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中国生物工程杂志

China Biotechnology
China Biotechnology  2022, Vol. 42 Issue (5): 69-80    DOI: 10.13523/j.cb.2111056
    
Advances in the Study of Antibody Composition and Targets of ADC Drugs
ZENG Hong-ye,NING Wen-jing,LUO Wen-xin**()
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China
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Abstract  

Antibody drug conjugates (ADCs) are a type of novel anti-tumor drugs, which are composed of three components: antibody, cytotoxic drugs and linker. Compared with traditional cytotoxic drugs, ADC has the ability to specifically target tumor cell and release small molecular drugs to achieve the effect of tumor-specific killing, showing good therapeutic potential in clinical practice. Particularly, the antibody of ADC can accurately deliver small molecule cytotoxin to the tumor by combining with targeted antigens on the surface of tumor cell, which is one of the core elements affecting the efficacy of ADCs. The review outlines advances in the study of antibody composition and targets of ADC drugs.



Key wordsAntibody drug conjugates(ADCs)      Antibody      Novel antibody      Target     
Received: 29 November 2021      Published: 17 June 2022
ZTFLH:  Q51  
Corresponding Authors: Wen-xin LUO     E-mail: wxluo@xmu.edu.cn
Cite this article:

ZENG Hong-ye,NING Wen-jing,LUO Wen-xin. Advances in the Study of Antibody Composition and Targets of ADC Drugs. China Biotechnology, 2022, 42(5): 69-80.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2111056     OR     https://manu60.magtech.com.cn/biotech/Y2022/V42/I5/69

Fig.1 Design of an antibody-drug conjugate and recommended biological properties
批准
年份
药物名称 抗体类型 靶点 适应证 连接子 毒性载荷 公司
2000 gemtuzumab
ozogamicin
人源化IgG4 CD33 CD33阳性急性髓系白血病 可清除腙键 卡奇霉素 Pfizer
2011 brentuximab
vedotin
嵌合抗体IgG1 CD30 霍奇金淋巴瘤、
大细胞淋巴瘤等
可清除val-cit连接子 MMAE Seattle
2013 ado-trastuzumab
emtansine
人源化IgG1 HER2 HER2阳性乳腺癌 不可清除硫醚键 DM1 Roche
2017 inotuzumab
ozogamicin
人源化IgG4 CD22 急性B淋巴细胞白血病 可清除腙键 卡奇霉素 Pfizer
gemtuzumab
ozogamicin*
人源化IgG4 CD33 CD33阳性急性髓系白血病 可清除腙键 卡奇霉素 Pfizer
2018 moxetumomab
pasudotox
鼠ScFv CD22 多毛细胞白血病 mc-vc-PABC 假单胞菌
外毒素A
AstraZeneca
2019 polatuzumab
vedotin-piiq
人源化IgG1k CD79β 弥漫性大B细胞淋巴瘤 可清除val-cit连接子 MMAE Roche
enfortumab
vedotin-ejfv
完全人源化
IgG1k
Nectin-4 晚期尿路上皮癌 可清除val-cit连接子 MMAE Seattle
fam-trastuzumab-
deruxtecan
人源化IgG1k HER2 转移性HER2阳性乳腺癌 可清除四肽连接子 Dxd Daiichi Sankyo
批准
年份
药物名称 抗体类型 靶点 适应证 连接子 毒性载荷 公司
2020 sacituzumab
govitecan-hziy
人源化IgG1k Trop-2 三阴性乳腺癌 Hydrolysable CL2A SN38 Immunomdecis
belantamab
mafodotin
人源化IgG1k BCMA 多发性骨髓瘤 Maleimidocaproyl MMAF Glaxo
SmithKline
cetuximab
sarotalocan sodium
嵌合抗体IgG1 EGFR 头颈部肿瘤 IRDye
700DX
Rakuten
Medical
2021 loncastuximab
tesirine
嵌合抗体 CD19 复发或难治性弥漫性大
B细胞淋巴瘤
Valine-alanine PBD ADC
Therapeutics
disitamab vedotin 人源化IgG1 HER2 HER2过表达的局部晚期或
转移性胃癌
可清除val-cit连接子 MMAE 荣昌生物
tisotumab
vedotin-tftv
完全人源化
IgG1tisotumab
TF 复发性或转移性宫颈癌 蛋白酶可切割连接子 MMAE Genmab A/S、
Seagen
Table 1 ADC drugs already on the market
抗体亚型 抗体血清
含量/%
半衰期 链间二硫
键数
通过FcγR的
免疫激活
通过C1q的
免疫激活
特点
IgG1 60 约21天 4 +++ ++ 半衰期长,ADCC与CDC效应强,含量高
IgG2 32 约21天 6 + + 会形成二硫键异构体,影响功能和结构
IgG3 4 约7天 13 ++++ +++ 能引发强的ADCC与CDC,但半衰期短
IgG4 4 约21天 4 ++ - 不稳定,容易形成半抗体或双特异抗体
Table 2 Subtypes of IgG antibodies
抗体类型 优点 限制
鼠源单克隆抗体 能产生大量针对特定靶点的单克隆抗体 具有免疫源性,引起人抗鼠免疫反应,人体清除快
嵌合抗体 更低的免疫原性 还是会存在与鼠IgG可变区有关的人抗鼠免疫反应
人源化抗体 外源序列相比于嵌合抗体更少,免疫原性更低 重组的抗体往往特异性和亲和力较低
全人源化抗体 不存在人抗鼠抗体效应 需要使用噬菌体展示库、转基因鼠等技术才能制备
Table 3 Antibodies of different sources
靶点 药物名称 适应证 临床阶段 载荷 抗体 临床试验
编号
HER2 trastuzumab
duocarmazine
HER2阳性局部晚期或转移性乳腺癌、实体瘤 III期 多卡霉素(duocarmycin) 人源化抗HER2曲妥珠单抗 NCT03262935
NCT04602117
NCT04205630
BAT8001 HER2阳性晚期乳腺癌、实体瘤 III期 美坦素(maytansine) 曲妥珠单抗生物类似药 NCT04151329
NCT04185649
NCT04189211
ARX788 HER2阳性转移期乳腺癌、HER2低表达乳腺癌 II期/III期 微管蛋白抑制剂AS269 抗HER2单克隆抗体 NCT04829604
NCT05018702
NCT05018676
MRG002 HER2阳性的晚期或转移性乳腺癌、尿路上皮癌、胆道癌、胃/胃食管交界处癌 II期 甲基澳瑞他汀E(MMAE) 抗HER2单克隆抗体 NCT04924699
NCT04742153
NCT04839510
NCT04837508
NCT04492488
A166 HER2阳性晚期乳腺癌、胃癌 I期/II期 微管蛋白抑制剂(DUO-5) 人源化抗HER2曲妥珠单抗 NCT03602079
XMT1522 HER2阳性晚期乳腺癌 I期 微管蛋白抑制剂澳瑞他汀(Auristatin) 抗HER2单克隆抗体 NCT02952729
BAY2701439 HER2阳性晚期癌症 I期 钍-227 抗HER2单克隆抗体 NCT04147819
靶点 药物名称 适应证 临床阶段 载荷 抗体 临床试验
编号
BDC-1001 HER阳性晚期实体瘤 I期 TLR7/8激动剂 人源化抗HER2曲妥珠单抗 NCT04278144
EGFR depatuxizumab
mafodotin
多形性胶质母细胞瘤 III期(失败) 甲基澳瑞他汀F(MMAF) 抗EGFR嵌合抗体 NCT03419403
MRG003 EGFR阳性晚期或转移性非小细胞肺癌、胆道癌、鼻咽癌、胃癌等 II期 甲基澳瑞他汀E(MMAE) 抗EGFR单克隆抗体 NCT05126719
NCT05188209
NCT04838964
NCT04868162
AMG595 复发性脑胶质瘤 I期 美登素DM1(maytansinoid DM1) 抗EGFRvⅢ单克隆抗体 NCT01475006
TROP2 datopotamab
deruxtecan
晚期或不可切除的非小细胞肺癌等 III期 拓扑异构酶1抑制剂(Dxd) 抗Trop2单克隆抗体 NCT05104866
NCT04940325
NCT04656652
SKB264 局部晚期、转移性实体瘤 I期/II期 拓扑异构酶抑制剂(KL610023) 抗Trop2单克隆抗体 NCT04152499
JS108 晚期实体瘤 I期 微管蛋白去稳定剂(tub196) 重组人源化抗Trop2抗体 NCT04601285
叶酸受体α Mirvetuximab
Soravtansine
卵巢上皮癌、腹膜癌、输卵管癌 III期 美登素DM4 人源化抗FOLRα单克隆抗体 NCT05041257
NCT04606914
NCT04296890
MORAb-202 晚期实体瘤 I期/II期 微管蛋白抑制剂艾瑞布林(eribulin) 抗FOLRα法妥组单抗 NCT04300556
STRO-002 卵巢上皮癌、子宫内膜癌 I期 微管蛋白靶向剂哈米特林(hemiasterlin) 抗FolRa人IgG1抗体(SP8166) NCT05200364
NCT03748186
BCMA AMG224 多发性骨髓瘤 I期 美登素DM1 抗人BCMA单抗 NCT02561962
MEDI2228 多发性骨髓瘤 I期 PBD二聚体 全人源抗BCMA抗体 NCT03489525
CC-99712 多发性骨髓瘤 I期 抗BCMA单抗 NCT04036461
MUC1 SAR566658 实体瘤 I期 美登素DM4 抗MUC1抗体huDS6 NCT01156870
M1231 实体瘤 I期 哈米特林(hemiasterlin) 抗CD3/MUC1双特异抗体 NCT04695847
ROR1 zilovertamab
vedotin
实体瘤 II期 甲基澳瑞他汀E(MMAE) 抗ROR1单克隆抗体 NCT04504916
NBE-002 实体瘤 I期/II期 抗ROR1单抗 NCT04441099
CD19 denintuzumab
mafodotin
急性淋巴细胞白血病、非霍奇金淋巴瘤等 II期 mcMMAF 抗CD19单抗 NCT02855359
SGN-CD19B 弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤 I期 PBD二聚体 抗CD19单抗 NCT02702141
CD37 naratuximab
emtansine
B细胞恶性肿瘤、非霍奇金淋巴瘤等 II期 美登素DM1 抗CD37单抗
(naratuximab)
NCT02564744
Lutetium
lilotomab
satetraxetan
非霍奇金淋巴瘤 I期/II期 177Lu 抗CD37单抗
(lilotomab)
NCT01796171
CD33 vadastuximab
talirine
急性髓系白血病 III期 PBD二聚体 抗CD33半胱氨酸工程化人源化鼠抗 NCT02785900
HER3 patritumab
deruxtecan
非小细胞肺癌、乳腺癌、结直肠癌等实体瘤 II期 DX-8951 抗HER3单抗
(patritumab)
NCT04479436
NCT04619004
NCT04965766
DLL3 rovalpituzumab
tesirine
晚期小细胞肺癌 III期 PBD二聚体 抗DLL3单抗
(rovalpituzumab)
NCT03033511
靶点 药物名称 适应证 临床阶段 载荷 抗体 临床试验
编号
mesothelin
(间皮素)
Anetumab
ravtansine
实体瘤 II期 美登素DM4 全人源抗mesothelin
抗体
NCT03926143
GPNMB
(糖蛋白NMB)
glembatumumab
vedotin
乳腺癌 II期(终止) 甲基澳瑞他汀E(MMAE) 抗GPNMB单抗
(glembatumumab )
NCT03326258
NCAM-1
(CD56)
lorvotuzumab
mertansine
多发性骨髓瘤等 II期 美登素DM1 抗CD56单抗
(lorvotuzumab)
NCT02452554
IL-2Rα camidanlumab
tesirine
血液瘤 II期 PBD二聚体 完全人源化抗IL-2Rα抗体(camidanlumab) NCT04052997
CEA(CD66) tusamitamab
ravtansine
非小细胞肺癌等实体瘤 II期 美登素DM4 抗CEA单抗
(tusamitamab)
NCT04524689
NCT04394624
c-Met telisotuzumab
vedotin
非小细胞肺癌 II期 甲基澳瑞他汀E(MMAE) ABT-700(telisotuzumab) NCT03574753
AXL受体酪
氨酸激酶
BA3011 非小细胞肺癌等 II期 抗AXL肿瘤微环境条件性抗体 NCT04681131
NaPi2b(钠依赖性
磷酸转运蛋白)
upifitamab
rilsodotin
卵巢癌、非小细胞肺癌 I期/II期 auristatin 抗NaPi2b单抗 NCT04907968
NCT03319628
PSMA(前列腺特
异性膜抗原)
rosopatamab
tetraxetan
前列腺癌 I期/II期 美登素DM1 抗PSMA单抗
(rosopatamab)
NCT04886986
CD46 FOR46 多发性骨髓瘤、前列腺癌 I期/II期 抗CD46单抗 NCT05011188
CD20 MRG001 非霍奇金淋巴瘤 I期 甲基澳瑞他汀E(MMAE) 抗CD20单抗 NCT05155839
DEC-205 MEN1309 乳腺癌等实体瘤、非霍奇金淋巴瘤 I期 美登素DM4 全人源抗DEC-205
(CD205)抗体
NCT04064359
FZD10 tabituximab
barzuxetan
复发或难治性滑膜肉瘤 I期 钇90 OTSA101(tabituximab) NCT04176016
PTK7 cofetuzumab
pelidotin
复发性非小细胞肺癌 I期 Aur0101 抗PTK7单抗
(cofetuzumab)
NCT04189614
Integrin αvβ6
(整合素αvβ6)
SGN-B6A 实体瘤 I期 甲基澳瑞他汀E
(MMAE)
抗整合素αvβ6单抗 NCT04389632
LRRC15 samrotamab
vedotin
(ABBV-085)
实体瘤 I期 甲基澳瑞他汀E(MMAE) 抗LRRC15单抗
(samrotamab)
NCT02565758
Table 4 Some of ADC drugs in clinical stage
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