAR씠 궙쑝硫 移섎즺슚怨쇨 궙븯떎. 삉븳 DAR씠 遺덇퇏吏덊븯寃 꽎뿬 엳뒗 ADC뿉꽌뒗 닾뿬 썑뿉 DAR씠 궙 빆泥닿 DAR씠 넂 빆泥댁 寃쎌웳븯뿬 ADC쓽 슚怨쇰 媛먯냼떆耳곕떎. 씠윭븳 臾몄젣瑜 빐寃고븯湲 쐞븯뿬 쐞移섑듅씠쟻씤 寃고빀 諛⑸쾿씠 媛쒕컻릺뿀떎. 쐞移섑듅씠씤 諛⑸쾿뿉꽌뒗 ADC쓽 援ъ“ 洹좎쭏꽦쓣 쑀吏븯硫댁꽌, 빟臾쇱쓣 빆泥댁쓽 듅젙븳 쐞移섏뿉 꽑깮쟻쑝濡 寃고빀떆궎怨, 寃고빀릺뒗 빟臾쇱쓽 닔瑜 뾼寃⑺븯寃 議곗젅븷 닔 엳寃 븳떎. 쐞移섑듅씠쟻씤 寃고빀 諛⑸쾿뿉뒗 겕寃 옄뿰쟻씤 빆泥(native antibody)瑜 궗슜븯뒗 諛⑸쾿怨 怨듯븰쟻쑝濡 媛쒕웾맂 빆泥(engineered antibodies)瑜 궗슜븯뒗 몢 媛吏 諛⑸쾿씠 엳떎.

6-4-1. 옄뿰쟻씤 빆泥(native antibody)瑜 닔떇븯뿬 쐞移섑듅씠쟻쑝濡 깮젒빀(bioconjugation) 븯뒗 諛⑸쾿

옄뿰쟻씤 빆泥대 궗슜븯뒗 寃껋 씤怨 빆泥대 留뚮뱾 븣 깮湲곕뒗 蹂듭옟븳 룎뿰蹂씠 빆泥 꽑蹂꾧낵젙씠굹 諛곗뼇 理쒖쟻솕 怨쇱젙쓣 뵾븷 닔 엳뼱꽌 렪由ы븳 諛⑸쾿씠떎. 빆泥댁뿉 궡옱쟻씤(endogenous) 씪씠떊, 엳뒪떚뵖, 떚濡쒖떊, 떆뒪뀒씤 옍湲 벑뿉 젒빀떆궓떎. 2021뀈源뚯 듅씤맂 紐⑤뱺 ADC뒗 씠 궡옱쟻씤 븘誘몃끂궛 옍湲곕 젒빀뿉 궗슜븯떎. 踰덉뿭썑媛怨듦낵젙뿉꽌 Fc 吏뿭뿉 湲由ъ뭏(glycan)쓣 궫엯븳(incorporated) 옄뿰쟻씤 빆泥대룄 궗슜릺뿀떎. IgG뒗 썝옒 떦떒諛깆쭏씠誘濡 媛 以묒뇙쓽 N-297踰 쐞移섏뿉 N-glycan씠 議댁옱븳떎. 씠 湲由ъ퐫떎(glycosyl) 옄由ъ뿉 留곸빱-빟臾 蹂듯빀泥대 젒빀떆궗 닔 엳떎(Zhou, 2017).

쟾넻쟻씤 諛⑸쾿뿉꽌뒗 빆泥댁쓽 씪씠떊 옍湲곗 떆뒪뀒씤 옍湲곗뿉 빟臾쇱쓣 寃고빀떆耳곕떎. 빆泥댁뿉뒗 씪씠떊 옍湲곌 뿬윭 援곕뜲뿉 留롮씠 엳뼱꽌 씪씠떊쓣 벐뒗 諛⑸쾿 遺덇퇏吏덉꽦(heterogeneity)쓣 뵾븯湲 뼱젮썱떎. 理쒓렐 遺遺쓽 ADC뒗 씠솴솕 寃고빀 떆뒪뀒씤 씤꽣泥댁씤(interchain disufide cysteine)쓣 젒빀紐⑹쟻쑝濡 궗슜븳떎. 떆뒪뀒씤 젒빀쓽 寃쎌슦 빆泥 궡뿉 떆뒪뀒씤쓽 닽옄媛 쟻뼱꽌 洹좎쭏꽦씠 醫뗭븘吏 肉먮쭔 븘땲씪 DAR쓽 議곗젅룄 슜씠븯寃 븯떎(Dean, 2021). 씪씠떊怨 엳뒪떚뵖 옍湲곗쓽 寃쎌슦 遺덇퇏吏덉꽦 臾몄젣瑜 洹밸났븯湲 쐞븯뿬 솕븰쟻씤 諛⑸쾿쑝濡 빆泥댁뿉꽌 듅젙븳 븯굹쓽 씪씠떊 옍湲곕굹 엳뒪떚뵖 옍湲곕쭔쓣 닔떇븯뿬 쐞移섑듅씠꽦쓣 솗蹂댄븯뒗 諛⑸쾿룄 媛쒕컻릺뿀떎(Kostova et al., 2021).

6-4-2. 怨듯븰쟻쑝濡 媛怨듬맂 빆泥(engineered antibody)瑜 궗슜븯뿬 쐞移섑듅씠쟻쑝濡 깮寃고빀(bioconjugation) 븯뒗 諛⑸쾿

怨듯븰쟻 빆泥대뒗 DAR쓣 떎猷④린媛 슜씠븯뿬 씠 諛⑸쾿쑝濡 븯硫 蹂대떎 洹좎쭏븳 ADC瑜 留뚮뱾湲 돺떎. 옄뿰쟻씤 샊 씤怨듭쟻씤 븘誘몃끂궛 옍湲곕 빆泥댁쓽 듅젙 쐞移섏뿉 꽔뼱꽌 빟臾쇰룞깭븰-빟臾쇰룞젰븰쟻 듅꽦쓣 醫뗪쾶 븷 닔 엳떎.

癒쇱 슚냼쟻씤 諛⑸쾿씠 엳뒗뜲, 빆泥댁뿉 쑀쟾怨듯븰쟻쑝濡 궫엯븳 븘誘몃끂궛 tag瑜 씠슜븯뿬 빟臾쇱쓣 怨좊룄濡 꽑깮쟻쑝濡 젒빀떆궗 닔 엳떎. 씠 tag뒗 formylglycine-generating enzyme (FGE), microbial transglutaminase (MTG), sortase, 샊 tyrosinase 媛숈 슚냼媛 듅씠쟻쑝濡 씤떇븯뿬 쐞移섑듅씠쟻씤 젒빀쓣 媛뒫븯寃 븳떎. SMARTag®씠씪 遺덈━뒗 諛⑸쾿뿉꽌뒗 쐞移섑듅씠쟻씤 젒빀쓣 쐞븯뿬 aldehyde tag瑜 遺숈떎. 떒씪겢濡좏빆泥댁쓽 듅젙 遺쐞뿉 엳뒗 떆뒪뀒씤뿉 aldhyde씤 formylglycine쓣 遺숈뿬꽌 씠怨녹뿉 젒빀쓣 븯룄濡 븳떎(Jain et al., 2015).

몢 踰덉㎏濡쒕뒗 떆뒪뀒씤 怨듯븰쟻씤 諛⑸쾿씠 엳뒗뜲, Thiomab® 湲곗닠 씠솴솕 寃고빀뿉 李몄뿬븯吏 븡 怨듯븰쟻쑝濡 궫엯맂 떆뒪뀒씤쓣 씠슜븯뿬 쐞移섑듅씠쟻쑝濡 寃고빀븯뿬 洹좎쭏꽦쓣 솗蹂댄빐以떎. Tiomab® 湲곗닠 빆-MUC16 떒씪겢濡좏빆泥댁뿉꽌 泥섏쓬 蹂닿퀬릺뿀뒗뜲 以묒뇙쓽 116踰 븣씪땶쓣 떆뒪뀒씤 옍湲곕줈 쑀쟾怨듯븰쟻씤 諛⑸쾿쑝濡 移섑솚븯떎(Junutula et al., 2008).

삉 떎瑜 諛⑸쾿 鍮꾩젙洹 븘誘몃끂궛쓣 빆泥댁뿉 꽔뼱 쐞移 듅씠쟻씤 젒빀쓣 븯寃 븯뒗 寃껋씠떎. 씠븣 궫엯릺뒗 씤怨 븘誘몃끂궛 빟臾-留곸빱 샎빀泥닿 꽑깮쟻쑝濡 젒빀씠 릺룄濡 룆듅븳 솕븰 援ъ“瑜 媛吏 寃껋쑝濡 븳떎. 鍮꾩젙洹 씤怨 븘誘몃끂궛 硫댁뿭썝꽦쓣 씪쑝궗 닔룄 엳뼱꽌 쑀쓽빐빞 븯뒗뜲, lysine쓽 cyclopropene 쑀룄泥, selenocysteine怨 媛숈 寃껊뱾씠 궗슜릺뿀떎(Kostova, 2021).

6-5. 빟臾 빆泥 鍮꾩쑉(drug-to-antibody ratio, DAR)

빟臾쇳빆泥 鍮꾩쑉씤 DAR ADC 媛쒕컻뿉꽌 빟臾쇰룞깭븰쟻 듅꽦怨 깮泥 궡 遺꾪룷瑜 寃곗젙븯뒗 留ㅼ슦 以묒슂븳 듅꽦씠떎. DAR씠 넂쓣 ADC 씪닔濡 in vitro 떆뿕뿉꽌뒗 슚뒫씠 넂寃 굹솕떎. 洹몃윭굹 젙옉 넂 DAR쓣 媛吏 ADC媛 湲곕 떖由 깮泥 궡 슚뒫씠 궙寃 굹삤뒗뜲, 洹 씠쑀뒗 寃고빀맂 빟臾쇱씠 留롮 ADC 씪닔濡 삁옣 泥냼쑉씠 넂湲 븣臾몄씤 寃껋쑝濡 異붿젙릺뿀떎. 씠뿉 뵲씪 븳룞븞 ADC 젣젣쓽 DAR 2~4 젙룄濡 留욎텛뼱 솕떎.

냼닔꽦(hydrophobicity)쑝濡 씤븳 臾몄젣룄 議댁옱븳떎. 二쇰줈 궗슜릺뒗 긽떦닔쓽 꽭룷룆꽦빟臾쇨낵 留곸빱媛 냼닔꽦씠떎. 씠 븣臾몄뿉 ADC媛 쓳吏묓븯嫄곕굹, 몴쟻 빆썝뿉 븳 移쒗솕젰쓣 긽떎븯嫄곕굹, 삁옣 泥냼쑉씠 넂븘吏뒗 벑쓽 臾몄젣媛 諛쒖깮븳떎. Sulfonate 샊 polyethylene glycol (PEG)쓣 븿쑀븳 移쒖닔꽦 留곸빱뒗 냼닔꽦 留곸빱濡 씤븳 臾몄젣젏쓣 빐寃고빐以떎. PEG 留곸빱뒗 닔슜꽦씠硫, 룆꽦씠 궙怨 삉븳 硫댁뿭썝꽦씠 궙 옣젏씠 엳떎.

DAR씠 4 젙룄媛 理쒖쟻씠씪怨 삤옯룞븞 깮媛곹빐솕뿀뒗뜲 궗떎 씠뒗 MMAE굹 DM1쓣 빟臾쇰줈 벐뒗 2꽭 留곸빱뿉 빐떦릺뒗 寃쎌슦씠硫 3꽭 留곸빱뿉꽌뒗 DAR씠 넂 寃껋씠 뜑 醫뗫떎怨 븳떎(Joubert et al., 2020; Shin et al., 2018). 洹쇰옒뿉 듅씤맂 ADC뒗 DAR 媛믪씠 嫄곗쓽 8뿉 떖븯뒗 寃껋씠 留롮쑝硫, 쁽옱 엫긽떆뿕 以묒씤 떊洹 ADC뱾 DAR 媛믪씠 1뿉꽌 15源뚯 떎뼇븯떎怨 븳떎(Dean et al., 2021).

7. 湲濡쒕쾶 鍮낇뙆留 諛붿씠삤젣빟궗쓽 ADC 吏꾩텧 쁽솴

젣빟뾽醫 떆옣議곗궗遺꾩꽍湲곌씤 씠諛몃쪟뿉씠듃뙆留(Evaluate Pharma)뿉 뵲瑜대㈃, 湲濡쒕쾶 ADC 移섎즺젣 떆옣 洹쒕え뒗 2019뀈 27뼲떖윭뿉꽌 2026뀈 248뼲떖윭濡 꽦옣븷 寃껋쑝濡 쟾留앸맂떎. 뿰룊洹 37%濡 꽦옣쓣 븯뿬 7뀈 留뚯뿉 떆옣 洹쒕え媛 臾대젮 9諛 씠긽쑝濡 뙺李쏀븷 쟾留앹씠떎(Evaluate pharma, 2020).

ADC 떊빟씠 US FDA뿉꽌 뿰씠뼱 듅씤릺怨 엳怨, ADC쓽 誘몃옒 쟾留앹씠 븳痢 諛앹븘吏옄 湲濡쒕쾶 젣빟궗뱾씠 ADC 移섎즺젣 媛쒕컻뿉 寃쎌웳쟻쑝濡 吏꾩텧븯怨 엳떎. 꽭怨꾩쟻씤 嫄곕젣빟궗뱾 ADC瑜 媛쒕컻븯뒗 젣빟쉶궗굹 ADC뿉 듅솕릺뼱 엳뒗 諛붿씠삤湲곗뾽뿉 닾옄븯嫄곕굹 씠瑜 씤닔븯뒗 쟾왂쟻씤 젣쑕 愿怨꾨 留븐뼱꽌 ADC 떆옣뿉 吏꾩엯븯怨 엳떎. 理쒓렐뿉 씪뼱궃 ADC 愿젴맂 鍮낅뵜 떎쓬怨 媛숇떎.

2020뀈 7썡 쁺援 븘뒪듃씪젣꽕移(AstraZeneca plc)媛 씪蹂 떎씠씠李뚯궛荑(Daichi Sankyo)쓽 ADC 썑蹂대Ъ吏덉씤 DS-162뿉 빐 珥 60뼲떖윭 洹쒕え쓽 怨듬룞 媛쒕컻 怨꾩빟쓣 泥닿껐뻽떎. DS-162뒗 Trop-2뿉 듅씠쟻씤 빆泥댁뿉 빟臾쇱쓣 寃고빀븳 ADC씠硫 誘몄씪 뼇援뿉꽌 鍮꾩냼꽭룷븫怨 쑀諛⑹븫뿉 븯뿬 엫긽떆뿕쓣 吏꾪뻾 以묒씠떎(Yoo, 2020).

2020뀈 9썡 誘멸뎅 젣빟궗 湲몃━뼱뱶 궗씠뼵뒪(Gilead Sciences)뒗 誘멸뎅쓽 諛붿씠삤湲곗뾽 씠裕ㅻ끂硫붾뵓뒪(Immunomedics)瑜 빟 210뼲떖윭뿉 씤닔븯떎. 湲몃━뼱뱶뒗 씠瑜 넻빐 씠裕ㅻ끂硫붾뵓뒪쓽 ADC 移섎즺젣瑜 蹂댁쑀븯寃 릺뼱 諛붿씠삤쓽빟뭹 떆옣쓽 吏諛곕젰쓣 넂떎. 븵꽌 씠裕ㅻ끂硫붾뵓뒪(Immunomedics)뒗 2020뀈 4썡 US FDA뿉꽌 듃濡쒕뜽鍮꾨 쑀諛⑹븫 移섎즺젣濡 듅씤諛쏆븯떎(Jang, 2020).

2020뀈 9썡 誘멸뎅 MSD (Merck Sharp & Dohme)뒗 誘멸뎅 떆븷 젣꽕떛뒪(Seattle Genetics) ADC 쑀諛⑹븫 移섎즺젣瑜 怨듬룞 媛쒕컻븳떎怨 諛쒗몴뻽떎. MSD媛 떆븷 젣꽕떛뒪뿉 怨꾩빟湲덉쑝濡 6뼲떖윭, 떒怨꾨퀎濡 湲곗닠猷뚮줈 理쒕 26뼲떖윭瑜 吏湲됲븯뒗 怨꾩빟씠떎. 蹂꾨룄濡 10뼲떖윭 긽떦쓽 吏遺꾪닾옄룄 룷븿릺뼱 珥 42뼲떖윭뿉 떖븯뒗 洹쒕え 닾옄씠떎. 몢 쉶궗뒗 쑀諛⑹븫怨 湲고 醫낆뼇 몢 媛吏뿉 빐 엫긽 2긽쓣 떒怨꾩씤 ADC 移섎즺 썑蹂대Ъ吏 '씪뵒씪닾二쇰쭥 踰좊룄떞'쓣 怨듬룞쑝濡 媛쒕컻븯뿬 긽슜솕븳떎(Lee, 2020).

2021뀈 6썡 誘멸뎅 釉뚮━뒪넧留덉씠뼱뒪뒪대툕(BMS)뒗 씪蹂 뿉옄씠(Eisai) 怨좏삎醫낆뼇 ADC瑜 媛쒕컻븯湲 쐞빐 삊젰 愿怨꾨 留븐뿀떎. ADC씤 MORAb-202쓣 怨듬룞쑝濡 媛쒕컻븯怨 怨듬룞쑝濡 긽뾽솕븯뒗 湲濡쒕쾶 쟾왂쟻 젣쑕씠떎. MORAb-202뒗 뿉옄씠媛 옄泥 媛쒕컻븳 빆泥댁씤 빆-뿽궛 닔슜泥 븣뙆(FRα) 빆泥댁뿉 빆븫젣씤 뿉由щ텋由(eribulin)쓣 슚냼 젅떒삎 留곸빱濡 寃고빀븳 寃껋씠떎. BMS뒗 뿉옄씠뿉寃 뿰援ш컻諛 鍮꾩슜 2뼲 떖윭瑜 룷븿빐 6뼲 5000留 떖윭瑜 吏湲됲븯硫, 뼢썑 媛쒕컻, 듅씤, 긽뾽쟻 씠젙몴쓽 떖꽦뿉 뵲씪 理쒕 24뼲 5000留 떖윭瑜 異붽濡 吏遺덊븯湲곕줈 뻽떎(Park, 2021).

8. 援궡 諛붿씠삤젣빟뾽怨꾩쓽 ADC 媛쒕컻 쁽솴

ADC媛 理쒓렐 븞쟾꽦怨 슚怨 痢〓㈃뿉꽌 寃利앹씠 릺怨 꽦怨 媛뒫꽦씠 넂븘吏옄 援궡 湲곗뾽뱾룄 ADC 떆옣쓽 꽑젏쓣 쐞빐 寃쎌웳뿉 쎇뼱뱾怨 엳떎. 諛붿씠삤踰ㅼ쿂肉먮쭔 븘땲씪 씪遺 젣빟 湲곗뾽뿉꽌룄 ADC 移섎즺젣 媛쒕컻 뿴뿉 李몄뿬븯怨 엳떎.

빋떚뒪뒗 ADC 媛쒕컻뿉 쟾臾명솕맂 湲곗뾽쑝濡 옄泥 媛쒕컻븳 留곸빱 뵆옯뤌 湲곗닠씤 AbClick®쓣 蹂댁쑀븯怨 엳떎. AbClick® 湲곗닠뿉꽌뒗 빆泥댁뿉 븘誘몃끂궛쓣 궫엯븯嫄곕굹 援먯껜븯뒗 蹂씠怨쇱젙씠 뾾씠 愿묒“궗留뚯쑝濡 꽭룷룆꽦빟臾쇱쓣 빆泥댁쓽 듅젙 씪씠떊뿉 꽑깮쟻쑝濡 寃고빀떆궓떎. 씠 湲곗닠 DAR쓣 돺寃 議곗젅븷 닔 엳쑝硫, 빆泥댁쓽 듅젙 遺쐞뿉 蹂씠瑜 씪쑝궎吏 븡湲 븣臾몄뿉 쟻슜遺꾩빞媛 꼻떎. 빋떚뒪뒗 씠 뵆옯뤌怨 떊洹 빆泥대 씠슜빐 쐞븫, 궪以묒쓬꽦쑀諛⑹븫 諛 鍮꾩냼꽭룷룓븫 벑뿉 븳 떊빟썑蹂대Ъ吏덉쓣 媛쒕컻븯怨 엳떎(Lee, 2020).

씤닾 ADC 媛쒕컻 湲곗뾽쑝濡 삤뙆뒪 留곸빱(ortho hydroxy-protected aryl sulfate (OHPAS®) linker)씪뒗 怨좎쑀쓽 留곸빱瑜 蹂댁쑀븯怨 엳떎. 떎瑜 留곸빱뒗 二쇰줈 븘誘(amine)湲곕 媛吏 빟臾쇰쭔쓣 뿰寃고븷 닔 엳吏留 OHPAS®뒗 럹(phenol)瑜 빟臾쇱뿉룄 뿰寃고븷 닔 엳떎. 럹湲곕뒗 떎뼇븳 빟臾쇰쪟媛 媛吏怨 엳뼱꽌 뿬윭 遺꾩빞쓽 빟臾쇱쓣 넀돺寃 뿰寃고븷 닔 엳떎. 뵲씪꽌 빆븫젣肉먮쭔 븘땲씪 떎瑜 吏덊솚 移섎즺 뿰援ъ뿉룄 쓳슜씠 맆 媛뒫꽦씠 넂떎(Hong, 2020).

젅怨좎폁諛붿씠삤궗씠뼵뒪뒗 ConjuALL®씠씪뒗 옄泥 ADC 뵆옯뤌 湲곗닠쓣 媛쒕컻븯뒗뜲, 옞옱젰쓣 씤젙諛쏆븘 떎닔쓽 빐쇅 鍮낇뙆留덉뿉 씪씠꽱떛 릺뿀떎. ConjuAll® 뵆옯뤌 쐞移섑듅씠쟻씤 젒빀쓣 넻빐 듅젙 遺쐞뿉留 留곸빱 빟臾쇱씠 寃고빀맆 닔 엳떎. 留곸빱媛 슦닔븯뿬 삁以 븞젙꽦씠 넂怨 寃잛뿉꽌 빟臾쇱쓣 슚怨쇱쟻쑝濡 諛⑹텧븳떎. 삉븳 寃고빀빟臾쇰줈 湲곗〈 PBD toxin쓽 븳怨꾨 洹밸났븳 PBD prodrug toxin쓣 媛吏怨 엳떎(Bae, 2019). ConjuALL® 쐞移섑듅씠쟻씤 젒빀 湲곗닠쓣 넻빐 DAR쓣 2 샊 4濡 씪젙븯寃 議곗젅븳떎. ConjuALL®쓽 留곸빱뒗 젅떒삎 留곸빱濡 꽑깮꽦씠 넂떎. 젅怨좎폁諛붿씠삤뒗 씡닔떎뀒씪벂떛뒪 2020뀈 2嫄댁쓣 怨꾩빟뻽怨 2021뀈뿉뒗 寃잛쓣 3媛쒖뿉꽌 6媛쒕줈 솗옣븯떎(Choi, 2021).

諛붿씠삤떆諛윭쓽 꽭怨꾩쟻씤 媛뺤옄씤 빆泥 諛붿씠삤쓽빟뭹 湲곗뾽씤 듃由ъ삩룄 ADC 遺꾩빞뿉 吏꾩텧븯떎. 듃由ъ삩 罹먮굹떎 븘씠봽濡쒖젨(iProgen Biotech)怨 4醫낆쓽 ADC 떊빟媛쒕컻쓣 吏꾪뻾 以묒씠떎. 듃由ъ삩쓽 빆泥 湲곗닠怨 븘씠봽濡쒖젨쓽 ADC 뵆젢뤌 湲곗닠, ADED®瑜 寃고빀떆耳곕떎. 듃由ъ삩 2021뀈 쁺援 ADC 湲곗뾽 씡닔떎 뀒씪벂떛뒪(Iksuda Therapeutics)뿉룄 吏遺 닾옄 삎깭濡 삊젰쓣 떆옉뻽떎(Seo, 2021).

븣뀒삤젨 옄泥 媛쒕컻븳 NexMab® 湲곗닠쓣 湲곕컲쑝濡 븯뿬 궃냼븫 移섎즺젣濡 궗슜븷 빆泥대 媛쒕웾빐 寃고빀젰쓣 넂씤 떊洹쒗빆泥대 媛쒕컻뻽떎. 씠 빆泥대줈 ADC 궃냼븫 移섎즺젣 ALT-Q5瑜 媛쒕컻븷 삁젙씠떎. 씠 빆泥대뒗 궃냼븫꽭룷 몴硫댁뿉 議댁옱븯뒗 FOLR1 (folate receptor alpha)뿉 듅씠쟻쑝濡 寃고빀븯뿬 FOLR1쓽 솢꽦쓣 李⑤떒븳떎(Ha, 2021).

븳誘몄빟뭹 젅怨좎폁諛붿씠삤 삊젰쓣 넻빐 씠以묓빆泥 ADC 빆븫젣瑜 媛쒕컻븯怨 엳떎. 遺곴꼍븳誘멸 媛쒕컻븳 씠以묓빆泥 뵆옯뤌씤 렂깘諛붾뵒瑜 쟻슜븯뒗뜲, 렂깘諛붾뵒뒗 븯굹쓽 빆泥닿 꽌濡 떎瑜 2媛쒖쓽 몴쟻뿉 룞떆뿉 寃고빀븯뿬, 떒씪빆泥대줈 젒洹쇱씠 뼱젮슫 븫醫낆뿉 슚怨쇨 엳쓣 寃껋쑝濡 湲곕맂떎(Hwang, 2021).

씠以묓빆泥 쟾臾멸린뾽씤 뿉씠鍮꾩뿕諛붿씠삤룄 ADC 뵆옯뤌쓣 媛쒕컻븯怨 엳떎. 뿉씠鍮꾩뿕諛붿씠삤뒗 룆꽦빆븫젣瑜 湲곗〈 諛⑹떇怨 떎瑜닿쾶 빆泥댁쓽 N-留먮떒뿉 遺숈떎. 씠 NTERM (N-terminal selective conjugation method, NTERM®) 諛⑸쾿 湲곗〈쓽 ADC 諛⑹떇뿉 鍮꾪빐 븞젙쟻씠硫 룆꽦 遺옉슜씠 궙븘 移섎즺슜웾踰붿쐞瑜 솗옣떆耳곕떎. 뿉씠鍮꾩뿕諛붿씠삤뒗 삉븳 젅怨좎폁諛붿씠삤 삊젰愿怨꾨 넻븯뿬 옄떊쓽 씠以묓빆泥 뵆옯뤌뿉 젅怨좎폁諛붿씠삤쓽 ADC 湲곗닠쓣 젒紐⑺븯뿬 빆븫젣 LCB71쓣 媛쒕컻븯怨 엳떎(Kim, 2021).

9. 끉쓽

ADC뒗 湲곗〈 빆븫솕븰슂踰뺤쓽 媛뺥빆 룆꽦 臾몄젣瑜 빐寃고빐 以 寃껋씠씪뒗 湲곕濡 異쒕컻뻽떎. 珥덉갹湲곗뿉 듅씤맂 ADC 빆븫젣뱾 빆븫슚怨쇰 넂씠硫 룆꽦씠 떖빐吏怨, 諛섎濡 븞쟾꽦쓣 넂씠硫 빆븫슚怨쇨 異⑸텇엳 諛쒗쐶릺吏 紐삵빐 移섎즺쁺뿭씠 醫곸븘吏뒗 궃愿씠 엳뿀떎. 洹몃윭굹 깉濡쒖슫 湲곗닠씠 벑옣븯硫댁꽌 ADC 빟臾쇱쓽 移섎즺쁺뿭씠 꼻뼱吏怨, 醫낆뼇 諛섏쓳쑉룄 넂븘吏怨 엳떎.

꽭룷룆꽦빟臾 payload 遺遺꾩뿉꽌 媛쒖꽑씠 留롮씠 씠猷⑥뼱吏怨 엳떎. 깉濡쒖슫 湲곗쟾쓽 ADC슜 꽭룷룆꽦빟臾쇱씠 떎뼇븯寃 媛쒕컻릺怨 엳떎. 怨쇨굅뿉뒗 슚뒫쓣 넂씠湲 쐞빐 꽭룷룆꽦 슚怨쇨 넂 빟臾쇱쓣 궗슜뻽쑝굹, 洹쇰옒뿉뒗 룆꽦씠 궙 빟臾쇱쓣 궗슜븯怨, DAR瑜 넂씠젮뒗 寃쏀뼢씠 굹궃떎.

뿰援ъ쓽 愿떖씠 쟾떖꽦씠 슦닔븳 留곸빱뿉룄 룧由ш퀬 엳떎. 留곸빱뒗 삁瑜 궡뿉꽌뒗 빟臾쇱쓣 苑 옟븘 븞젙꽦씠 넂怨, 몴쟻꽭룷뿉꽌뒗 젙솗븯寃 諛⑹텧릺뼱 젙諛꽦씠 넂븘빞 븳떎. Mersana Therapeutics 궗쓽 寃쎌슦 듅닔븳 솕븰留곸빱瑜 씠슜빐 15媛 씠긽 넚떊쓣 쟾떖븯뒗 ADC 뵆옯뤌 湲곗닠쓣 Takeda 븿猿 媛쒕컻 以묒씠떎. Sorrento Therapeutics 벑 떎瑜 뿬윭 湲곗뾽룄 깉濡쒖슫 湲곗쟾쓽 ADC슜 留곸빱瑜 媛쒕컻 以묒씠떎. 룆듅븳 留곸빱瑜 媛쒕컻븯硫 룆젏쟻씤 臾쇱쭏듅뿀瑜 솗蹂댄븷 닔 엳뒗 옣젏룄 엳떎(Kim, 2018).

꽭怨꾩쟻쑝濡 떎뼇븳 ADC젣젣쓽 엫긽떆뿕 뿰援ш 吏꾪뻾릺怨 엳떎. 珥덉갹湲곗뿉 鍮꾪빐꽌 ADC 젣젣媛 쟻슜릺뒗 쟻쓳利앹씠 솗릺怨 엳떎. ADC뒗 二쇰줈 빆븫젣濡 媛쒕컻릺뿀吏留 理쒓렐뿉뒗 硫댁뿭씠굹 媛먯뿼利앹뿉룄 쟻슜븯뒗 뿰援ш 吏꾪뻾릺怨 엳떎(Jun, 2020).

븫쓣 移섎즺븯뒗 뜲 꽑깮븷 닔 엳뒗 빆븫젣뒗 뿬윭 媛吏媛 엳떎. 洹몃윭굹 떒룆슂踰뺤쑝濡 洹뱀쟻씤 슚怨쇰 蹂 닔 엳뒗 빆븫젣뒗 洹몃━ 留롮 븡湲 븣臾몄뿉 몢 媛吏 씠긽쓣 꽎뼱꽌 벐뒗 蹂묒슜슂踰뺤씠 留롮씠 뿰援щ릺怨 엳떎. ADC뒗 빆븫솕븰슂踰뺢낵 몴쟻빆븫젣쓽 옣젏쓣 룞떆뿉 媛吏 듅꽦쑝濡 씤븯뿬 硫댁뿭愿臾 뼲젣젣쓽 蹂묒슜슂踰뺤젣濡 媛쒕컻맆 媛뒫꽦룄 엳떎. 留롮 ADC媛 硫댁뿭愿臾 뼲젣젣쓽 蹂묒슜슂踰뺤뿉 븳 뙆듃꼫濡쒖쓽 媛쒕컻릺怨 엳떎.

깉濡쒖슫 ADC 젣젣뱾 깉濡쒖슫 媛쒕뀗쓽 빟臾쇱쓣, 깉濡쒖슫 寃잜똿 빆泥댁뿉, 깉濡쒖슫 留곸빱濡 寃고빀븯뿬 留뚮뱾뼱吏꾨떎. 꽭怨꾩쓽 ADC 쉶궗뱾 깉濡쒖슫 꽭룷룆꽦빟臾, 깉濡怨 떎뼇븯怨 븞젙쟻씤 留곸빱, 깉濡쒖슫 쐞移섑듅씠쟻 깮젒빀 湲곗닠 벑쓽 湲곕컲 湲곗닠쓣 媛쒕컻븯怨 엳떎. ADC 媛쒕컻쓣 쐞븳 댋諛뺤뒪 냽뿉 깉濡怨 쑀슜븳 뿰옣뱾씠 븯굹뵫 梨꾩썙吏怨 엳떎. 빆泥닿났븰 湲곗닠씠 諛쒕떖븯뿬 떎뼇븳 빆썝뿉 븳 빆泥대룄 솗蹂대릺뼱 쟻슜븷 닔 엳뒗 寃잙룄 솗옣릺怨 엳떎. 꽑깮븷 닔 엳뒗 댋諛뺤뒪 냽쓽 뿰옣씠 留롮븘吏硫댁꽌 ADC濡 珥됰쭩릺뒗 떊빟쓣 媛쒕컻븷 닔 엳뒗 뿬嫄댁씠 臾대Ⅴ씡뼱媛怨 엳떎(Bae, 2019).

醫낆뼇 媛쒕퀎솕맂 吏덊솚씠씪 씪而ъ뼱吏 留뚰겮 쑀쟾쟻쑝濡 蹂듭옟븯怨 떎뼇븯떎. 媛 醫낆뼇쓽 遺꾩옄깮臾쇳븰쟻 湲곗쟾뿉 뵲씪꽌 젒洹쇱쓣 꽭遺꾪솕븯뿬 醫낆뼇蹂꾨줈 理쒖쟻쓽 빟臾, 留곸빱, 빆泥, 젒빀湲곗닠 벑쓣 議고빀븷 닔 엳쓣 寃껋씠떎. 留욎땄쓽븰 떆뿉 嫄몃쭪뒗 떎뼇븳 ADC 湲곕컲 移섎즺젣媛 媛쒕컻릺뼱꽌 븵쑝濡 媛곸쥌 븫쓣 移섎즺븯怨 誘몄땐議깆쓽猷뚯닔슂瑜 빐寃고븯뒗뜲 湲곗뿬븷 寃껋쓣 湲곕븳떎.

ACKNOWLEDGEMENT

None.

CONFLICT OF INTEREST

The author certifies that I have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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