药学学报

Brand name	Company	Tumor type	Approval date	Approval authority
Mylotarg	Pfizer	AML	2000. 5, 2017. 9	FDA
Adcetris	Seagen, Takeda	HL, ALCL	2011. 8	FDA
Kadcyla	Genentech	Breast cancer	2013. 2	FDA
Besponsa	Pfizer	ALL	2017. 8	EMA
Lumoxiti	AstraZeneca	HCL	2018. 9	FDA
Polivy	Genentech	DLBCL	2019. 6	FDA
Padcev	Seagen, Astellas	UC	2019. 12	FDA
Enhertu	AstraZeneca, Daiichi Sankyo	Breast cancer	2019. 12	FDA
Trodelvy	Immunomedics	Breast cancer	2020. 4	FDA
Blenrep	GSK	MM	2020. 8	FDA
Akalux	Lotte Chemical	HNSCC	2020. 9	PMDA
Zynlonta	ADC Therapeutics	R/R, LBCL	2021. 4	FDA
Aidixi	RemeGen	GC, UC	2021. 6	NMPA
Tivdak	Seagen	Cervical cancer	2021. 9	FDA
Elahere	ImmunoGen	Ovarian cancer	2022. 11	FDA
Azedra	Kelun-Biotech	TNBC	2024. 11	NMPA
Datroway	DaiichiI	NSCLC	2025. 1	FDA
Emrelis	ABBV.US	NSCLC	2025. 5	FDA
Trastuzumab rezetecan	Hengrui	NSCLC	2025. 5	NMPA

Brand name	Company	Tumor type	Approval date	Approval authority
Mylotarg	Pfizer	AML	2000. 5, 2017. 9	FDA
Adcetris	Seagen, Takeda	HL, ALCL	2011. 8	FDA
Kadcyla	Genentech	Breast cancer	2013. 2	FDA
Besponsa	Pfizer	ALL	2017. 8	EMA
Lumoxiti	AstraZeneca	HCL	2018. 9	FDA
Polivy	Genentech	DLBCL	2019. 6	FDA
Padcev	Seagen, Astellas	UC	2019. 12	FDA
Enhertu	AstraZeneca, Daiichi Sankyo	Breast cancer	2019. 12	FDA
Trodelvy	Immunomedics	Breast cancer	2020. 4	FDA
Blenrep	GSK	MM	2020. 8	FDA
Akalux	Lotte Chemical	HNSCC	2020. 9	PMDA
Zynlonta	ADC Therapeutics	R/R, LBCL	2021. 4	FDA
Aidixi	RemeGen	GC, UC	2021. 6	NMPA
Tivdak	Seagen	Cervical cancer	2021. 9	FDA
Elahere	ImmunoGen	Ovarian cancer	2022. 11	FDA
Azedra	Kelun-Biotech	TNBC	2024. 11	NMPA
Datroway	DaiichiI	NSCLC	2025. 1	FDA
Emrelis	ABBV.US	NSCLC	2025. 5	FDA
Trastuzumab rezetecan	Hengrui	NSCLC	2025. 5	NMPA

BsADCs	Targets	Company	Clinical development phase
BL-B01D1	EGFR/HER3	Sichuan Biokin, Bristol Myers Squib	Phase Ⅲ
TQB2102	HER2 (ECD2/ECD4)	Chia Tai Tianqing	Phase Ⅲ
JSKN003	HER2/TROP1	Alphamab Oncology, CSPC Pharmaceutical	Phase Ⅲ
JSKN016	HER3/TROP2	Alphamab Oncology	Phase Ⅱ
IMGN-151	FOLR1	ImmunoGen	Phase Ⅱ
SKB571	EGFR/c-MET	Sichuan Kelun-Biotech Biopharmaceutical	Phase Ⅱ
REGN5093-M114	MET	Regeneron Pharmaceuticals	Phase Ⅰ/Ⅱ
DB-1418	HER3/EGFR	Duality Biologics, Avenzo Therapeutics	Phase Ⅰ/Ⅱ
DB-1419	B7-H3/PD-L1	Duality Biologics	Phase Ⅰ/Ⅱ
SHR-1681	HER3/c-MET	Jiangsu Hengrui Pharmaceuticals	Phase Ⅰ/Ⅱ
PRO-1286	EGFR/c-MET	ProfoundBio	Phase Ⅰ/Ⅱ
M-1231	EGFR/MUC1	Merck, Sutro Biopharma	Phase Ⅰ
ZW-49	HER2 (ECD2/ECD4)	Zymeworks	Phase Ⅰ
KM501	HER2	Xuanzhu Biopharmaceutical	Phase Ⅰ
TQB6411	EGFR/MET	Chia Tai Tianqing	Phase Ⅰ
AK146D1	TROP2/Nectin-4	Akeso	Phase Ⅰ
BR-111	ROR1	BrightGene Bio-Medical Technology	Phase Ⅰ
ALK202	EGFR/c-MET	Shanghai Allink Biotherapeutics	Phase Ⅰ
DM005	EGFR/c-MET	Doma Pharmaceutical Technology, Biocytogen Pharmaceuticals	Phase Ⅰ
IBI-3001	B7-H3/EGFR	Innovent Biologics	Phase Ⅰ
BL-B16D1	EGFR/HER3	Sichuan Biokin	Phase Ⅰ
AZD9592	EGFR/c-MET	AstraZeneca	Phase Ⅰ
TJ-101	EGFR/ B7-H3	Shanghai Tuoji Pharmaceutical	Phase Ⅰ
IBI-3005	EGFR/HER3	Innovent Biologics	Phase Ⅰ

BsADCs	Targets	Company	Clinical development phase
BL-B01D1	EGFR/HER3	Sichuan Biokin, Bristol Myers Squib	Phase Ⅲ
TQB2102	HER2 (ECD2/ECD4)	Chia Tai Tianqing	Phase Ⅲ
JSKN003	HER2/TROP1	Alphamab Oncology, CSPC Pharmaceutical	Phase Ⅲ
JSKN016	HER3/TROP2	Alphamab Oncology	Phase Ⅱ
IMGN-151	FOLR1	ImmunoGen	Phase Ⅱ
SKB571	EGFR/c-MET	Sichuan Kelun-Biotech Biopharmaceutical	Phase Ⅱ
REGN5093-M114	MET	Regeneron Pharmaceuticals	Phase Ⅰ/Ⅱ
DB-1418	HER3/EGFR	Duality Biologics, Avenzo Therapeutics	Phase Ⅰ/Ⅱ
DB-1419	B7-H3/PD-L1	Duality Biologics	Phase Ⅰ/Ⅱ
SHR-1681	HER3/c-MET	Jiangsu Hengrui Pharmaceuticals	Phase Ⅰ/Ⅱ
PRO-1286	EGFR/c-MET	ProfoundBio	Phase Ⅰ/Ⅱ
M-1231	EGFR/MUC1	Merck, Sutro Biopharma	Phase Ⅰ
ZW-49	HER2 (ECD2/ECD4)	Zymeworks	Phase Ⅰ
KM501	HER2	Xuanzhu Biopharmaceutical	Phase Ⅰ
TQB6411	EGFR/MET	Chia Tai Tianqing	Phase Ⅰ
AK146D1	TROP2/Nectin-4	Akeso	Phase Ⅰ
BR-111	ROR1	BrightGene Bio-Medical Technology	Phase Ⅰ
ALK202	EGFR/c-MET	Shanghai Allink Biotherapeutics	Phase Ⅰ
DM005	EGFR/c-MET	Doma Pharmaceutical Technology, Biocytogen Pharmaceuticals	Phase Ⅰ
IBI-3001	B7-H3/EGFR	Innovent Biologics	Phase Ⅰ
BL-B16D1	EGFR/HER3	Sichuan Biokin	Phase Ⅰ
AZD9592	EGFR/c-MET	AstraZeneca	Phase Ⅰ
TJ-101	EGFR/ B7-H3	Shanghai Tuoji Pharmaceutical	Phase Ⅰ
IBI-3005	EGFR/HER3	Innovent Biologics	Phase Ⅰ

Payload	Mechanism of action	IC₅₀ value	Key advantage	Major limitation	Example ADCs
Methotrexat; doxorubicin; mitomycin C	Antifolate agent; DNA intercalator	μmol·L^-1	Broad-spectrum	Poor selectivity; drug resistance	-
Calicheamicin	DNA double-strand breaker	μmol·L^-1	Pioneered potent DNA damage	Off-target toxicity due to an unstable linker	Mylotarg
DM1; DM4; MMAE; MMAF	Microtubule polymerization inhibitor	10^-9-10^-10 mol·L^-1	High potency & broad applicability	Off-target toxicity; narrow therapeutic window	Adcetris; Kadcyla
DXD; SN-38	DNA intercalator	nmol·L^-1	High DAR & bystander effect	Lower potency vs microtubule agents	Trodelvy; Enhertu
PBD dimer; duocarmycin	DNA alkylating agent	pmol·L^-1	Effective for low antigen tumors	Limited clinical use (only Zynlonta)	Zynlonta

Payload	Mechanism of action	IC₅₀ value	Key advantage	Major limitation	Example ADCs
Methotrexat; doxorubicin; mitomycin C	Antifolate agent; DNA intercalator	μmol·L^-1	Broad-spectrum	Poor selectivity; drug resistance	-
Calicheamicin	DNA double-strand breaker	μmol·L^-1	Pioneered potent DNA damage	Off-target toxicity due to an unstable linker	Mylotarg
DM1; DM4; MMAE; MMAF	Microtubule polymerization inhibitor	10^-9-10^-10 mol·L^-1	High potency & broad applicability	Off-target toxicity; narrow therapeutic window	Adcetris; Kadcyla
DXD; SN-38	DNA intercalator	nmol·L^-1	High DAR & bystander effect	Lower potency vs microtubule agents	Trodelvy; Enhertu
PBD dimer; duocarmycin	DNA alkylating agent	pmol·L^-1	Effective for low antigen tumors	Limited clinical use (only Zynlonta)	Zynlonta

Linker type	Linker	Approved ADC	Plasma stability	Cleavage condition	Cleavage site
pH-sensitive	Hydrazone linker	Mylotarg	Moderate	pH 4.5-5.5	Lysosome/endosome
Reduction-sensitive	Disulfide linker	Zynlonta	Moderate	High reducing environment (e.g., GSH)	Cytoplasm
Protease-cleavable	Peptide linker (e.g., Val-Cit)	Adcetris	High	Protease hydrolysis (e.g., Cathepsin B)	Lysosome
β-Glucuronide	β-Glucuronide linker	Trodelvy	High	1, 6-Elimination upon glucuronidase cleavage	Lysosome
Phosphate	Phosphate ester linker	-	High	Phosphatase-mediated hydrolysis	Lysosome
Non-cleavable linker	Maleimido-thioether linker	Kadcyla	Very high	Lysosomal degradation of the entire ADC	Lysosome

Linker type	Linker	Approved ADC	Plasma stability	Cleavage condition	Cleavage site
pH-sensitive	Hydrazone linker	Mylotarg	Moderate	pH 4.5-5.5	Lysosome/endosome
Reduction-sensitive	Disulfide linker	Zynlonta	Moderate	High reducing environment (e.g., GSH)	Cytoplasm
Protease-cleavable	Peptide linker (e.g., Val-Cit)	Adcetris	High	Protease hydrolysis (e.g., Cathepsin B)	Lysosome
β-Glucuronide	β-Glucuronide linker	Trodelvy	High	1, 6-Elimination upon glucuronidase cleavage	Lysosome
Phosphate	Phosphate ester linker	-	High	Phosphatase-mediated hydrolysis	Lysosome
Non-cleavable linker	Maleimido-thioether linker	Kadcyla	Very high	Lysosomal degradation of the entire ADC	Lysosome

Key component	Antibody	Payload	Linker
Core characteristics	Targeting specificity; PK modulation; effector function; mature human mab platforms	High potency; diverse MOAs; novel payload; controllable toxicity	Stability optimization; site-specific conjugation; biodegradable scaffolds; improved solubility
Current technical bottlenecks	Poor solid tumor penetration; target-dependent resistance; inefficient internalization; off-target binding	MDR-mediated resistance; limited membrane permeability; narrow therapeutic window; payload-linker incompatibility	Stability-release trade-off; DAR heterogeneity; limited TME responsiveness; scalability challenges
Future directions	Nanobody/single-chain antibody; bispecific antibodies; enhanced internalization; TME-responsive design	Resistance reversal payloads; enhanced membrane permeability; high-selectivity payloads; payload-linker innovation	Dual/multi-responsive linkers; homogeneous conjugation; novel cleavable linkers; industrial process optimization

Key component	Antibody	Payload	Linker
Core characteristics	Targeting specificity; PK modulation; effector function; mature human mab platforms	High potency; diverse MOAs; novel payload; controllable toxicity	Stability optimization; site-specific conjugation; biodegradable scaffolds; improved solubility
Current technical bottlenecks	Poor solid tumor penetration; target-dependent resistance; inefficient internalization; off-target binding	MDR-mediated resistance; limited membrane permeability; narrow therapeutic window; payload-linker incompatibility	Stability-release trade-off; DAR heterogeneity; limited TME responsiveness; scalability challenges
Future directions	Nanobody/single-chain antibody; bispecific antibodies; enhanced internalization; TME-responsive design	Resistance reversal payloads; enhanced membrane permeability; high-selectivity payloads; payload-linker innovation	Dual/multi-responsive linkers; homogeneous conjugation; novel cleavable linkers; industrial process optimization

抗体偶联药物关键组分解析: 抗体、载荷与连接子的发展脉络

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张雯 ¹ , 常俊标 ¹^,² , 孟勇刚 ²^,^*

药学学报 | 综述 2026,61(6): 2035-2049

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药学学报 |综述 2026 , 61 (6) : 2035 -2049

抗体偶联药物关键组分解析: 抗体、载荷与连接子的发展脉络

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张雯¹, 常俊标¹^,², 孟勇刚²^,^*

作者信息

¹郑州大学化学学院, 平原实验室, 抗病毒性传染病创新药物全国重点实验室, 河南郑州 450001

²郑州大学药学院, 河南郑州 450001

通讯作者:

孟勇刚, E-mail: mengyonggang@zzu.edu.cn

作者简介:

作者贡献:

张雯负责相关文献的收集、文章作图及综述的撰写; 常俊标对综述的构思提出建议并进行了修改和检查; 孟勇刚是综述框架的构思者及负责人, 指导综述写作并对综述进行了修改和检查。全体作者都阅读并同意最终的文本。

Antibody drug conjugates key components: The evolution of antibody, payload and linker

Wen ZHANG¹, Jun-biao CHANG¹^,², Yong-gang MENG²^,^*

Affiliations

¹State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, College of Chemistry, Zhengzhou University, Zhengzhou 450001, China

²School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

出版时间: 2026-06-12 doi: 10.16438/j.0513-4870.2025-0843

文章导航

摘要

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抗体偶联药物(antibody drug conjugates, ADCs)是一类治疗癌症的新型药物, 在结构上由单克隆抗体与细胞毒性药物通过连接子偶联而成。在治疗效果上具有耐受性良好、靶向识别精准、对非癌细胞影响较小等优势。截至目前已有19个ADCs被批准上市, 超300个ADCs处于不同临床试验阶段。本综述系统梳理了抗体偶联药物三大核心组分——抗体、有效载荷及连接子的发展历程, 构建抗体偶联药物研发的基础知识框架, 推动该领域的技术普及与认知提升。期待本综述能成为研究者探索抗体偶联药物创新疗法的起点, 激发对这一革命性治疗策略的深入思考。

关键词

抗体偶联药物 / 抗体 / 有效载荷 / 细胞毒性物质 / 连接子

Abstract

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Antibody drug conjugates (ADCs) are a novel class of cancer therapeutics, structurally composed of monoclonal antibodies conjugated to cytotoxic agents via linkers. They offer advantages such as good tolerability, precise target recognition, and minimal impact on non-cancerous cells. To date, 19 ADCs have been approved for marketing, and over 300 ADCs are in various clinical trial phases. This review systematically outlines the developmental history of the three core components of ADCs—antibodies, payloads, and linkers. It aims to establish a foundational knowledge framework in ADCs development, thereby promoting technological dissemination and advancing awareness in the field. We anticipate that this review will serve as a foundational stepping stone for researchers exploring innovative ADCs therapies, igniting in-depth contemplation for this revolutionary therapeutic strategy.

Key words

antibody drug conjugate / antibody / payload / cytotoxic substance / linker

引用本文

张雯, 常俊标, 孟勇刚. 抗体偶联药物关键组分解析: 抗体、载荷与连接子的发展脉络. 药学学报, 2026 , 61 (6) : 2035 -2049 . DOI: 10.16438/j.0513-4870.2025-0843

Wen ZHANG, Jun-biao CHANG, Yong-gang MENG. Antibody drug conjugates key components: The evolution of antibody, payload and linker[J]. Acta Pharmaceutica Sinica, 2026 , 61 (6) : 2035 -2049 . DOI: 10.16438/j.0513-4870.2025-0843

正文

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在癌症治疗领域, 手术、化疗、放疗、靶向治疗及免疫治疗构成了主要治疗手段^[1]。手术治疗的方式对早期实体瘤有根治效果, 能直接切除肿瘤, 但创伤大、对转移癌效果差。化疗作为全身治疗手段, 可杀灭原发肿瘤、转移灶或潜在的微小转移病灶, 然而该手段缺乏选择性的药物, 正常细胞也会受到影响, 引发诸多严重的不良反应。放疗的治疗方案是利用射线精准杀伤局部癌细胞, 但同时也会对癌细胞周围正常的组织造成一定损伤。免疫治疗虽可激活免疫系统对抗癌细胞, 但效率有限, 还存在免疫相关的毒性问题^[2]。靶向治疗的方式则聚焦于肿瘤细胞特有的分子靶点, 如特定基因突变、异常蛋白表达等, 通过精准设计的药物展开攻击。其特异性极强, 对正常细胞损伤极小, 这使得对患者引发的不良反应明显减轻, 多表现为皮疹、腹泻等相对轻微的症状。在疗效方面, 靶向治疗表现突出, 尤其对于携带特定靶点的患者可显著延长生存期。以非小细胞肺癌为例, 表皮生长因子受体(epidermal growth factor receptor, EGFR)突变患者的治疗使用吉非替尼、厄洛替尼^[3], 间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)阳性患者使用克唑替尼, 均可实现病情的长期有效控制。此外, 多数靶向药为口服制剂, 具有服用便捷的特点, 显著提升了患者依从性^[4]。

基于靶向治疗对肿瘤细胞特异性靶点的精准作用, 抗体偶联药物(antibody drug conjugates, ADCs)应运而生, 成为癌症治疗的创新策略^[5]。ADCs通过化学偶联技术将单克隆抗体(monoclonal antibody, mAb)与细胞毒性药物结合起来, 使抗体精准携带药物至肿瘤细胞, 实现药物在肿瘤组织内高效释放的目的。与传统靶向治疗方式相比, 抗体偶联药物兼具靶向特异性与强效杀伤能力的优势, 这种优势既减少患者给药量, 减少其全身毒性, 又突破了单一靶向药的疗效局限, 为乳腺癌、肺癌等多癌种的治疗带来新突破^[6]。

1　ADCs简介

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在肿瘤治疗领域, 抗体药物偶联物作为一类极具创新性的药物, 正发挥着日益重要的作用。抗体偶联药物的出现最早可追溯到20世纪初, 德国科学家Paul Ehrlich提出了“魔法子弹”这一概念, 希望通过这一“魔法子弹”能够精准作用于病变靶点, 在治愈疾病的同时不影响其他正常细胞^[7]。但直至1958年, Mathe首次将小鼠抗体与甲氨蝶呤偶联用于白血病治疗, ADCs的研究才正式起步^[8]。但由于免疫原性和抗体制备等难题, 后续几十年抗体偶联药物发展近乎停滞。直至1975年单克隆抗体技术及后来人源化抗体技术的出现, 才为其发展带来转机^[9]。2000年, 首个抗体偶联药物吉妥珠单抗奥佐米星Mylotarg获美国食品药品监督管理局(Food and Drug Administration, FDA)批准用于成人急性髓系白血病(acute myeloid leukemia, AML), 标志着ADCs靶向治疗癌症时代的开启, Mylotarg被视为第一代抗体偶联药物^[10-12]。但第一代抗体偶联药物存在诸多缺陷, 如药物效力不足、对肿瘤靶向性不强、连接子不稳定、单克隆抗体为鼠源易引发免疫反应等, 导致其临床应用受限, Mylotarg也因致命肝毒性于2010年撤市^[13]。为克服第一代抗体偶联药物的不足, 第二代抗体偶联药物在研发中改进了单克隆抗体技术, 选用更有效的小分子作为毒性载荷, 提高了肿瘤细胞靶向性并减少与健康细胞交叉反应。例如2013年获批用于治疗人表皮生长因子受体2 (human epidermal growth factor receptor 2, HER2)阳性乳腺癌的恩美曲妥珠单抗Kadcyla, 它由人源抗HER2抗体曲妥珠单抗、有效载荷美登新(maytansine derivative, DM1)及不可裂解的连接子马来酰亚胺己酸(maleimide caproic acid, MCC)组成^{[14, 15]}。第二代抗体偶联药物展现出更好的临床疗效和安全性, 但仍存在脱靶毒性、未结合抗体、药物抗体比(drug antibody ratio, DAR)不合理等问题, 导致其治疗窗口较窄。随着技术的不断进步, 第三代抗体偶联药物应运而生。其核心突破在于通过小分子药物与单克隆抗体的位点特异性结合技术, 精准调控DAR至2或4, 相较前两代展现出多维度优势: 通过抗体工程引入特异性突变(如Thiomab技术在抗体铰链区引入半胱氨酸)或酶催化偶联(如转谷氨酰胺酶介导), 避免前两代随机偶联导致的DAR异质性, 使抗体偶联药物成为均一化分子, 显著降低游离抗体引发的免疫原性, 同时避免高DAR偶联物的快速清除, 提升血浆稳定性, 同时位点特异性偶联使ADCs的药代动力学性能显著改善。第三代抗体偶联药物搭载的高活性细胞毒性物质, 结合连接子的双触发释放机制, 即使在肿瘤细胞抗原表达较低时, 仍能通过高效胞内递药或旁观者杀伤效应维持细胞毒性, 突破前两代对高抗原密度的依赖^{[16, 17]}。自首个抗体偶联药物获批以来, 全球已有19个ADCs上市(表1), 超过100个ADCs正在开展不同阶段的临床研究^[18]。新一代抗体偶联药物凭借靶点拓展、连接子技术优化、双抗/双载荷创新设计及联合治疗策略的协同应用, 在显著提升疗效与安全性的同时, 为癌症治疗领域的突破性发展奠定了坚实基础。

2　抗体偶联药物的组成及作用机制

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ADCs是将抗体(antibody)通过偶联臂(linker)与有效载荷(payload)共价连接的复合药, 这一新药有3个组成部分, 即抗体、连接子、细胞毒性药物(图1)。其作用机制融合了抗体的靶向性与细胞毒性药物的杀伤能力, 通过精准递药实现对肿瘤细胞的选择性杀伤, 其核心过程可拆解为以下关键步骤(图2)^[6]: ① ADCs进入血液循环后, 其抗体组分凭借高度特异性, 识别并结合靶癌细胞表面高表达的抗原。这种结合具有严格的靶向性, 仅在抗原阳性细胞表面发生, 避免了对正常细胞的非特异性攻击。以HER2阳性乳腺癌为例, 抗体偶联药物的抗HER2抗体可精准锚定至肿瘤细胞表面, 形成ADCs-抗原复合物; ② ADCs抗原复合物形成后, 通过受体介导的内吞作用被细胞摄取, 进入胞内形成内体。这一过程依赖于细胞膜的流动性和细胞的内吞机制, 确保ADCs从细胞外环境转移至胞内区室。内吞效率与抗原-抗体的结合亲和力、细胞类型等因素密切相关, 直接影响后续药物释放的效率; ③内吞形成的囊泡与溶酶体融合, 在酸性环境(pH 4.5~5.5)及溶酶体酶(如蛋白酶、酯酶)的作用下, ADCs中可裂解的连接子发生裂解, 细胞毒性药物释放。若为不可裂解连接子, ADCs需通过抗体降解途径间接释放药物, 但效率通常低于可裂解连接子; ④释放的细胞毒性药物在胞内扩散, 靶向作用于关键分子, 破坏脱氧核糖核酸(deoxyribonucleic acid, DNA)或阻止肿瘤细胞分裂, 杀死细胞。以拓扑异构酶抑制剂为例, 其可抑制酶活性, 导致DNA复制受阻, 引发细胞周期停滞或凋亡; 微管抑制剂则通过破坏微管聚合, 干扰细胞分裂^[19]。ADCs的作用机制通过三大核心设计规避传统化疗缺陷: 抗体的靶向性可引导药物富集于肿瘤组织, 显著降低其在正常组织中的分布, 从而减少脱靶毒性; 血液循环中连接子的稳定性确保药物不提前释放, 避免系统性毒性; 仅当ADCs被肿瘤细胞内吞后, 溶酶体环境触发药物释放, 保证细胞内高药物浓度, 实现“靶向激活”。

3　ADCs各组分发展脉络

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抗体偶联药物在设计上虽具备靶向毒性的理论优势, 但在实际应用中仍面临多种问题, 可能与抗体与靶点不匹配、连接子的稳定性、细胞毒性的局限性等方面有关。通过优化靶点的选择, 有效载荷、连接子技术及偶联工艺的改进, 抗体偶联药物中存在的问题也将逐渐被解决。

3.1　抗体——靶点

在抗体偶联药物的发展历程中, 抗体类型的迭代与技术突破密切相关, 其核心目标是降低免疫原性、提高靶向性(图3)^{[6, 20]}。最初, 研究人员因在鼠源单克隆抗体方面技术成熟, 且其筛选周期短和亲和力强被选用, 但该抗原在人体内受免疫反应影响大, 导致药物清除快, 过敏性高被放弃使用^[21]。后来, 将鼠源可变区与人源恒定区(fragment crystallizable region, Fc段)进行拼接, 即人鼠嵌合单克隆抗体, 其人源程度约60%~70%。尽管嵌合单克隆抗体恒定区为人源, 但鼠源Ⅴ区仍含有大量的异源氨基酸序列, 这部分抗体可被人体免疫系统识别为“外来抗原”, 人体产生排斥性免疫应答, 即人抗鼠抗体反应(human anti-mouse antibody reaction, HAMA)^{[21, 22]}。如果患者长期用药, 约30%~50%的患者会产生HAMA反应, 这一免疫原性问题显著限制了嵌合抗体的临床应用。此外, 嵌合抗体的鼠源Ⅴ区可能会干扰抗体的空间构象, 导致抗原结合位点的结构异常, 进而引起抗原结合亲和力不稳定^[23]。鼠源Ⅴ区还可能间接影响抗体与新生儿Fc受体(neonatal fc receptor, FcRn)的结合效率, 使其半衰期缩短至约7~14天, 因此患者需要频繁给药, 这不仅增加了治疗成本, 还会加重患者生理与心理上的负担^{[24, 25]}。为了进一步控制和降低免疫原性的风险, 研究人员通过互补性决定区域(complementarity-determining region, CDR)移植技术得到人源性单克隆抗体, 这类抗体仅保留鼠源互补决定区, 使得人源化程度达90%以上。使用这种抗原几乎消除了HAMA反应, 药物的半衰期相比嵌合抗体类药物有所增长(约3周), 含人源性单克隆抗体的ADCs上市药物有恩美曲妥珠单抗Kadcyla、奥加伊妥珠单抗Besponsa^[26]。后来, 为求免疫原性最小化和治疗效果最大化, 全人源性抗体应运而生。目前全人源性抗体主要通过转基因动物平台、噬菌体展示技术、单细胞B细胞测序及基因编辑技术等方法制备, 这种抗体彻底避免了鼠源序列。全人源性抗体的ADCs上市药物有德曲妥珠单抗Enhertu、戈沙妥珠单抗Trodelvy^[16]。2020年后, 为突破传统抗体的性能瓶颈, 满足复合疾病治疗的需求, 研究人员构造出新的抗体, 如双特异性抗体和纳米抗体/抗体片段。双特异性抗体(bispecific antibody, BsAb)是在单克隆抗体的基础上设计出的一种能同时识别和结合两种不同抗原或同一抗原两个不同表位的一类抗体分子。这些分子有些与传统的IgG类似, 由两个抗原结合片段(fragment of antigen binding, Fab段)与Fc片段通过铰链区结合在一起, 两个Fab片段分别识别不同的抗原或表位。另一些分子则通过各种手段在IgG的特定位置附加上第二个抗原结合域^[27]。双特异性抗体实现了从单一靶点到协同作用, 该类抗体通过同时阻断两个致癌信号通路或协同激活免疫检查点的方式增强治疗效果并减少耐药性。具有双特异性抗体的Ⅲ期临床药物有BL-B01D1^[28]和JSKN003^[29]。抗体偶联药物治疗实体瘤面临分子质量大、难穿透生物屏障的问题, 纳米抗体的分子质量(12~14 kDa)仅为传统抗体的1/10, 可穿透血脑屏障或实体瘤间质, 适用于中枢神经系统疾病(如阿尔茨海默病)和深部肿瘤治疗, 同时还具有稳定性良好、研发周期短、半衰期长等优势^{[30, 31]}。

进入体内后未结合的单克隆抗体(monoclonal antibody, mAbs)有多种作用机制, 包括靶受体中和、受体下调、信号传导中断、抗体依赖的细胞介导的细胞毒性作用(antibody-dependent cellular cytotoxicity, ADCC)、补体依赖的细胞介导的细胞毒性作用(complement-dependent cytotoxicity, CDC)及免疫检查点抑制。因此, 选择合适的靶抗原是抗体-药物偶联物成功的关键步骤。

根据目前公认的原则, 理想的抗体偶联药物的靶点应当是一种表面暴露(或细胞外)的抗原, 它可作为靶向mAb载体的递送地址和结合锚点, 具有以下特点^{[32, 33]}: ①在肿瘤细胞表面高表达, 正常组织低表达/不表达, 比如部分黑色素瘤细胞系由于高表达肝细胞生长因子受体(hepatocyte growth factor receptor, HGFR), 对特定抗体偶联药物表现出敏感性^[34]; ②与ADCs结合后, 能被肿瘤细胞内吞, 且在细胞内可转运、降解, 保证有效载荷释放, 用于治疗AML的Mylotarg靶点是CD33, 其疗效与CD33表达量呈正相关, 此外, 释放的细胞毒性药物可扩散至邻近细胞, 对低表达CD33的肿瘤细胞发挥旁观者杀伤作用, 进一步拓展了药物的抗肿瘤范围^[35]。Kadcyla以HER2为靶点, 依赖HER2的高表达确保抗体偶联药物的充分内化, 经溶酶体降解释放细胞毒性载荷DM1, 从而发挥抗癌功效^[36]; ③结构相对稳定, 低突变率与抗下调能力, 例如, Nectin-4作为Padcev的靶点, 在尿路上皮癌中突变率 < 1%, 且因其细胞黏附分子的属性, 不易被肿瘤细胞下调, 这一特性保障了ADCs的持续结合效率与内化稳定性^[37]; ④靶抗原最好不是分泌型抗原, 因为分泌至循环系统中的抗原会与ADCs结合后消耗药物而导致其可能无法以高浓度富集于肿瘤组织, 形成抗原-抗体复合物, 不仅减少肿瘤细胞表面ADCs蓄积, 还可能通过FcRn介导的回收机制延长复合物半衰期, 增加脱靶毒性, 降低疗效^[26]。

与正常的组织相比, 靶抗原的表达应主要存在于肿瘤组织, 最好是仅在肿瘤组织中表达, 以确保有广泛且特异的治疗窗口。有效抗肿瘤活性通常需要抗原高表达且表达均一。而对于表达异质性的靶点, 可利用旁观者效应或搭配具有非常规作用机制的强效有效载荷。双特异性抗体-药物偶联物代表了一种创新的治疗类别, 其将ADCs和BsAbs的优点结合起来, 既能提升抗体偶联药物递送效率, 又能克服肿瘤细胞耐药性, 其性能表现优于单克隆抗体。通过精确调控双特异性抗体不同结合臂的亲和力, 可有效减轻抗体偶联药物的靶上及脱瘤毒性^[38]。根据靶点组合方式的不同, 双特异性ADCs可分为双表位型和双靶向型。双表位抗体偶联药物通过驱动受体交联与聚集, 形成大型免疫复合物, 增强抗体偶联药物的内化能力。双靶向ADCs专门针对不同的肿瘤相关抗原, 这种特异性靶向方式可最大限度减少与正常组织的非特异性相互作用, 提升抗体偶联药物的安全性。另一类双靶向ADCs通过联合靶向肿瘤相关抗原与快速内化受体, 促进抗体偶联药物的内化及溶酶体运输。目前已有超过20种基于上述设计的双特异性ADCs进入临床试验(表2)^[39], 尽管双靶向ADC的临床布局已逐步拓展, 但可用靶点仍集中在HER2、EGFR、TROP2等少数已验证的实体瘤抗原上, 可用靶点仍有限制。拓展双特异性抗体偶联药物靶点选择的具体策略包括: 采用非内化型或条件激活型ADCs设计, 在下一代双特异性ADCs开发中靶向肿瘤特异性抗原或新抗原。这些方法能降低靶向治疗相关毒副作用。此外, 通过将亲合力原理应用于抗体抗癌治疗, 已出现具有增强选择性和安全性的多靶点ADCs, 新一代抗体偶联药物的设计也可采用多种支架结构。

尽管双特异性ADCs的研究在临床前和临床阶段已取得显著进展, 但仍面临疗效与安全性平衡等挑战, 传统的单抗药代动力学主要受其FcRn和分子大小(影响肾清除)支配。而BsAb的药代动力学额外增加了两个决定性维度: 靶点介导的药物处置和可逆的“桥接”效应, 主要表现在双重靶点介导的清除、组织分布差异与穿透性挑战、免疫原性的复杂影响等。为解决这些问题, 可以通过引入点突变增强Fc与FcRn的亲和力, 增强循环回收能力, 以抵消靶点介导的药物处置带来的快速清除, 延长半衰期; 或降低对某些靶点的亲和力(特别是对CD3的亲和力), 可以减少外周激活和非特异性结合, 防止药物被过快清除, 同时提高安全性, 让药物更有效地在肿瘤中发挥作用。

由于单克隆抗体的CDR较小, 其对深层抗原的识别效率远低于纳米抗体, 将纳米抗体引入抗体偶联药物中得到的纳米抗体偶联药物(nanobody-drug conjugates, NDCs)使得药物在性能上优于ADCs。这类NDCs对癌细胞的毒性可达皮摩尔至飞摩尔级别, 远低于现有多数化疗药物的毒性阈值。除此之外, NDCs还具备其他关键优势: 更强的血液滞留能力, 以及对耐药性肿瘤优异的杀伤效果。但同时纳米抗体远低于肾小球滤过阈值, 会迅速被肾脏过滤并进入尿液, 导致其半衰期非常短; 天然的纳米抗体缺乏Fc片段, 与传统IgG抗体相比缺乏Fc介导的回收机制, 这大大限制了其临床应用(尤其是慢性病治疗)。为解决这些问题, 研究人员尝试增大分子尺寸以规避肾清除或引入FcRn结合能力以激活回收机制的手段来延长半衰期和改善药物的溶解性和降低免疫原性。目前, 科研界已投入大量精力研发NDCs, NDCs在多种疾病的临床试验中已处于不同阶段, 这为其最终实现临床转化奠定了基础^[40]。现有证据充分表明, 基于纳米抗体的化学药物递送策略有望克服基于传统抗体的药物递送系统的缺陷。

3.2　有效载荷——细胞毒性药物

有效载荷, 作为抗体偶联药物的“弹头”是ADCs发挥细胞毒作用的关键组件, 通过连接子与抗体偶联后, 经抗体靶向运输至肿瘤细胞内释放, 直接杀伤肿瘤细胞。细胞毒性药物的作用机制(如抑制微管聚合、损伤DNA)决定了ADCs的抗癌效力及适用瘤种(表3)^[41]。

早期抗体偶联药物开发主要采用传统化疗药物作为有效载荷, 如甲氨蝶呤(methotrexate)、多柔比星(doxorubicin)、丝裂霉素C (mitomycin C)等。这些药物虽然具有抗肿瘤活性, 但缺乏对肿瘤细胞的选择性, 且细胞毒性较弱^[42-45]。传统化疗药的半抑制浓度(half maximal inhibitory concentration, IC₅₀)在微摩尔级别, 需高剂量药物才能起到杀死癌细胞的作用, 同时其毒性也将增大, 不良反应显著^{[46, 47]}。1990年, 有一种以抗代谢类药物甲氨蝶呤为有效载荷的抗体偶联药物进入临床试验阶段^[48]。第一代ADCs常与传统化疗药物(如紫杉类、蒽环类)偶联, 但仅有一小部分ADCs能成功将有效载荷递送至靶细胞内。最终第一代ADCs因载荷效力不足及递送效率低失败。

2000年, 辉瑞公司研发的获全球首款批准上市的ADCs药物Mylotarg由人源化的IgG4单克隆抗体与细胞毒性药物卡利奇毒素(calicheamicin, CLM)通过可裂解连接子共价连接而成^[49]。卡利奇毒素不是传统化疗药物, 而是一种高效DNA嵌入剂, 属于DNA损伤剂中的一类DNA双链破坏剂, DNA双链破坏剂进入细胞核后, 特异性与DNA小沟结合, 使DNA局部构象扭曲, 结合后的卡利霉素衍生物γ1在细胞内发挥作用, 最终导致不可逆的双链断裂, 诱导肿瘤细胞凋亡。但Mylotarg因连接子不稳定导致具有脱靶毒性, 辉瑞主动将其撤出美国市场。

微管蛋白作为细胞骨架的主要构成物质, 除能够支撑细胞结构完整性外, 同时还在细胞增殖的有丝分裂阶段发挥着至关重要的作用^[50]。微管蛋白抑制剂通过与微管蛋白特异性结合, 破坏微管聚合-解聚动态平衡, 诱导细胞有丝分裂停滞并触发凋亡, 从而抑制肿瘤细胞增殖。微管蛋白抑制剂类化合物的特点是: 具有显著的细胞杀伤效能且起效迅速, 其半抑制浓度(IC₅₀)可达皮摩尔至纳摩尔级别。将此类抑制剂作为抗体药物偶联物的有效载荷时, 其对靶肿瘤细胞的体外靶向杀伤活性, 较非靶向的传统化疗药提升100~1 000倍, 且因药物本身的强效特性, 其对靶细胞的IC₅₀仍处于纳摩尔甚至皮摩尔水平^{[42, 51, 52]}。微管蛋白抑制剂主要有从非洲灌木美登木中提取的天然产物衍生物美登素类化合物、从海洋海绵素中分离的天然产物合成衍生物奥瑞他汀类化合物。美登素类微管蛋白抑制剂代表化合物有美登素Ⅰ (maytansine Ⅰ, DM1)、美登素Ⅳ (maytansine Ⅳ, DM4), 作用机制是与β-微管蛋白的长春花碱结合位点结合, 抑制微管聚合。奥瑞他汀类微管蛋白抑制剂代表化合物有单甲基奥瑞他汀E (monomethyl auristatin E, MMAE)、单甲基奥瑞他汀F (monomethyl auristatin F, MMAF), 其作用是与β-微管蛋白的秋水仙碱结合位点结合, 抑制微管聚合, 毒性较DM1更强。2011年, 维布妥昔单抗Adcetris获批用于治疗霍奇金淋巴瘤和系统性间变性大细胞淋巴瘤, 它使用微管蛋白抑制剂MMAE作为有效载荷, 这是微管蛋白抑制剂在抗体偶联药物中应用的重要标志^[53]。以有效载荷为微管蛋白抑制剂的第二代ADCs在血液瘤和实体瘤中均取得突破, 但仍存在脱靶毒性(如MMAE的神经毒性)和治疗窗口窄的问题^{[9, 47]}。

拓扑异构酶Ⅰ抑制剂是第三代ADCs中最早获批的有效载荷类别, 属于DNA损伤剂中的另一类DNA插入剂, 以喜树碱(camptothecine, CPT)衍生物为代表, 包括德卢替康(deruxtecan, DXD)和伊立替康活性代谢物(SN-38)^{[54, 55]}。拓扑异构酶位于细胞核内, 其作用是控制和修复DNA解链、转录上游及复制过程中出现的超螺旋和缠绕。这些催化酶可切割、修复超螺旋并重新连接DNA链。拓扑异构酶抑制剂特异性结合至DNA-拓扑异构酶复合物的界面, 从而抑制拓扑异构酶的修复机制, 阻止DNA的复制和转录, 诱导肿瘤细胞死亡^{[56, 57]}。这类有效载荷其IC₅₀值处于低纳摩尔范围(1~17.8 nmol·L^-1), 虽效力低于传统微管抑制剂, 但通过高DAR设计和旁观者效应补偿了抗原表达异质性^{[58, 59]}。戈沙妥珠单抗Trodelvy和德曲妥珠单抗Enhertu是第三代ADCs的代表性药物, Trodelvy对三阴性乳腺癌、尿路上皮癌及HR⁺/HER2^-乳腺癌疗效显著^[60-62], Enhertu则通过精准靶向HER2, 在乳腺癌、胃癌、肺癌及泛癌种中实现了疗效突破^{[16, 63]}, 两者的获批标志着ADCs从“靶向化疗”向“精准肿瘤学”的进阶, 为晚期癌症患者提供了更个体化的治疗方案。

第三代ADCs上市药物的有效载荷分别有DXD、SN-38、MMAE、DM1和SG3199。SG3199是一种DNA烷基化剂, 常用的DNA烷基化试剂有吡咯并嘧啶(pyrrolobenzodiazepine, PBD)二聚体^[64]和多卡霉素(duocarmycin)^{[65, 66]}两类化合物, 作用机制是通过共价修饰DNA碱基诱导不可修复的双链断裂, 阻止DNA的复制和转录过程, 导致肿瘤细胞凋亡。这类有效载荷作用时IC₅₀达皮摩尔级别, 是迄今合成的强效抗肿瘤化合物之一, 即使抗原表达水平较低, 低DAR (通常为2)也可实现强效杀伤, 适用于血液瘤等靶点密度高的肿瘤。目前仅有朗妥昔单抗Zynlonta于2021年获得FDA批准, 用于治疗复发或难治性大B细胞淋巴瘤的成人患者^[16]。

新型ADCs有效载荷的核心特点是突破单一毒性杀伤模式, 通过多机制协同实现精准调控与免疫激活。以免疫刺激型(immune-stimulating antibody conjugates, ISACs)载荷为例, 通过抗体递送Toll样受体(toll-like receptor, TLR)激动剂(如TLR7/8配体), 靶向激活肿瘤微环境中的树突状细胞和T细胞, 引发全身性抗肿瘤免疫^[67]。目前, 信达生物研发的靶向人滋养细胞表面抗原2 (trophoblast cell-surface antigen 2, TROP2)的IBI3007已在中国获批Ⅰ期临床, 在猴模型中显示良好耐受性, 且在TROP2阳性肿瘤异种移植模型中抑制效果显著^{[51, 68]}。抗体偶联蛋白降解剂(degrader-antibody conjugates, DACs)有效载荷通过抗体递送蛋白降解靶向嵌合分子(proteolysis-targeting chimeras, PROTAC), 诱导肿瘤细胞内致病蛋白(如BRD4、突变p53)的泛素化降解。这种新型方式克服了传统抑制剂的耐药性, 实现精准降解^[69-71]。例如, GNE-987由特异性识别并结合急性髓系白血病(AML)细胞表面CLL1蛋白的单抗和BRD4 PROTAC构成, 在多种肿瘤模型中展现出了良好的抗癌效果^[72]。Orum公司的ORM-5029 (靶向HER2的DACs)在HER2阳性乳腺癌模型中疗效优于T-DM1和DS-8201, 且在Ⅰ期临床中显示可控毒性^[73]。具有协同效应的新型ADCs中同时携带两种作用机制不同的载荷(如DNA损伤剂+微管抑制剂)或靶向两个共表达抗原, 增强抗肿瘤活性并应对异质性^{[74, 75]}。康宁杰瑞研发的JSKN021 (靶向EGFR/HER3, 载荷为拓扑异构酶抑制剂T01和MMAE)在多种肿瘤模型中显示协同杀伤效果, 肿瘤抑制率显著高于单载荷抗体偶联药物, 通过糖基定点偶联技术实现载荷均一化, JSKN021的DAR值精确控制为4 (T01)和2 (MMAE), 稳定性在大鼠、猴血清中表现优异^[76-78]。靶向RNA的有效载荷通过干扰RNA合成或降解致癌RNA, 对化疗耐药肿瘤和休眠期细胞有效^[79]。如靶向B7-H3的MHB088C在2025年公布的Ⅱ期数据显示对广泛期小细胞肺癌的客观缓解率达46.7%~57.6%, 但目前仍处于临床试验阶段, 尚未获批上市^[80]。此外, 还可以利用特定条件激活的策略实现药物定点精准释放^[68]; 也可与免疫检查点抑制剂[如程序性死亡受体-1 (programmed death-1, PD-1)单抗]^[81]或靶向药物联用^[82]等手段使药物开发更趋多元化。

ADCs有效载荷正逐步实现从“传统细胞毒性分子”向“免疫激活、基因调控与精准协同”模式的演进(表2)。未来将通过双载荷设计、人工智能(artificial intelligence, AI)优化、个性化定制, 成为连接靶向治疗、免疫治疗、基因治疗的核心枢纽, 推动癌症治疗进入“精准制导+ 系统瓦解”的新时代, 为更多难治性肿瘤患者提供突破方案。

3.3　连接子

在ADCs设计中, 连接子发挥着关键作用, 需要保证连接的细胞毒性药物在血液循环中保持稳定, 避免药物过早脱落, 同时要确保其在靶细胞内能够正常释放药物^[83]。目前根据其可裂解性进行区分将已开发出两类连接子分为可裂解连接子和不可裂解连接子两大类, 可裂解连接子又分为pH敏感型、还原敏感型、肽基连接、β-葡萄糖醛酸苷、磷酸酶裂解型连接子(表4)。

不可裂解连接子包含硫醚连接子、马来酰亚胺己酰连接子等^[84]。硫醚键的连接子因其本身具有一定的极性, 相应的抗体偶联药物具有亲水性, 使其在血液中溶解度良好; 由于硫醚键具有较好的化学稳定性, 使药物在血浆中结构稳定, 减少提前释放细胞毒性药物的风险, 从而降低脱靶毒性^[85]。同时, 稳定的连接子结构使药物在体内的消除速率相对减慢, 有助于延长药物半衰期, 提高在体内的有效浓度。马来酰亚胺基-己酰基(maleimidocaproyl, MC)连接子含有较长的烷基链, 具有较强的疏水性, 使得此类抗体偶联药物可能在血浆中发生聚集, 影响药物的稳定性和有效性。马来酰亚胺基-己酰基连接子的化学结构也相对稳定, 在血浆中不易被酶或化学物质轻易裂解。由于MC结构的疏水性使得药物易与脂蛋白结合, 从而改变在组织中的分布, 也会影响肿瘤富集和清除过程^{[86, 87]}。这类不可裂解连接子通过稳定共价键连接抗体与细胞毒性药物, 依赖溶酶体对抗体的酶促降解释放有效载荷, 但其载荷释放完全依赖于肿瘤细胞内溶酶体对抗体的降解, 即若溶酶体功能异常或降解效率低, 会导致载荷释放不足或延迟, 影响疗效^[88]。此外, 不可裂解连接子释放速率较慢, 需经数小时至数天的降解过程, 难以快速达到有效载荷浓度, 可能减弱对肿瘤的杀伤效果并增加耐药风险; 在与快速起效药物联合治疗时, 也可能因时间不匹配而降低协同作用。第二代ADCs上市药物恩美曲妥珠单抗Kadcyla使用不可裂解的连接子MCC将有效载荷DM1与抗HER2单克隆抗体曲妥珠单抗的赖氨酸残基相连^[89]。总体而言, 采用不可裂解连接子时, 需对不可裂解连接子ADCs所有可能代谢产物的药代动力学/药效学(pharmacokinetics/pharmacodynamics, PK/PD)特性及毒性谱进行全面评估, 同时精心筛选和设计载荷结构, 确保修饰后的载荷分子能保持相当或更优的抗肿瘤效力。

可裂解连接子又分为化学可裂解连接子和酶可裂解连接子, 这类连接子有pH敏感型的腙键连接子、谷胱甘肽敏感型的二硫键连接子和蛋白酶敏感型的肽连接子。腙键类连接子在碱性环境中稳定, 但对酸性环境高度敏感。它们利用内体(pH = 5~6)和溶酶体(pH = 4.8)的低pH环境, 腙键连接子在该环境下易水解, 继而释放有效载荷^[90]。采用腙键偶联策略开发的嵌合型抗体BR96-多柔比星偶联物DOX (BR96-DOX)曾进入转移性乳腺癌Ⅱ期临床试验: 尽管该偶联物的毒性特征较游离多柔比星显著改善, 但仍存在明显胃肠道毒性, 且因耐受性低下导致临床疗效不佳^[44]。Mylotarg也曾因连接子不稳定, 在血液循环中会部分发生断裂, 导致卡奇霉素过早释放, 从而引发严重的肝毒性等不良反应于2010年撤市^[12]。这两种ADCs的毒性与低耐受性问题, 根源均指向腙键连接子在循环系统中的不稳定性——已有研究证实, 腙键连接子在生理条件(pH 7.4、37 ℃)下会发生缓慢水解反应, 半衰期远短于理想连接子, 导致细胞毒性载荷提前从抗体上释放, 进而引发脱靶毒性与耐受性问题, 最终影响临床效果。谷胱甘肽敏感型连接子是另一类常见可裂解连接子, 也是酸不稳定腙键连接子的替代选择。该策略基于肿瘤细胞内细胞质中还原性分子(如谷胱甘肽)浓度(1~10 mmol·L^-1)显著高于细胞外环境(血液中约5 µmol·L^-1)的特性。连接子中嵌入的二硫键可抵抗循环系统中的还原裂解, 但内化后细胞内谷胱甘肽浓度远高于细胞外, 导致二硫键被还原裂解释放游离载荷^[91]。在肿瘤细胞处于缺氧等应激状态时, 其内部硫醇水平会显著升高^[92]。利用细胞质与细胞外环境中谷胱甘肽浓度的差异性, 可通过二硫键连接子的断裂实现药物载荷向靶向肿瘤的选择性递送^[93]。除谷胱甘肽外, 细胞内蛋白质二硫键异构酶(protein disulfide isomerase, PDI)同样具备还原二硫键的能力。该酶活性位点上的两个半胱氨酸残基可催化底物间或底物内的硫醇-二硫键交换反应^[94]。为增强循环稳定性, 常在二硫键邻近位点引入甲基^[95]。此类连接子已应用于Mylotarg及多个处于临床试验阶段的美登素类候选药物^[96-98]。

研究人员使用蛋白酶敏感型的肽连接子, 在可控药物释放方面已取得临床成功。与化学不稳定的连接子不同, 酶可切割连接子利用细胞区室中高浓度的独特水解酶来降解肽和碳水化合物^{[99, 100]}。这种策略利用细胞内蛋白酶(如组织蛋白酶B)识别并切割二肽键(如缬氨酸-瓜氨酸Val-Cit、苯丙氨酰-赖氨酸Phe-Lys)的特性, 实现药物的精准释放。由于血清蛋白酶抑制剂的存在及不适宜的血浆pH环境, 肽基连接子(又称溶酶体蛋白酶敏感连接子)表现出更高的全身稳定性, 同时在靶细胞溶酶体内可通过酶促反应快速释放有效载荷^[101]。布妥昔单抗维多汀Adcetris是由靶向CD30的布妥昔单抗和小分子毒性药物MMAE通过可裂解的二肽连接子(Val-Cit)偶联而成, 其药物中的抗体与肿瘤细胞表面CD30结合后, ADCs能被细胞内化, 溶酶体中的组织蛋白酶可以识别并切割二肽连接子(Val-Cit), 释放出具有细胞毒性的MMAE, MMAE可抑制微管聚合, 使肿瘤细胞周期停滞于G₂/M期, 最终诱导肿瘤细胞凋亡^[51]。

糖苷酶敏感型连接子以糖苷键为核心结构, 通过该键连接功能分子(如细胞毒素、荧光基团)与载体分子(如抗体、纳米颗粒)。当环境中存在特异性糖苷酶时, 糖苷键被水解, 释放功能分子并发挥作用。β-葡萄糖醛酸酶是一类溶酶体水解酶, 可将β-葡萄糖醛酸残基降解为单糖。该酶主要定位于细胞溶酶体中, 在酸性环境(pH 4.5~5.5)下发挥活性, 使有效载荷从偶联物中释放。与组织蛋白酶B (可主动分泌至细胞外)类似, β-葡萄糖醛酸酶在肿瘤坏死区域可因细胞破裂释放到细胞外微环境中, 从而在细胞外具备酶活性^[102]。利用这一特性, ADCs可实现“双重微环境响应”—既可以在肿瘤细胞溶酶体内被酶切, 也能在肿瘤坏死区因酶释放触发药物载荷释放, 扩大作用范围。基于此, 用β-葡萄糖醛酸作为连接子偶联抗体与毒素, 同时加入自剪切对氨基苄基氨基甲酸酯(para-amino benzyl carbamate, PABC)间隔臂。其中, 连接子负责被β-葡萄糖醛酸酶切断糖苷键; 间隔臂在连接子断裂后, PABC自动剪切, 确保毒素完全游离。这一设计稳定性更高, PABC间隔臂减少药物在血液循环中的过早释放; 释放更可控, 细胞毒性药物分两步释放(酶促水解→自发分解), 保证毒素精准、完全释放。另一类溶酶体水解酶是β-半乳糖苷酶, 它可降解半乳糖与其有机部分之间形成的β-糖苷键^[103]。Kolodych等^[104]研究了β-半乳糖苷酶切割抗体偶联药物的体外和体内活性。研究表明, 与获批用于治疗乳腺癌的T-Kadcyla相比, 基于β-半乳糖苷酶可切割连接子的ADCs在体外酶解实验或荷瘤小鼠模型中表现出更高的药物释放效率或肿瘤抑制效果。

磷酸酶可切割连接子属于另一类重要的酶响应型连接子, 其作用机制依赖于溶酶体区室中特异性靶酶的表达。这类连接子主要靶向焦磷酸酶和酸性磷酸酶, 通过酶解作用将焦磷酸盐或末端单磷酸酯键水解为相应的醇类化合物。Garbaccio团队^[105]曾报道过一种含磷酸盐桥且对组织蛋白酶B敏感的连接子, 以PABC作为间隔分子, 设计了水溶性的磷酸盐药物偶联物, 其结构包含可切割的Val-Cit-PABC连接子。具体作用机制为: 当二肽连接子(Val-Cit)被蛋白酶水解后, PABC基团发生自发消除, 进而暴露末端磷酸盐基团, 经磷酸酶水解后释放细胞毒性药物。体外实验表明, 含有该连接子的ADCs具有高血液稳定性、快速溶酶体切割能力及良好水溶性。这些特性支持其在生物偶联反应及亲脂性有效载荷ADCs中的应用, 但其体内有效性仍需进一步实验验证。之后, Garbaccio团队^[106]又开展了一项更深入的研究, 报道了一种具有高水溶性、含焦磷酸盐抗体偶联药物。该研究利用连接子的生物正交特性, 将磷酸二酯键引入烷基链结构中, 所制备ADCs需要经过焦磷酸酶与酸性磷酸酶的双重酶解切割, 最终释放糖皮质激素。焦磷酸结构在溶酶体中的裂解速度比单磷酸盐快3~5倍, 且双重酶解的级联效应进一步增强了靶向释放的精确性。以肽键连接或磷酸裂解的连接子采用生物可降解结构, 降解产物无毒性, 对ADCs药代影响较小。

连接子通常会影响ADC的稳定性、毒性、药代动力学性质和药效学, 因此在ADC设计中选择合适的连接子必须相当谨慎。此外, 连接子必须考虑细胞毒性药物上的反应性基团, 包括单抗和衍生物官能团。大多数临床阶段的ADCs使用常见的Lys和Cys残基偶联。在这种背景下, 研究人员目前正致力于研究新的连接子, 例如光敏ADC连接子和生物双正交可裂解连接子。光响应性可裂解触发因素具有以下优势: ①可实现药物释放的精准调控, 有效降低脱靶毒性; ②裂解机制明确, 且不受细胞内释放条件的限制。此外, 该类触发因素还具备毒性低、响应速度快、灵敏度及特异性高等特点。2019年, Zang等^[107]报道了一种基于光笼化C40-氧化脱碱基位点(PC4AP)的光响应性自裂解连接子。该连接子通过精巧设计在单一化学触发器中实现了“双重保险”机制: 在365 nm光照下, PC4AP的羟基与其自身抗体上的邻近胺基发生分子内加成反应, 随后通过消除反应实现连接子裂解及载荷释放。释放研究证实, 只有在同时存在N端胺基和光照的条件下, 载荷才能于1 h孵育后完全释放, 单一光照条件无法触发释放。生物正交化学是指能在生物体内发生却不干扰正常生理过程的化学反应, 具有高选择性、快速简便处理及无毒副产物的特征^{[108, 109]}。因此生物正交裂解对可作为理想的可裂解触发器。2019年, Wang等^[110]开发了一种采用经典生物正交裂解对—Cu (Ⅰ)-2-(4-((双((1-叔丁基三唑-4-基)甲基)氨基)甲基)三唑-1-基)乙酸[2-(4-((bis((1-tertbutyltriazol-4-yl)methyl)amino)methyl)triazol-1-yl) acetic acid, BTTAA] 与双取代炔丙氧羰基(dsProc)的生物正交可裂解连接子。该含生物正交裂解触发器的抗体偶联药物能在癌细胞表面释放载荷。尽管游离铜离子广泛分布, 但已证实dsProc仅对Cu (Ⅰ)-BTTAA具有高选择性和裂解反应性。新型光响应裂解触发器和生物正交裂解触发器的开发, 不仅能突破传统ADCs的细胞内药物释放限制, 为非内吞性抗体的应用创造机会, 但其对底膜渗透性载荷(如MMAF)的适用性仍存疑。尽管连接子的开发已取得巨大进展, 但此类基于特异性、高效力且低毒性连接子的抗体偶联药物的上市仍有很长的路要走。

连接子-抗体偶联键是连接连接子与抗体的桥梁。过去10年的广泛研究揭示了将载荷连接至抗体的策略具有至关重要的意义。尽管早期ADCs主要合成为异质混合物, 但研究发现其药代动力学特性、稳定性、耐受性和/或疗效均未达最优, 当前研究重点已转向生成具有精确载药量及预设可控连接位点的均质化构建体。与异质ADCs相比, 均质化ADCs展现出更优异的整体药理学特征。目前已获批的ADCs本质上是不同DAR值组分的混合物, 开发均质化ADCs一直是领域内的目标。当前主要通过两种策略实现: 位点特异性偶联技术^{[111, 112]}和连接子-抗体连接结构的化学修饰^{[113, 114]}。位点特异性偶联技术可以通过化学修饰、酶法修饰或二者联用技术对特定氨基酸或糖残基进行精确修饰实现。连接子-抗体连接结构的化学修饰可通过微小结构解决硫醇与马来酰亚胺偶联中的逆迈克尔消除反应问题, 在一定成熟度上显著提升抗体偶联药物稳定性, 应用前景广阔。

4　总结与展望

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抗体偶联药物凭借其独特的作用机制, 在历经三代技术革新后实现了多维度升级: 药物稳定性、DAR的均一性及抗肿瘤活性, 治疗窗口也随之扩大(表5)。但是, 抗体偶联药物是由高靶向性抗体、设计优良的连接子与高活性有效载荷组合形成的精准药物递送系统。由于其组成复杂, 当前ADCs的研发与应用仍面临以下挑战: ①毒性问题亟待解决, ADCs的有效载荷毒性通常是传统化疗药物的100倍, 若连接子导致其在正常组织中发生非特异性释放, 最终会引发全身性不良反应。未来, 更具选择性的连接子需同时实现“在肿瘤组织中快速释放有效载荷”与“在正常组织中有效降低脱靶毒性”, 这一重要科学假设是当前需要研究的核心方向; ②耐药性是ADCs面临的另一大挑战: 尽管ADCs耐药机制尚未完全明确, 但研究表明, 靶抗原下调、ADCs内吞效率降低、活性有效载荷外排可能是主要原因。MMAE、DM1等传统有效载荷易因肿瘤细胞外排泵(如P-gp)过表达或靶点突变导致耐药。因此, 研究人员将SN-38、PBD等新型有效载荷应用于ADCs, 而新型低毒性高选择性载荷的开发也需要配套新型连接子的支撑; 同时通过结构修饰(如引入亲脂性基团)提升载荷膜通透性, 强化“旁观者效应”, 也可适配实体瘤治疗; ③连接子结构相对复杂, 导致其临床前研究与临床应用难度较大, 因此, 开发结构简化、功能集成的连接子可能成为另一重要研究方向, 优化非天然氨基酸插入技术(如基因密码子扩展), 或开发新型化学偶联试剂(如硫醇-烯烃点击试剂), 以低成本获得均质ADCs也是新的挑战。

除此之外, 通过将抗体部分替换为多肽或核酸适体, 可衍生出多肽偶联药物(peptide-drug conjugates, PDC)、核酸适体偶联药物(aptamer-drug conjugate, ApDC)等新型药物形式; 若替换细胞毒性载荷为免疫刺激分子或寡核苷酸, 则可开发抗体免疫刺激偶联药物(immunostimulatory antibody conjugates, ApDC)、抗体寡核苷酸偶联药物(antibody-oligonucleotide conjugates, AOC)等创新疗法。通过构建抗体-抗菌药偶联物(antibody-antibacterial conjugates, AACs)、抗体-病毒靶向偶联物(antibody-virus targeted conjugates)等新型组合, 形成覆盖多元化疾病领域的创新药物研发模式。随着技术的持续创新与优化, 抗体偶联药物及其衍生技术平台有望在感染性疾病、自身免疫病等更广泛的疾病领域实现突破性进展。

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2026年第61卷第6期

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doi: 10.16438/j.0513-4870.2025-0843

接收时间：2025-07-18
首发时间：2026-09-21
出版时间：2026-06-12

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收稿日期：2025-07-18
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¹郑州大学化学学院, 平原实验室, 抗病毒性传染病创新药物全国重点实验室, 河南郑州 450001

²郑州大学药学院, 河南郑州 450001

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孟勇刚, E-mail: mengyonggang@zzu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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EndNote
RefWorks
TxT

Brand name	Company	Tumor type	Approval date	Approval authority
Mylotarg	Pfizer	AML	2000. 5, 2017. 9	FDA
Adcetris	Seagen, Takeda	HL, ALCL	2011. 8	FDA
Kadcyla	Genentech	Breast cancer	2013. 2	FDA
Besponsa	Pfizer	ALL	2017. 8	EMA
Lumoxiti	AstraZeneca	HCL	2018. 9	FDA
Polivy	Genentech	DLBCL	2019. 6	FDA
Padcev	Seagen, Astellas	UC	2019. 12	FDA
Enhertu	AstraZeneca, Daiichi Sankyo	Breast cancer	2019. 12	FDA
Trodelvy	Immunomedics	Breast cancer	2020. 4	FDA
Blenrep	GSK	MM	2020. 8	FDA
Akalux	Lotte Chemical	HNSCC	2020. 9	PMDA
Zynlonta	ADC Therapeutics	R/R, LBCL	2021. 4	FDA
Aidixi	RemeGen	GC, UC	2021. 6	NMPA
Tivdak	Seagen	Cervical cancer	2021. 9	FDA
Elahere	ImmunoGen	Ovarian cancer	2022. 11	FDA
Azedra	Kelun-Biotech	TNBC	2024. 11	NMPA
Datroway	DaiichiI	NSCLC	2025. 1	FDA
Emrelis	ABBV.US	NSCLC	2025. 5	FDA
Trastuzumab rezetecan	Hengrui	NSCLC	2025. 5	NMPA

Brand name

Company

Tumor type

Approval date

Approval authority

Mylotarg

Pfizer

AML

2000. 5, 2017. 9

FDA

Adcetris

Seagen, Takeda

HL, ALCL

2011. 8

FDA

Kadcyla

Genentech

Breast cancer

2013. 2

FDA

Besponsa

Pfizer

ALL

2017. 8

EMA

Lumoxiti

AstraZeneca

HCL

2018. 9

FDA

Polivy

Genentech

DLBCL

2019. 6

FDA

Padcev

Seagen, Astellas

2019. 12

FDA

Enhertu

AstraZeneca, Daiichi Sankyo

Breast cancer

2019. 12

FDA

Trodelvy

Immunomedics

Breast cancer

2020. 4

FDA

Blenrep

GSK

2020. 8

FDA

Akalux

Lotte Chemical

HNSCC

2020. 9

PMDA

Zynlonta

ADC Therapeutics

R/R, LBCL

2021. 4

FDA

Aidixi

RemeGen

GC, UC

2021. 6

NMPA

Tivdak

Seagen

Cervical cancer

2021. 9

FDA

Elahere

ImmunoGen

Ovarian cancer

2022. 11

FDA

Azedra

Kelun-Biotech

TNBC

2024. 11

NMPA

Datroway

DaiichiI

NSCLC

2025. 1

FDA

Emrelis

ABBV.US

NSCLC

2025. 5

FDA

Trastuzumab rezetecan

Hengrui

NSCLC

2025. 5

NMPA

BsADCs	Targets	Company	Clinical development phase
BL-B01D1	EGFR/HER3	Sichuan Biokin, Bristol Myers Squib	Phase Ⅲ
TQB2102	HER2 (ECD2/ECD4)	Chia Tai Tianqing	Phase Ⅲ
JSKN003	HER2/TROP1	Alphamab Oncology, CSPC Pharmaceutical	Phase Ⅲ
JSKN016	HER3/TROP2	Alphamab Oncology	Phase Ⅱ
IMGN-151	FOLR1	ImmunoGen	Phase Ⅱ
SKB571	EGFR/c-MET	Sichuan Kelun-Biotech Biopharmaceutical	Phase Ⅱ
REGN5093-M114	MET	Regeneron Pharmaceuticals	Phase Ⅰ/Ⅱ
DB-1418	HER3/EGFR	Duality Biologics, Avenzo Therapeutics	Phase Ⅰ/Ⅱ
DB-1419	B7-H3/PD-L1	Duality Biologics	Phase Ⅰ/Ⅱ
SHR-1681	HER3/c-MET	Jiangsu Hengrui Pharmaceuticals	Phase Ⅰ/Ⅱ
PRO-1286	EGFR/c-MET	ProfoundBio	Phase Ⅰ/Ⅱ
M-1231	EGFR/MUC1	Merck, Sutro Biopharma	Phase Ⅰ
ZW-49	HER2 (ECD2/ECD4)	Zymeworks	Phase Ⅰ
KM501	HER2	Xuanzhu Biopharmaceutical	Phase Ⅰ
TQB6411	EGFR/MET	Chia Tai Tianqing	Phase Ⅰ
AK146D1	TROP2/Nectin-4	Akeso	Phase Ⅰ
BR-111	ROR1	BrightGene Bio-Medical Technology	Phase Ⅰ
ALK202	EGFR/c-MET	Shanghai Allink Biotherapeutics	Phase Ⅰ
DM005	EGFR/c-MET	Doma Pharmaceutical Technology, Biocytogen Pharmaceuticals	Phase Ⅰ
IBI-3001	B7-H3/EGFR	Innovent Biologics	Phase Ⅰ
BL-B16D1	EGFR/HER3	Sichuan Biokin	Phase Ⅰ
AZD9592	EGFR/c-MET	AstraZeneca	Phase Ⅰ
TJ-101	EGFR/ B7-H3	Shanghai Tuoji Pharmaceutical	Phase Ⅰ
IBI-3005	EGFR/HER3	Innovent Biologics	Phase Ⅰ

BsADCs

Targets

Company

Clinical development phase

BL-B01D1

EGFR/HER3

Sichuan Biokin, Bristol Myers Squib

Phase Ⅲ

TQB2102

HER2 (ECD2/ECD4)

Chia Tai Tianqing

Phase Ⅲ

JSKN003

HER2/TROP1

Alphamab Oncology, CSPC Pharmaceutical

Phase Ⅲ

JSKN016

HER3/TROP2

Alphamab Oncology

Phase Ⅱ

IMGN-151

FOLR1

ImmunoGen

Phase Ⅱ

SKB571

EGFR/c-MET

Sichuan Kelun-Biotech Biopharmaceutical

Phase Ⅱ

REGN5093-M114

MET

Regeneron Pharmaceuticals

Phase Ⅰ/Ⅱ

DB-1418

HER3/EGFR

Duality Biologics, Avenzo Therapeutics

Phase Ⅰ/Ⅱ

DB-1419

B7-H3/PD-L1

Duality Biologics

Phase Ⅰ/Ⅱ

SHR-1681

HER3/c-MET

Jiangsu Hengrui Pharmaceuticals

Phase Ⅰ/Ⅱ

PRO-1286

EGFR/c-MET

ProfoundBio

Phase Ⅰ/Ⅱ

M-1231

EGFR/MUC1

Merck, Sutro Biopharma

Phase Ⅰ

ZW-49

HER2 (ECD2/ECD4)

Zymeworks

Phase Ⅰ

KM501

HER2

Xuanzhu Biopharmaceutical

Phase Ⅰ

TQB6411

EGFR/MET

Chia Tai Tianqing

Phase Ⅰ

AK146D1

TROP2/Nectin-4

Akeso

Phase Ⅰ

BR-111

ROR1

BrightGene Bio-Medical Technology

Phase Ⅰ

ALK202

EGFR/c-MET

Shanghai Allink Biotherapeutics

Phase Ⅰ

DM005

EGFR/c-MET

Doma Pharmaceutical Technology, Biocytogen Pharmaceuticals

Phase Ⅰ

IBI-3001

B7-H3/EGFR

Innovent Biologics

Phase Ⅰ

BL-B16D1

EGFR/HER3

Sichuan Biokin

Phase Ⅰ

AZD9592

EGFR/c-MET

AstraZeneca

Phase Ⅰ

TJ-101

EGFR/ B7-H3

Shanghai Tuoji Pharmaceutical

Phase Ⅰ

IBI-3005

EGFR/HER3

Innovent Biologics

Phase Ⅰ

Payload	Mechanism of action	IC₅₀ value	Key advantage	Major limitation	Example ADCs
Methotrexat; doxorubicin; mitomycin C	Antifolate agent; DNA intercalator	μmol·L^-1	Broad-spectrum	Poor selectivity; drug resistance	-
Calicheamicin	DNA double-strand breaker	μmol·L^-1	Pioneered potent DNA damage	Off-target toxicity due to an unstable linker	Mylotarg
DM1; DM4; MMAE; MMAF	Microtubule polymerization inhibitor	10^-9-10^-10 mol·L^-1	High potency & broad applicability	Off-target toxicity; narrow therapeutic window	Adcetris; Kadcyla
DXD; SN-38	DNA intercalator	nmol·L^-1	High DAR & bystander effect	Lower potency vs microtubule agents	Trodelvy; Enhertu
PBD dimer; duocarmycin	DNA alkylating agent	pmol·L^-1	Effective for low antigen tumors	Limited clinical use (only Zynlonta)	Zynlonta

Payload

Mechanism of action

IC₅₀ value

Key advantage

Major limitation

Example ADCs

Methotrexat; doxorubicin; mitomycin C

Antifolate agent; DNA intercalator

μmol·L^-1

Broad-spectrum

Poor selectivity; drug resistance

Calicheamicin

DNA double-strand breaker

μmol·L^-1

Pioneered potent DNA damage

Off-target toxicity due to an unstable linker

Mylotarg

DM1; DM4; MMAE; MMAF

Microtubule polymerization inhibitor

10^-9-10^-10 mol·L^-1

High potency & broad applicability

Off-target toxicity; narrow therapeutic window

Adcetris;
Kadcyla

DXD; SN-38

DNA intercalator

nmol·L^-1

High DAR & bystander effect

Lower potency vs microtubule agents

Trodelvy;
Enhertu

PBD dimer; duocarmycin

DNA alkylating agent

pmol·L^-1

Effective for low antigen tumors

Limited clinical use (only Zynlonta)

Zynlonta

Linker type	Linker	Approved ADC	Plasma stability	Cleavage condition	Cleavage site
pH-sensitive	Hydrazone linker	Mylotarg	Moderate	pH 4.5-5.5	Lysosome/endosome
Reduction-sensitive	Disulfide linker	Zynlonta	Moderate	High reducing environment (e.g., GSH)	Cytoplasm
Protease-cleavable	Peptide linker (e.g., Val-Cit)	Adcetris	High	Protease hydrolysis (e.g., Cathepsin B)	Lysosome
β-Glucuronide	β-Glucuronide linker	Trodelvy	High	1, 6-Elimination upon glucuronidase cleavage	Lysosome
Phosphate	Phosphate ester linker	-	High	Phosphatase-mediated hydrolysis	Lysosome
Non-cleavable linker	Maleimido-thioether linker	Kadcyla	Very high	Lysosomal degradation of the entire ADC	Lysosome

Linker type

Linker

Approved ADC

Plasma stability

Cleavage condition

Cleavage site

pH-sensitive

Hydrazone linker

Mylotarg

Moderate

pH 4.5-5.5

Lysosome/endosome

Reduction-sensitive

Disulfide linker

Zynlonta

Moderate

High reducing environment (e.g., GSH)

Cytoplasm

Protease-cleavable

Peptide linker (e.g., Val-Cit)

Adcetris

High

Protease hydrolysis (e.g., Cathepsin B)

Lysosome

β-Glucuronide

β-Glucuronide linker

Trodelvy

High

1, 6-Elimination upon glucuronidase cleavage

Lysosome

Phosphate

Phosphate ester linker

High

Phosphatase-mediated hydrolysis

Lysosome

Non-cleavable linker

Maleimido-thioether linker

Kadcyla

Very high

Lysosomal degradation of the entire ADC

Lysosome

Key component	Antibody	Payload	Linker
Core characteristics	Targeting specificity; PK modulation; effector function; mature human mab platforms	High potency; diverse MOAs; novel payload; controllable toxicity	Stability optimization; site-specific conjugation; biodegradable scaffolds; improved solubility
Current technical bottlenecks	Poor solid tumor penetration; target-dependent resistance; inefficient internalization; off-target binding	MDR-mediated resistance; limited membrane permeability; narrow therapeutic window; payload-linker incompatibility	Stability-release trade-off; DAR heterogeneity; limited TME responsiveness; scalability challenges
Future directions	Nanobody/single-chain antibody; bispecific antibodies; enhanced internalization; TME-responsive design	Resistance reversal payloads; enhanced membrane permeability; high-selectivity payloads; payload-linker innovation	Dual/multi-responsive linkers; homogeneous conjugation; novel cleavable linkers; industrial process optimization

Key component

Antibody

Payload

Linker

Core characteristics

Targeting specificity; PK modulation; effector function; mature human mab platforms

High potency; diverse MOAs; novel payload; controllable toxicity

Stability optimization; site-specific conjugation; biodegradable scaffolds; improved solubility

Current technical bottlenecks

Poor solid tumor penetration; target-dependent resistance; inefficient internalization; off-target binding

MDR-mediated resistance; limited membrane permeability; narrow therapeutic window; payload-linker incompatibility

Stability-release trade-off; DAR heterogeneity; limited TME responsiveness; scalability challenges

Future directions

Nanobody/single-chain antibody; bispecific antibodies; enhanced internalization; TME-responsive design

Resistance reversal payloads; enhanced membrane permeability; high-selectivity payloads; payload-linker innovation

Dual/multi-responsive linkers; homogeneous conjugation; novel cleavable linkers; industrial process optimization