药学学报

Category	Structure
Cleavable linker	pH sensitive linker
Reducible disulfide
Cathepsin-B-cleavable linker
β-Glucuronidase-cleavable linker
Non-cleavable linker

Category

Structure

Cleavable linker

pH sensitive linker

Reducible disulfide

Cathepsin-B-cleavable linker

β-Glucuronidase-cleavable linker

Non-cleavable linker

Category	Structure
Cleavable linker	pH sensitive linker
Reducible disulfide
Cathepsin-B-cleavable linker
β-Glucuronidase-cleavable linker
Non-cleavable linker

Category

Structure

Cleavable linker

pH sensitive linker

Reducible disulfide

Cathepsin-B-cleavable linker

β-Glucuronidase-cleavable linker

Non-cleavable linker

Category	Structure
Tubulin inhibitor
DNA damaging agent	DNA double strand break inducer
DNA alkylating agent
DNA topoisomerase I inhibitor
DNA crosslinker
Immunomodulator	TLR agonist
STING agonist
Radionuclide	β-Emitting radionuclide	¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re
α-Emitting radionuclide	²¹³Bi, ²¹¹At

Category

Structure

Tubulin inhibitor

DNA damaging agent

DNA double strand break inducer

DNA alkylating agent

DNA topoisomerase I inhibitor

DNA crosslinker

Immunomodulator

TLR agonist

STING agonist

Radionuclide

β-Emitting radionuclide

¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re

α-Emitting radionuclide

²¹³Bi, ²¹¹At

Category	Structure
Tubulin inhibitor
DNA damaging agent	DNA double strand break inducer
DNA alkylating agent
DNA topoisomerase I inhibitor
DNA crosslinker
Immunomodulator	TLR agonist
STING agonist
Radionuclide	β-Emitting radionuclide	¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re
α-Emitting radionuclide	²¹³Bi, ²¹¹At

Category

Structure

Tubulin inhibitor

DNA damaging agent

DNA double strand break inducer

DNA alkylating agent

DNA topoisomerase I inhibitor

DNA crosslinker

Immunomodulator

TLR agonist

STING agonist

Radionuclide

β-Emitting radionuclide

¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re

α-Emitting radionuclide

²¹³Bi, ²¹¹At

Target antigen	ADC name	Payload	Linker	Pre-clinical model	Status
Mesothelin	Anetumab ravtansine (BAY 94-934)	DM4	Cleavable SPDB	MIA PaCa-2/meso pancreatic xenograft and patient-derived pancreatic model (PAXF736)	Phase Ⅰ: NCT01439152; Phase Ⅱ: NCT03023722; Phase Ⅰb: NCT03816358
Globo H	OBI-999	MMAE	Cleavable Val-Cit	HPAC pancreatic xenograft	Phase Ⅰ/Ⅱ: NCT04084366
Claudin18.2	CMG901	MMAE	Cleavable linker	Not available	Phase Ⅰa: NCT04805307
SYSA-1801	MMAE	Cleavable linker	Not available	Phase Ⅰ: NCT05009966
RC118	MMAE	Cleavable linker	Not available	Phase Ⅰ/Ⅱ: NCT05205850
CLDN18.2-307-ADC	MMAE	Cleavable Val-Cit	HUPT4 and PATU8998S pancreatic xenograft	Phase Ⅰ: NCT05156866
c-MET	SHR-A1403 (HTI-1066)	SHR152852	Non-cleavable thioether linker ATPPA	AsPC-1 pancreatic xenograft	Phase Ⅰ: NCT03398720; Phase Ⅰ: NCT03856541
TR1801	SG3199	Cleavable Val-Ala	Patient-derived pancreatic model (PDX1334 and PDX1342)	Phase Ⅰ: NCT03859752
RC108	MMAE	Cleavable Val-Cit	Not available	Phase Ⅰ: NCT04617314; Phase Ⅱ: NCT05628857
CEACAM5	Labetuzumab-SN-38	SN-38	Cleavable CL2 linker	Capan-1 pancreatic xenograft	Preclinical
Tusamitamab ravtansine (SAR408701)	DM4	Cleavable SPDB	Not available	Phase Ⅰ: NCT02187848
Trop2	Sacituzumab govitecan (IMMU-132)	SN-38	Cleavable CL2A linker	Capan-1 and BxPC-3 pancreatic xenograft	Phase Ⅰ/Ⅱ: NCT01631552
¹⁷⁷Lu-DOTA-hIMB1636	¹⁷⁷Lu	DOTA-NHS-ester	T3M4 pancreatic xenograft	Preclinical
hIMB1636-MMAE	MMAE	Cleavable Val-Cit	T3M4 and BxPc-3 pancreatic xenograft	Preclinical
HuNb_TROP2-HSA-MMAE	MMAE	Cleavable Val-Cit	BxPC-3 pancreatic xenograft	Preclinical
EGFR	RC68-MMAE	MMAE	Cleavable Val-Cit	BxPC-3 pancreatic xenograft	Preclinical
CTX-MMAE	MMAE	Cleavable Val-Cit	MIA PaCa-2 and PANC-1 pancreatic xenograft	Preclinical
LR004-DM1	DM1	Noncleavable SMCC	Capan-2 pancreatic xenograft	Preclinical
ICAM-1	ICAM-1-DM1	DM1	Noncleavable SMCC	PANC-1 pancreatic xenograft	Preclinical
MUC1	SAR566658	DM4	Cleavable SPDB	Capan-2 pancreatic xenograft	Preclinical
HzMUC1-MMAE	MMAE	Cleavable Val-Cit	CFPAC-1 and Capan-2 pancreatic xenograft	Preclinical
GPC-1	GPC-1-MMAE	MMAE	Cleavable Val-Cit	Patient-derived pancreatic model (PK565, PK645, PK175 and KPK1)	Preclinical

Target antigen

ADC name

Payload

Linker

Pre-clinical model

Status

Mesothelin

Anetumab ravtansine (BAY 94-934)

DM4

Cleavable SPDB

MIA PaCa-2/meso pancreatic xenograft and patient-derived pancreatic model (PAXF736)

Phase Ⅰ: NCT01439152; Phase Ⅱ: NCT03023722; Phase Ⅰb: NCT03816358

Globo H

OBI-999

MMAE

Cleavable Val-Cit

HPAC pancreatic xenograft

Phase Ⅰ/Ⅱ: NCT04084366

Claudin18.2

CMG901

MMAE

Cleavable linker

Not available

Phase Ⅰa: NCT04805307

SYSA-1801

MMAE

Cleavable linker

Not available

Phase Ⅰ: NCT05009966

RC118

MMAE

Cleavable linker

Not available

Phase Ⅰ/Ⅱ: NCT05205850

CLDN18.2-307-ADC

MMAE

Cleavable Val-Cit

HUPT4 and PATU8998S pancreatic xenograft

Phase Ⅰ: NCT05156866

c-MET

SHR-A1403 (HTI-1066)

SHR152852

Non-cleavable thioether linker ATPPA

AsPC-1 pancreatic xenograft

Phase Ⅰ: NCT03398720; Phase Ⅰ: NCT03856541

TR1801

SG3199

Cleavable Val-Ala

Patient-derived pancreatic model (PDX1334 and PDX1342)

Phase Ⅰ: NCT03859752

RC108

MMAE

Cleavable Val-Cit

Not available

Phase Ⅰ: NCT04617314; Phase Ⅱ: NCT05628857

CEACAM5

Labetuzumab-SN-38

SN-38

Cleavable CL2 linker

Capan-1 pancreatic xenograft

Preclinical

Tusamitamab ravtansine (SAR408701)

DM4

Cleavable SPDB

Not available

Phase Ⅰ: NCT02187848

Trop2

Sacituzumab govitecan (IMMU-132)

SN-38

Cleavable CL2A linker

Capan-1 and BxPC-3 pancreatic xenograft

Phase Ⅰ/Ⅱ: NCT01631552

¹⁷⁷Lu-DOTA-hIMB1636

¹⁷⁷Lu

DOTA-NHS-ester

T3M4 pancreatic xenograft

Preclinical

hIMB1636-MMAE

MMAE

Cleavable Val-Cit

T3M4 and BxPc-3 pancreatic xenograft

Preclinical

HuNb_TROP2-HSA-MMAE

MMAE

Cleavable Val-Cit

BxPC-3 pancreatic xenograft

Preclinical

EGFR

RC68-MMAE

MMAE

Cleavable Val-Cit

BxPC-3 pancreatic xenograft

Preclinical

CTX-MMAE

MMAE

Cleavable Val-Cit

MIA PaCa-2 and PANC-1 pancreatic xenograft

Preclinical

LR004-DM1

DM1

Noncleavable SMCC

Capan-2 pancreatic xenograft

Preclinical

ICAM-1

ICAM-1-DM1

DM1

Noncleavable SMCC

PANC-1 pancreatic xenograft

Preclinical

MUC1

SAR566658

DM4

Cleavable SPDB

Capan-2 pancreatic xenograft

Preclinical

HzMUC1-MMAE

MMAE

Cleavable Val-Cit

CFPAC-1 and Capan-2 pancreatic xenograft

Preclinical

GPC-1

GPC-1-MMAE

MMAE

Cleavable Val-Cit

Patient-derived pancreatic model (PK565, PK645, PK175 and KPK1)

Preclinical

Target antigen	ADC name	Payload	Linker	Pre-clinical model	Status
Mesothelin	Anetumab ravtansine (BAY 94-934)	DM4	Cleavable SPDB	MIA PaCa-2/meso pancreatic xenograft and patient-derived pancreatic model (PAXF736)	Phase Ⅰ: NCT01439152; Phase Ⅱ: NCT03023722; Phase Ⅰb: NCT03816358
Globo H	OBI-999	MMAE	Cleavable Val-Cit	HPAC pancreatic xenograft	Phase Ⅰ/Ⅱ: NCT04084366
Claudin18.2	CMG901	MMAE	Cleavable linker	Not available	Phase Ⅰa: NCT04805307
SYSA-1801	MMAE	Cleavable linker	Not available	Phase Ⅰ: NCT05009966
RC118	MMAE	Cleavable linker	Not available	Phase Ⅰ/Ⅱ: NCT05205850
CLDN18.2-307-ADC	MMAE	Cleavable Val-Cit	HUPT4 and PATU8998S pancreatic xenograft	Phase Ⅰ: NCT05156866
c-MET	SHR-A1403 (HTI-1066)	SHR152852	Non-cleavable thioether linker ATPPA	AsPC-1 pancreatic xenograft	Phase Ⅰ: NCT03398720; Phase Ⅰ: NCT03856541
TR1801	SG3199	Cleavable Val-Ala	Patient-derived pancreatic model (PDX1334 and PDX1342)	Phase Ⅰ: NCT03859752
RC108	MMAE	Cleavable Val-Cit	Not available	Phase Ⅰ: NCT04617314; Phase Ⅱ: NCT05628857
CEACAM5	Labetuzumab-SN-38	SN-38	Cleavable CL2 linker	Capan-1 pancreatic xenograft	Preclinical
Tusamitamab ravtansine (SAR408701)	DM4	Cleavable SPDB	Not available	Phase Ⅰ: NCT02187848
Trop2	Sacituzumab govitecan (IMMU-132)	SN-38	Cleavable CL2A linker	Capan-1 and BxPC-3 pancreatic xenograft	Phase Ⅰ/Ⅱ: NCT01631552
¹⁷⁷Lu-DOTA-hIMB1636	¹⁷⁷Lu	DOTA-NHS-ester	T3M4 pancreatic xenograft	Preclinical
hIMB1636-MMAE	MMAE	Cleavable Val-Cit	T3M4 and BxPc-3 pancreatic xenograft	Preclinical
HuNb_TROP2-HSA-MMAE	MMAE	Cleavable Val-Cit	BxPC-3 pancreatic xenograft	Preclinical
EGFR	RC68-MMAE	MMAE	Cleavable Val-Cit	BxPC-3 pancreatic xenograft	Preclinical
CTX-MMAE	MMAE	Cleavable Val-Cit	MIA PaCa-2 and PANC-1 pancreatic xenograft	Preclinical
LR004-DM1	DM1	Noncleavable SMCC	Capan-2 pancreatic xenograft	Preclinical
ICAM-1	ICAM-1-DM1	DM1	Noncleavable SMCC	PANC-1 pancreatic xenograft	Preclinical
MUC1	SAR566658	DM4	Cleavable SPDB	Capan-2 pancreatic xenograft	Preclinical
HzMUC1-MMAE	MMAE	Cleavable Val-Cit	CFPAC-1 and Capan-2 pancreatic xenograft	Preclinical
GPC-1	GPC-1-MMAE	MMAE	Cleavable Val-Cit	Patient-derived pancreatic model (PK565, PK645, PK175 and KPK1)	Preclinical

Target antigen

ADC name

Payload

Linker

Pre-clinical model

Status

Mesothelin

Anetumab ravtansine (BAY 94-934)

DM4

Cleavable SPDB

MIA PaCa-2/meso pancreatic xenograft and patient-derived pancreatic model (PAXF736)

Phase Ⅰ: NCT01439152; Phase Ⅱ: NCT03023722; Phase Ⅰb: NCT03816358

Globo H

OBI-999

MMAE

Cleavable Val-Cit

HPAC pancreatic xenograft

Phase Ⅰ/Ⅱ: NCT04084366

Claudin18.2

CMG901

MMAE

Cleavable linker

Not available

Phase Ⅰa: NCT04805307

SYSA-1801

MMAE

Cleavable linker

Not available

Phase Ⅰ: NCT05009966

RC118

MMAE

Cleavable linker

Not available

Phase Ⅰ/Ⅱ: NCT05205850

CLDN18.2-307-ADC

MMAE

Cleavable Val-Cit

HUPT4 and PATU8998S pancreatic xenograft

Phase Ⅰ: NCT05156866

c-MET

SHR-A1403 (HTI-1066)

SHR152852

Non-cleavable thioether linker ATPPA

AsPC-1 pancreatic xenograft

Phase Ⅰ: NCT03398720; Phase Ⅰ: NCT03856541

TR1801

SG3199

Cleavable Val-Ala

Patient-derived pancreatic model (PDX1334 and PDX1342)

Phase Ⅰ: NCT03859752

RC108

MMAE

Cleavable Val-Cit

Not available

Phase Ⅰ: NCT04617314; Phase Ⅱ: NCT05628857

CEACAM5

Labetuzumab-SN-38

SN-38

Cleavable CL2 linker

Capan-1 pancreatic xenograft

Preclinical

Tusamitamab ravtansine (SAR408701)

DM4

Cleavable SPDB

Not available

Phase Ⅰ: NCT02187848

Trop2

Sacituzumab govitecan (IMMU-132)

SN-38

Cleavable CL2A linker

Capan-1 and BxPC-3 pancreatic xenograft

Phase Ⅰ/Ⅱ: NCT01631552

¹⁷⁷Lu-DOTA-hIMB1636

¹⁷⁷Lu

DOTA-NHS-ester

T3M4 pancreatic xenograft

Preclinical

hIMB1636-MMAE

MMAE

Cleavable Val-Cit

T3M4 and BxPc-3 pancreatic xenograft

Preclinical

HuNb_TROP2-HSA-MMAE

MMAE

Cleavable Val-Cit

BxPC-3 pancreatic xenograft

Preclinical

EGFR

RC68-MMAE

MMAE

Cleavable Val-Cit

BxPC-3 pancreatic xenograft

Preclinical

CTX-MMAE

MMAE

Cleavable Val-Cit

MIA PaCa-2 and PANC-1 pancreatic xenograft

Preclinical

LR004-DM1

DM1

Noncleavable SMCC

Capan-2 pancreatic xenograft

Preclinical

ICAM-1

ICAM-1-DM1

DM1

Noncleavable SMCC

PANC-1 pancreatic xenograft

Preclinical

MUC1

SAR566658

DM4

Cleavable SPDB

Capan-2 pancreatic xenograft

Preclinical

HzMUC1-MMAE

MMAE

Cleavable Val-Cit

CFPAC-1 and Capan-2 pancreatic xenograft

Preclinical

GPC-1

GPC-1-MMAE

MMAE

Cleavable Val-Cit

Patient-derived pancreatic model (PK565, PK645, PK175 and KPK1)

Preclinical

抗体偶联药物在胰腺癌治疗中的研究进展

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李泓璇 , 王莹 , 王菊仙 ^*

药学学报 | 综述 2024,59(10): 2697-2708

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药学学报 | 综述 2024, 59(10): 2697-2708

抗体偶联药物在胰腺癌治疗中的研究进展

全屏

李泓璇, 王莹, 王菊仙^*

作者信息

中国医学科学院、北京协和医学院, 医药生物技术研究所, 北京 100050

通讯作者:

^*王菊仙，Tel: 86-10-63131053, E-mail: wangjuxian@imb.pumc.edu.cn

Advances of antibody drug conjugates in pancreatic cancer therapy

Hong-xuan LI, Ying WANG, Ju-xian WANG^*

Affiliations

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2024-10-12 doi: 10.16438/j.0513-4870.2024-0403

文章导航

摘要

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胰腺癌是致命的恶性肿瘤之一, 现有的手术切除和化疗手段均未能很好地改善患者的预后情况, 因此亟需寻找更安全有效的治疗方法以满足临床治疗需求。抗体偶联药物(antibody drug conjugate, ADC) 是一类利用化学连接子将单克隆抗体与小分子细胞毒药物偶联而成的靶向抗肿瘤药物, 具有选择性高、效力高、毒副作用低等优势。近年来, ADC在多种肿瘤治疗中的成功应用掀起了抗胰腺癌ADC的研究热潮。本文就ADC的结构和作用机制及其在抗胰腺癌领域中的研究现状作一综述, 为今后抗胰腺癌ADC的研究提供一定的参考依据。

关键词

抗体偶联药物 / 胰腺癌 / 靶点 / 连接子 / 有效载荷

Abstract

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Pancreatic cancer is one of the most lethal malignant tumors. While the existing surgical resection and chemotherapy have failed to improve the prognosis of patients well, it is urgent to find safer and more effective therapies to meet the clinical therapeutic needs. Antibody drug conjugate (ADC) is a class of targeted antitumor agents that combines monoclonal antibodies with small molecule cytotoxic drugs via chemical linkers. ADC provided wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties which depended on their characteristics of high selectivity, high efficacy and low toxicity. In recent years, the successful application of ADC in the treatment of multiple tumors has aroused a research upsurge in ADC for pancreatic cancer. This review summarizes the structure and mechanism of ADC and the current status of ADC for pancreatic cancer in order to provide some references for the future development of ADC for pancreatic cancer.

Key words

antibody drug conjugate / pancreatic cancer / target / linker / payload

引用本文

李泓璇, 王莹, 王菊仙. 抗体偶联药物在胰腺癌治疗中的研究进展. 药学学报, 2024 , 59 (10) : 2697 -2708 . DOI: 10.16438/j.0513-4870.2024-0403

Hong-xuan LI, Ying WANG, Ju-xian WANG. Advances of antibody drug conjugates in pancreatic cancer therapy[J]. Acta Pharmaceutica Sinica, 2024 , 59 (10) : 2697 -2708 . DOI: 10.16438/j.0513-4870.2024-0403

正文

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胰腺癌(pancreatic cancer, PC) 被称为“癌中之王”, 是一种侵袭性极强、预后极差的消化道恶性肿瘤, 通常在晚期才被确诊, 5年生存率只有10%左右, 是癌症相关死亡的主要原因^[1]。随着全球人口老龄化加剧, 胰腺癌的发病率和死亡率均成上升趋势, 对全球人类生命健康构成了严重威胁^[2]。

目前, 手术切除和化疗仍然是胰腺癌治疗的主要手段。然而, 只有15%~20%的患者符合手术条件, 且术后仍然伴有复发的可能。大多数患者在确诊时已出现肿瘤的远处转移, 难以再进行根治性手术切除^[3]。因此, 化疗仍然在胰腺癌临床治疗中占据着重要地位。目前常用的一线化疗药物包括5-氟尿嘧啶、亚叶酸钙、伊立替康、奥沙利铂、吉西他滨和白蛋白结合型紫杉醇等, 通常会根据患者的具体情况制定联合化疗方案, 但由于疗效有限、肿瘤细胞耐药及引发严重不良反应等问题, 未能很好地改善患者的预后情况^[4]。面对当前常规疗法的局限性, 人们亟需寻找更安全有效的治疗方法以改善胰腺癌的临床治疗现状。为此, 高特异性的抗体偶联药物(antibody drug conjugate, ADC) 成为了一种极具吸引力的靶向疗法。

ADC是一类新型靶向抗肿瘤药物, 利用抗体与肿瘤相关抗原之间的特异性结合作用, 将细胞毒性药物选择性递送至肿瘤部位, 在实现对肿瘤细胞的高效杀伤作用的同时降低对正常组织的毒副作用, 是近年来肿瘤靶向治疗的研究热点。目前全球已有15种ADC获批上市, 超过100种ADC处于临床试验阶段, 在血液系统恶性肿瘤及包括乳腺癌、尿路上皮癌和HER2⁺胃癌等在内的实体瘤的临床治疗中取得了良好的效果^{[5, 6]}。令人遗憾的是, 迄今为止尚无ADC被批准用于胰腺癌的治疗, 但人们对新的胰腺癌靶向疗法的迫切需求以及ADC在多种肿瘤治疗中的成功应用, 使得抗胰腺癌ADC受到越来越多的关注。本文就ADC的结构和作用机制以及其在抗胰腺癌领域中的研究现状作一综述。

1 ADC的结构及作用机制

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ADC由能够特异性靶向肿瘤相关抗原的单克隆抗体、被称为有效载荷的高效细胞毒性药物和将二者偶联的化学连接子三部分组成, 每个部分对ADC最终的有效性和安全性都至关重要。

1.1 抗体

抗体部分的主要功能是将有效载荷靶向递送至肿瘤部位。为了降低脱靶毒性, 理想的抗体靶标应在肿瘤细胞表面特异性高表达而在正常组织中低表达或不表达^[5]。除常规肿瘤细胞抗原外, 肿瘤微环境如脉管系统和肿瘤基质中的成分也可作为ADC开发的重要靶点, 受到了研究者的广泛关注, 此类ADC有望具有更广泛的疗效, 并为应对转移性肿瘤和肿瘤细胞基因突变引起的耐药性提供了一种有希望的解决方法^{[7, 8]}。

抗体是靶抗原和ADC之间的特异性相互作用的关键载体。抗体应对靶抗原具有高结合亲和力和高效内化的能力, 并具有低免疫原性和较长的血浆半衰期^[9]。目前ADC采用的抗体多为人源化免疫球蛋白G (immunoglobulin G, IgG) 中的IgG1亚型, 其在血清中含量最高, 可触发Fc介导的免疫效应功能, 如抗体依赖性细胞介导的细胞毒作用(antibody-dependent cell-mediated cytotoxicity, ADCC)、抗体依赖性细胞介导的吞噬作用(antibody-dependent cellular phagocytosis, ADPC) 及补体依赖的细胞毒作用(complement-dependent cytotoxicity, CDC), 有助于增强ADC整体的抗肿瘤效力^[10]。

值得一提的是, ADC的肿瘤渗透率也是影响其抗肿瘤疗效的关键因素之一, 尤其在针对实体瘤的情况下, ADC的分布不均匀会降低其在临床研究中的疗效^[11]。有学者指出, 在实体瘤中, 过高的抗原亲和力和内化能力可能会使抗体聚集在肿瘤血管周围而不能均匀渗透至远离血管的肿瘤细胞, 进而形成结合位点屏障(binding-site-barrier, BSB), 削弱ADC的肿瘤杀伤效力^[12]。因此, 在设计ADC时应充分考虑抗体的靶标亲和力和抗癌效力之间的平衡, 同时, 还有研究表明采用单抗联合给药策略有助于克服ADC的BSB, 改善其抗肿瘤疗效^{[12, 13]}。此外, IgG抗体的大分子量(约150 kDa) 也可能影响其对实体瘤复杂脉管系统的穿透性, 进而影响ADC的肿瘤渗透率。对此, 研究人员试图开发具有更小分子量的抗体片段, 使其在保留高亲和力和特异性的同时更易于穿过血管进入实体瘤, 从而提高其对实体瘤的杀伤效果^[14]。

1.2 连接子

连接子将抗体和有效载荷偶联, 保证ADC在血浆中保持稳定, 而当其到达靶向部位时可以有效释放出活性药物。目前使用的连接子主要分为可裂解和不可裂解两种类型(表 1)。

可裂解连接子利用正常组织和肿瘤组织之间的环境差异, 使ADC在肿瘤组织中特异性释放出游离的细胞毒药物^[15]。如果释放的有效载荷具有一定疏水性, 则其可扩散至邻近细胞发挥细胞毒作用, 引发旁观者效应(bystander killing effect)^[16]。这一作用可杀伤周围不表达靶抗原的肿瘤细胞, 但也可能将有效载荷递送至正常组织而产生脱靶毒性。常见的可裂解连接子包括: pH敏感型连接子, 如可在溶酶体酸性环境下水解的腙型连接子; 可在肿瘤细胞内高水平还原型谷胱甘肽(glutathione, GSH) 条件下被还原的二硫键连接子; 对肿瘤组织中高表达的酶敏感的酶促裂解型连接子, 如组织蛋白酶B可裂解的缬氨酸-瓜氨酸(valine-citrulline, Val-Cit) 二肽连接子和甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(glycine-glycine-phenylalanine-glycine, Gly-Gly-Phe-Gly) 四肽连接子以及β-葡萄糖醛酸酶可裂解连接子^[17]。

相反, 不可裂解连接子不易受到体内化学环境或酶的影响, 具有更高的血浆稳定性和较低的脱靶毒性, 如SMCC连接子和MC连接子^[18]。采用此类连接子的ADC被肿瘤细胞内吞后, 单抗部分在溶酶体中降解, 释放出带电氨基酸-连接子-有效载荷的复合物, 其带电性质限制了它通过细胞膜扩散^[15]。因此, 采用不可裂解连接子时需要考虑原型药物和复合物之间的活性差异, 如果化学修饰会影响小分子药物的细胞毒活性, 则不适合使用该类连接子进行ADC的制备^{[5, 18]}。

1.3 有效载荷

有效载荷是ADC被内吞进入癌细胞后发挥细胞毒性的主体部分。由于可以与抗体偶联的药物数量有限, 并且给药后需经过体内循环、肿瘤微环境屏障及肿瘤细胞的内吞过程, 所以仅有一小部分ADC可到达肿瘤内部, 所以需要高效的细胞毒性药物(半数抑制浓度IC₅₀在纳摩尔和皮摩尔范围内) 才能达到治疗效果^[19]。

如今, 微管蛋白抑制剂、DNA损伤剂、免疫调节剂和放射性核素均可用作ADC的有效载荷(表 2)^[20-22]。微管蛋白抑制剂在获批ADC中应用较多, 通过抑制微管形成、干扰细胞有丝分裂来杀伤肿瘤细胞, IC₅₀值一般在纳摩尔范围内, 常见的有澳瑞他汀(auristatin) 衍生物MMAE、MMAF和美登素衍生物DM1、DM4。而DNA损伤剂可在细胞周期的任一阶段发挥细胞毒作用, 通过不同机制破坏DNA结构从而诱导细胞凋亡, IC₅₀值可达皮摩尔级, 包括DNA双链断裂诱导剂, 如卡奇霉素(calicheamicin); DNA烷化剂, 如多卡霉素(duocarmycin); DNA拓扑异构酶I抑制剂, 如喜树碱衍生物SN-38和Dxd; DNA交联剂, 如吡咯并苯并二氮杂卓(pyrrolobenzodiazepine, PBD) 二聚体^{[9, 21]}。除了传统的细胞毒素外, 包括Toll样受体(Toll like receptor, TLR) 激动剂和干扰素基因刺激蛋白(stimulator of interferon genes, STING) 激动剂在内的小分子免疫调节剂也作为有效载荷用于新型ADC的开发, 这类ADC被称为免疫刺激抗体偶联物(immune-stimulating antibody conjugates, ISAC)。一些ISAC候选药物已陆续进入临床试验阶段, 并被证明其可激活抗肿瘤免疫反应, 引起肿瘤消退^{[20, 23]}。而放射性核素抗体偶联物(radionuclide antibody conjugate, RAC) 则是由放射性核素与抗体偶联而成, 是近年来放射免疫疗法的研究热点, 常用的放射性核素包括β辐射核素¹³¹I、⁹⁰Y、¹⁷⁷Lu和¹⁸⁸Re以及α辐射核素²¹³Bi和²¹¹At, 目前已有⁹⁰Y-ibritumomab tiuxetan、¹³¹I-tositumomab等多种RAC获批用于癌症的诊断和治疗^{[22, 24, 25]}。

1.4 ADC的作用机制

理想的ADC应当在血液循环中保持稳定, 当到达肿瘤部位后, ADC的抗体部分与肿瘤细胞表面特异性高表达的靶抗原结合, ADC被内吞进入靶细胞, 在溶酶体的作用下降解释放出有效载荷, 通过靶向DNA或微管蛋白诱导细胞凋亡^[26]。如果释放的有效载荷具有一定的膜渗透性, 则可引发旁观者效应, 有助于增强其对异质性肿瘤的疗效^[16]。除此之外, 某些ADC的抗体部分可保留其原有的活性特征, 与靶抗原结合后抑制抗原受体的下游信号转导以抑制肿瘤生长, 还可通过ADCC、ADPC、CDC等免疫活性发挥肿瘤杀伤作用^{[5, 27]}。

2 ADC在治疗胰腺癌中的应用

收起

尽管目前尚无抗胰腺癌ADC获批, 但已有许多靶向胰腺癌相关抗原的ADC被构建并在活性评价中表现出显著的抗肿瘤活性, 表明ADC在胰腺癌治疗中拥有巨大的应用潜力。在此, 本综述对正在研究中的胰腺癌相关抗原及其相关ADC进行总结和梳理(表 3)。

2.1 间皮素(mesothelin)

间皮素是一种糖基磷脂酰肌醇锚定的细胞表面糖蛋白, 其在间皮瘤、卵巢癌、胰腺癌等恶性肿瘤中的选择性高表达使其成为诊断和预后的生物标志物及治疗靶点^{[28, 29]}。

Anetumab ravtansine (BAY 94-934, AR) 由人源化抗间皮素单克隆抗体MF-T、可裂解的二硫键连接子SPDB和有效载荷DM4组成, 药物抗体偶联比(drug-antibody ratio, DAR) 为3.2, 当其被肿瘤细胞内化后, 连接子被还原裂解释放出DM4, 干扰细胞微管聚合, 引起细胞周期停滞和细胞凋亡。游离的DM4还可产生旁观者效应杀伤邻近间皮素表达阴性的肿瘤细胞, 这一作用使其在患者来源的异质性间皮瘤、胰腺癌和卵巢癌异种移植模型中表现出强大的抗肿瘤活性^[30]。在一项I期临床试验中共招募了148例表达间皮素的晚期实体瘤患者, 其中包括9例胰腺癌患者, AR在这些患者中表现出可控的安全性和良好的药代动力学特征并观察到初步抗肿瘤活性^[31]。随后开展了一项多中心、非随机的Ⅱ期临床研究, 评估了AR作为单药治疗对表达间皮素的晚期胰腺癌患者的疗效, 完成研究的14名受试者中有2名病情稳定, 中位进展时间为63.5天^[32]。此外, 还开展了AR联合免疫治疗和常规化疗治疗晚期胰腺癌患者的Ib期研究, 在接受AR联合纳武利尤单抗(抗PD-1单抗) 和吉西他滨治疗的所有8名患者中观察到疾病稳定, 该联合疗法将在扩展队列中开展进一步测试^[33]。

2.2 Globohexaosylceramide (Globo H)

Globo H是最初从人乳腺癌细胞系MCF-7中分离得到的一种己糖, 属于肿瘤相关糖抗原(tumor-associated carbohydrate antigens, TACAs) 中的一员, 在正常组织中表达水平较低, 而在乳腺癌、卵巢癌、胰腺癌等多种癌症中高表达, 可诱导肿瘤血管生成及免疫抑制, 与癌症进展密切相关。因此, Globo H成为了开发疫苗、单克隆抗体和ADC等抗癌药物的有吸引力的靶标^{[34, 35]}。

OBI-999是首个靶向Globo H的新型ADC, 运用ThioBridge技术, 通过Val-Cit连接子将MMAE定点偶联到抗Globo H抗体OBI-888被还原的链间半胱氨酸残基上, 获得DAR值为4的均质ADC。临床前研究结果显示, OBI-999被Globo H高表达的肿瘤细胞内化后释放出游离MMAE, 表现出纳摩尔级细胞毒性, 同时MMAE的膜渗透性使其能够引发旁观者效应以杀死周围Globo H表达水平较低的肿瘤细胞。在表达Globo H的乳腺癌、胃癌和胰腺癌异种移植模型中, OBI-999表现出剂量依赖性的肿瘤抑制作用, 并在食蟹猴中初步确认了其安全性^[36]。

以上临床前研究结果支持了其进一步的人体试验, 目前已在结直肠癌、食管癌和胰腺癌等多种晚期实体瘤患者中开展了OBI-999作为单药治疗的I期临床研究。实验结果显示, OBI-999最大耐受剂量为1.2 mg·kg^-1, 具有良好的耐受性, 最常见的不良反应是轻度或中度中性粒细胞减少和贫血。在0.4~1.6 mg·kg^-1剂量范围内, OBI-999表现出非线性药代动力学特征, 清除率随剂量增加而降低。值得注意的是, 该研究未将Globo H表达水平纳入患者招募的筛选条件中, 大多数患者不表达Globo H或Globo H表达有限, 因此OBI-999的抗肿瘤疗效有待进一步证实。现正在招募高表达Globo H的胰腺癌、结直肠癌和其他癌症患者进行Ⅱ期扩展队列研究, 并根据I期研究结果确定Ⅱ期推荐给药剂量为1.2 mg·kg^-1, 每3周给药1次, 以进一步评估OBI-999的药效^[37]。

2.3 Claudin18.2 (CLDN18.2)

CLDN18.2是紧密连接蛋白家族中Claudin18的亚型, 在正常组织中表达有限, 在胰腺癌、胃癌、食管癌等癌症中过表达, 参与肿瘤细胞的增殖、分化和迁移, 是近年来癌症治疗的新兴靶点^[38]。

虽然尚无针对CLDN18.2的ADC被批准用于临床治疗, 但一些候选药物已被开发出来, 初期结果令人欣慰。CMG901、SYSA-1801、RC118及CLDN18.2-307-ADC是4种靶向CLDN18.2的ADC, 均以MMAE为有效载荷, 采用可裂解连接子将其与抗CLDN18.2单克隆抗体偶联, 在临床前研究中表现出良好的体内外抗肿瘤活性和安全性, 其中CMG901还被证明可通过激活ADCC和CDC等免疫效应诱导肿瘤细胞的凋亡。目前这4种ADC均已获批进入I期临床试验用于胃癌和胰腺癌患者的治疗^[38-41]。

2.4 间质表皮转化因子(c-mesenchymal-epithelial transition factor, c-MET)

c-MET也被称为肝细胞生长因子受体(hepatocyte growth factor receptor, HGFR), 是一种由MET原癌基因编码的酪氨酸激酶受体, 在包括胰腺癌在内的多种实体瘤中过表达, 在癌细胞的增殖侵袭和化疗耐药进程中发挥着重要作用, 是一个极具潜力的癌症治疗靶点^[42]。

SHR-A1403 (HTI-1066) 是一种新型抗c-MET ADC, 由针对c-MET的人源化IgG2单克隆抗体通过不可裂解的硫醚接头ATPPA与澳瑞他汀类似物SHR152852偶联而成, 在高表达c-MET的AsPC-1胰腺癌异种移植小鼠模型中表现出强大的抗肿瘤效力。有趣的是, 研究人员发现, SHR-A1403可通过3种不同的作用机制发挥抗胰腺癌作用: ①通过介导微管解聚以抑制细胞增殖并诱导G2/M细胞周期阻滞和细胞凋亡; ②通过抑制上皮-间充质转化(epithelial-mesenchymal transition, EMT) 以减少胰腺癌细胞的迁移和侵袭; ③通过抑制胰腺癌细胞中的胆固醇生物合成来调节细胞代谢^[43]。目前, SHR-A1403已被证明在啮齿动物和非人灵长类动物中具有良好的药代动力学特性, 并被批准进入I期临床研究以评估其在晚期实体瘤患者中的安全性、耐受性、药代动力学特性及抗肿瘤疗效^[44]。

而Gymnopoulos等^[45]在抗c-MET的人源化IgG2单克隆抗体hD12的重链CH2结构域中引入半胱氨酸残基, 通过可裂解的缬氨酸-丙氨酸(valine-alanine, Val-Ala) 连接子将其与PBD二聚体SG3199定点偶联, 生成DAR值约为2的均质ADC TR1801。相关研究表明, 该ADC在体内外均显示出显著的抗胰腺癌活性, 其与吉西他滨联合使用时在吉西他滨耐药的患者来源的胰腺癌异种移植模型中表现出良好的疗效^[46]。2019年开展了一项针对c-MET阳性实体瘤患者的I期临床试验以评估TR1801的安全性和药代动力学特性, 但目前该研究因投资者撤资而处于停止状态^[47]。

除此之外, 由靶向c-MET的单抗、Val-Cit连接子和有效载荷MMAE组成的ADC RC108也同样备受瞩目, 其在针对c-MET阳性晚期实体瘤的I期临床研究以及针对包括胰腺癌在内的c-MET阳性晚期消化系统恶性肿瘤的Ⅱ期临床研究正在进行中^{[47, 48]}。

2.5 癌胚抗原细胞黏附分子5 (carcinoembryonic antigen cell adhesion molecule 5, CEACAM5)

CEACAM5又称为CD66e, 是一种细胞表面糖蛋白, 在正常成人组织中表达有限, 在胃肠道癌、乳腺癌、非小细胞肺癌和胰腺癌等多种肿瘤中高表达, 促进癌症的侵袭和转移^[49]。CEACAM5在肿瘤和正常组织中表达水平的差异使其成为一个有吸引力的治疗靶点。

Govindan等^[50]设计了一系列连接子, 其马来酰亚胺部分用于和抗CEACAM5单克隆抗体labetuzumab偶联, 另一端则通过pH敏感的碳酸酯键或酯键与SN-38的20位羟基连接, 其中部分连接子还含有组织蛋白酶B可裂解的苯丙氨酸-赖氨酸(phenylalanine-lysine, Phe-Lys) 二肽部分。通过体内外实验对得到的ADC进行评价, 最终确定含有碳酸酯键和组织蛋白酶B可裂解肽的labetuzumab-CL2-SN-38偶联物表现最佳, 其在人结肠癌和胰腺癌异种移植裸鼠模型中显著抑制了肿瘤生长并延长了生存期。

Tusamitamab ravtansine (SAR408701) 是由人源化抗CEACAM5单克隆抗体SAR40837通过可裂解的SPDB连接子与DM4偶联而成的一种新型ADC, 在体外对表达CEACAM5的胰腺癌细胞系具有细胞毒活性^[51]。虽然未在胰腺癌模型中进行体内实验, 但该ADC在患者来源的结肠癌、肺癌和胃癌异种移植小鼠模型中表现出良好疗效, 目前已在晚期结直肠癌、胃癌和非小细胞肺癌等实体瘤患者的扩展队列中评估其临床活性^[51-53]。以上研究表明SAR408701是治疗CEACAM5阳性上皮肿瘤的有前途的候选药物, 值得进一步发掘其对胰腺癌的治疗潜力。

2.6 滋养层细胞表面抗原2 (trophoblast cell surface antigen 2, Trop2)

Trop2是一种跨膜糖蛋白, 参与多种致癌信号通路, 促进肿瘤细胞的增殖、侵袭和转移, 其在多种实体瘤中的过表达使其成为肿瘤治疗的理想靶点^[54]。

目前, 靶向Trop2的ADC已在临床上取得了可喜的结果, 由人源化抗Trop2单克隆抗体hRS7、含有碳酸酯键的pH敏感型CL2A连接子和SN-38组成的sacituzumab govitecan (IMMU-132, SG) 于2020年被FDA批准用于治疗三阴性乳腺癌^[55]。SG在临床前研究中便对Capan-1和BxPC-3胰腺癌异种移植小鼠模型表现出显著的抗肿瘤作用, 在Ⅰ/Ⅱ期临床试验中纳入了16例胰腺癌患者, 其中7例病情稳定, 中位总生存期为4.5个月, 中位无进展生存期为2个月, 但因其对胰腺癌的疗效并不十分理想, 后续的临床研究主要集中于乳腺癌和尿路上皮癌, 而未再对胰腺癌开展进一步的疗效评估^[56-58]。

然而, 针对Trop2的抗胰腺癌ADC的研究并未止步。Li等^[59]开发了一种靶向Trop2的人源化单克隆抗体hIMB1636, 分别与p-SCN-Bn-NOTA (NOTA) 和DOTA-NHS-ester (DOTA) 偶联后, 采用⁶⁴Cu和¹⁷⁷Lu对抗体进行放射性标记, 得到的⁶⁴Cu-NOTA-hIMB1636T3M4可无创性评估体内Trop2的表达水平, 而¹⁷⁷Lu-DOTA-hIMB1636可抑制T3M4异种移植肿瘤的生长。Sun等^[60]则采用Val-Cit连接子将hIMB1636与MMAE偶联, 得到的hIMB1636-MMAE可诱导胰腺癌细胞的G2/M细胞周期阻滞并引起细胞凋亡, 还能有效抑制肿瘤细胞的迁移并能引发旁观者效应和ADCC效应, 在T3M4和BxPc-3胰腺癌异种移植模型中表现出良好疗效。尤其在BxPc-3模型中, 同一剂量的hIMB1636-MMAE比SG具有更高肿瘤抑制率, 是一种有前途的胰腺癌治疗药物。Xu等^[61]则另辟蹊径, 不再选择传统的单克隆抗体作为靶向载体, 而是开发了一种人源化抗Trop2纳米抗体Nb4, 并将其与抗人血清白蛋白(human serum albumin, HSA) 的纳米抗体连接以延长其血浆半衰期, 得到的分子HuNb_TROP2-HSA再通过Val-Cit连接子与MMAE偶联, 生成一种DAR值为1的新型靶向Trop2的纳米抗体偶联药物(nanobody drug conjugate, NDC), 对Trop2具有较强的亲和力并能被肿瘤细胞有效内化, 在BxPC-3胰腺癌异种移植模型中表现出良好的疗效。该项研究填补了当前抗Trop2 ADC用于胰腺癌治疗的研究空白, 为治疗胰腺癌和其他Trop2阳性肿瘤提供了新的可能性, 并为新一代ADC的设计研发提供了值得借鉴的思路。

2.7 表皮生长因子受体(epidermal growth factor receptor, EGFR)

EGFR是一种受体酪氨酸激酶, 属于ErbB家族蛋白, 通过激活下游MAPK、PI3K/AKT和JAK/STAT等信号通路促进细胞增殖和存活。已在多种恶性肿瘤中观察到EGFR基因的突变或扩增, 并发现其与肿瘤的生长、侵袭和转移有关^[62]。因此, EGFR一直是极具吸引力的癌症治疗靶点。

Li等^[63]通过两种接头不同的可裂解Val-Cit连接子MC-VC-PAB和PY-VC-PAB, 将MMAE偶联到人源化抗EFGR单克隆抗体RC68上, 合成了两种ADC, RC68-MC-VC-PAB-MMAE和RC68-PY-VC-PAB-MMAE, DAR均为4左右。体内外活性评价结果显示, 这两种ADC可与肿瘤细胞表面的EGFR结合并被有效内化, 导致EGFR阳性胰腺癌细胞死亡, 对BxPC-3异种移植肿瘤的抑制作用强于盐酸吉西他滨。值得一提的是, 前者的MC接头只能随机与抗体上的单个巯基反应, 而后者的PY接头可在抗体链间二硫键被还原后同时与形成的两个巯基反应, 将断开的两条链重新共价连接, 因此RC68-PY-VC-PAB-MMAE在人血浆中具有更好的稳定性。Greene等^[64]采用了与PY接头类似的链间半胱氨酸桥接定点偶联策略, 使用含二溴哒嗪二酮(dibromopyridazinedione, diBrPD) 接头的Val-Cit连接子, 将MMAE偶联到靶向EGFR的西妥昔单抗(cetuximab, CTX) 上, 得到平均DAR值为3.9的ADC, 在KRAS突变的MIA PaCa-2和PANC-1异种移植模型中表现出剂量依赖性的肿瘤生长抑制作用。Zhu等^[65]则以单克隆抗体LR004为靶向载体, DM1为有效载荷, 采用不可裂解的SMCC连接子将二者偶联, 构建了靶向EGFR的抗胰腺癌ADC, 在体内外均表现出显著的肿瘤抑制活性。以上研究结果展现了以EGFR为靶点的ADC在胰腺癌治疗方面的应用潜力, 但其最终能否实现临床转化还需进一步的临床研究验证。

2.8 细胞间黏附分子-1 (intercellular adhesion molecule-1, ICAM-1)

ICAM-1又称CD54, 是免疫球蛋白超家族的一种跨膜糖蛋白, 在三阴性乳腺癌、黑色素瘤、胰腺癌等多种癌症中过表达, 且与肿瘤的侵袭性和不良预后有关。胰腺癌中常见的致癌突变KRAS^G12D可诱导胰腺腺泡细胞上调ICAM-1的表达水平以吸引巨噬细胞进而驱动胰腺癌病变的形成。ICAM-1在胰腺肿瘤中特异性高表达并能被细胞有效内化的特性使其成为抗胰腺癌ADC的靶点之一^[66]。

Huang等^[67]使用SMCC连接子和DM1构建了一种靶向ICAM-1的ADC, 其对人胰腺癌细胞的杀伤活性是当前治疗胰腺癌的一线化疗药物吉西他滨的2 000多倍, 而在不表达ICAM-1的人正常胰管上皮细胞中未显示出细胞毒性。在具有KRAS^G12D突变的PANC-1胰腺癌小鼠模型中, ICAM-1-SMCC-DM1表现出有效且持久的肿瘤消退作用, 并能有效抑制胰腺癌向肺、肝和脾脏等正常器官转移。以上临床前研究数据证明了该靶向ICAM-1 ADC的抗胰腺癌效力, 有望用于胰腺癌的靶向治疗, 但在进入临床应用之前还需进一步评估其安全性和有效性。

2.9 黏蛋白1 (mucin 1, MUC1)

MUC1是一种高度糖基化的I型跨膜糖蛋白, 在90%的胰腺癌患者中异常高表达, 且与其不良预后有关, 是胰腺癌治疗的重要靶点之一^[68]。MUC1的CA6唾液酸糖表位在正常组织中表达有限, 但在胰腺癌、乳腺癌、卵巢癌等上皮癌中过表达。Nicolazzi等^[69]以此为靶点, 生成了人源化单克隆抗体huDS6, 通过含二硫键的可裂解SPDB连接子与DM4偶联, 得到的ADC SAR566658在Capan-2胰腺癌异种移植模型中表现出剂量依赖性的肿瘤抑制活性。Wu等^[70]则开发了一种靶向MUC1的SEA结构域的人源化单克隆抗体HzMUC1, 通过Val-Cit连接子与MMAE偶联生成HzMUC1-MMAE, 该ADC能够有效抑制CFPAC-1和Capan-2异种移植肿瘤的生长, 是一种有前途的胰腺癌靶向治疗药物。

2.10 磷脂酰肌醇蛋白聚糖-1 (glypican-1, GPC-1)

迄今为止, FDA批准的所有用于治疗实体瘤的ADC都直接靶向肿瘤细胞中特异性表达的抗原, 然而, 肿瘤基质中肿瘤相关成纤维细胞(cancer associated fibroblasts, CAFs) 产生的细胞外基质蛋白会阻碍药物的有效递送, 这也是这些ADC对胰腺癌等富含基质的实体瘤治疗效果欠佳的原因之一^[71]。有趣的是, 研究发现胰腺肿瘤中的癌细胞和CAF均存在GPC-1的特异性过表达, 并与胰腺癌细胞的增殖、转移和血管生成有关^[72]。

在此基础上, Tsujii等^[73]提出了通过靶向CAF的ADC的旁观者杀伤效应治疗富含基质的实体瘤的新策略。该团队构建了一种由Val-Cit连接子将MMAE和具有高内化活性的小鼠抗GPC-1单克隆抗体01a033偶联而成的抗GPC-1 ADC, 其可在体外抑制GPC-1阳性胰腺癌细胞的增殖, 在GPC-1阳性CAF/GPC-1异质性癌细胞以及GPC-1阳性CAF/GPC-1阴性癌细胞的胰腺癌肿瘤异种移植模型中均表现出显著的肿瘤生长抑制作用。进一步实验证明, GPC-1-MMAE被递送到CAF并被有效内化后, 连接子被蛋白酶水解释放出具有膜渗透性的游离MMAE, 因CAF高表达多药耐药蛋白-1 (multi drug resistance-1, MDR-1) 而未观察到CAF的凋亡, 但CAF可通过MDR-1将MMAE输送到邻近癌细胞从而产生旁观者效应, 诱导其凋亡。而使用MMAF作有效载荷时, 游离MMAF的羧酸末端会限制其穿过细胞膜而不能产生旁观者效应, GPC-1-MMAF对上述两种肿瘤异种移植模型的疗效有限^[74]。由此可见, 旁观者效应是抗GPC-1 ADC发挥体内抗肿瘤活性的关键。基于以上研究, 该团队进一步开发了人源化抗GPC-1单克隆抗体T2, 用相同的方法与MMAE偶联, 得到的ADC被证明在胰腺癌患者来源的肿瘤异种移植模型中表现出良好的体内疗效, 有望进一步推进其临床开发^[75]。此项研究为克服肿瘤基质屏障导致的药物递送问题提供了新的ADC设计思路, 推进了ADC治疗胰腺癌等富含基质的实体瘤的应用研究。

3 小结与展望

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ADC药物在治疗血液病肿瘤、乳腺癌和肺癌等疾病中的良好临床疗效激发了研究者对抗胰腺癌ADC的研究兴趣。然而, 胰腺癌复杂的肿瘤微环境和ADC本身的特性为抗胰腺癌ADC的临床转化提出了诸多挑战, 尽管临床前研究数据已显示ADC在胰腺癌治疗领域有着广阔的应用前景, 但其对胰腺癌患者的临床疗效仍未得到证实。

胰腺肿瘤微环境具有高度促结缔组织增生、强免疫抑制、缺乏血管分布等特性, 限制了高分子量ADC对肿瘤组织的渗透效率, 进而影响其疗效^[71]。对此, 摒弃传统的单克隆抗体结构, 选择将有效载荷偶联到分子量更小的靶向运输载体上成为了新的研究方向。已有研究报道, 由多肽或纳米抗体与有效载荷偶联而成的偶联物在胰腺癌治疗方面有着强大的应用潜力。如柔红霉素(daunomycin, Dau) 通过肟键与Ser-Lys-Ala-Ala-Lys-Asn (SKAAKN) 归巢肽偶联而成的肽-药物偶联物被证明对PANC-1荷瘤小鼠具有显著的抗肿瘤活性^[76]; 靶向癌胎抗原5T4的纳米抗体n501、CL2A连接子和SN-38组成的偶联物, 相较于传统的基于全序列IgG1的ADC而言, 具有更强的肿瘤渗透性、更高的肿瘤摄取率和更快的肿瘤部位积累速度, 在BxPC-3胰腺癌异种移植模型中表现出更强的疗效^[77]。这些新型偶联物为突破当前传统ADC在胰腺癌治疗方面的局限提供了新的可能。

另一方面, 以肿瘤微环境中的成分作为ADC的治疗靶点亦是一种有前途的研发策略。相关研究表明, 靶向肿瘤基质的ADC可克服基质屏障, 通过可裂解连接子释放疏水性游离药物, 产生旁观者效应杀伤邻近癌细胞, 是将细胞毒药物递送至富含基质的实体瘤的有效方法, 且有助于应对肿瘤细胞下调靶抗原表达水平导致的耐药性问题。如靶向肿瘤基质中表达GPC-1的CAF的ADC被证明在治疗富含基质的肿瘤方面有广阔的应用前景^[73]。此外, ADC与其他作用机制的药物的联合使用也是未来临床应用研究中值得关注的重点。合理设计的联合用药方案有利于克服耐药性问题、增强疗效、减少给药剂量并减轻毒副作用。已有的临床数据显示, ADC与抗PD-1单抗等免疫检查点抑制剂和吉西他滨等常规化疗药物的联合使用可能有助于提高整体疗效, 后续有待更多的临床研究来进一步证实^[33]。总体而言, 尽管抗胰腺癌ADC还未成功实现临床转化, 但其在胰腺癌治疗方面有着强大的应用潜力。随着人们对胰腺癌的研究逐步深入以及ADC研发技术的不断提升, ADC将在胰腺癌临床治疗领域大放异彩。

作者贡献: 李泓璇负责文献检索和文章撰写; 王莹负责文章内容核对和修改; 王菊仙负责文章选题、指导和审校。

利益冲突: 所有作者声明本文无任何利益冲突。

基金

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中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-026)

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2024年第59卷第10期

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doi: 10.16438/j.0513-4870.2024-0403

接收时间：2024-04-25
首发时间：2025-11-24
出版时间：2024-10-12

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收稿日期：2024-04-25
修回日期：2024-07-09

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中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-026)

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中国医学科学院、北京协和医学院, 医药生物技术研究所, 北京 100050

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^*王菊仙，Tel: 86-10-63131053, E-mail: wangjuxian@imb.pumc.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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TxT

Category	Structure
Cleavable linker	pH sensitive linker
Reducible disulfide
Cathepsin-B-cleavable linker
β-Glucuronidase-cleavable linker
Non-cleavable linker

Category

Structure

Cleavable linker

pH sensitive linker

Reducible disulfide

Cathepsin-B-cleavable linker

β-Glucuronidase-cleavable linker

Non-cleavable linker

Category	Structure
Tubulin inhibitor
DNA damaging agent	DNA double strand break inducer
DNA alkylating agent
DNA topoisomerase I inhibitor
DNA crosslinker
Immunomodulator	TLR agonist
STING agonist
Radionuclide	β-Emitting radionuclide	¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re
α-Emitting radionuclide	²¹³Bi, ²¹¹At

Category

Structure

Tubulin inhibitor

DNA damaging agent

DNA double strand break inducer

DNA alkylating agent

DNA topoisomerase I inhibitor

DNA crosslinker

Immunomodulator

TLR agonist

STING agonist

Radionuclide

β-Emitting radionuclide

¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re

α-Emitting radionuclide

²¹³Bi, ²¹¹At

Target antigen	ADC name	Payload	Linker	Pre-clinical model	Status
Mesothelin	Anetumab ravtansine (BAY 94-934)	DM4	Cleavable SPDB	MIA PaCa-2/meso pancreatic xenograft and patient-derived pancreatic model (PAXF736)	Phase Ⅰ: NCT01439152; Phase Ⅱ: NCT03023722; Phase Ⅰb: NCT03816358
Globo H	OBI-999	MMAE	Cleavable Val-Cit	HPAC pancreatic xenograft	Phase Ⅰ/Ⅱ: NCT04084366
Claudin18.2	CMG901	MMAE	Cleavable linker	Not available	Phase Ⅰa: NCT04805307
SYSA-1801	MMAE	Cleavable linker	Not available	Phase Ⅰ: NCT05009966
RC118	MMAE	Cleavable linker	Not available	Phase Ⅰ/Ⅱ: NCT05205850
CLDN18.2-307-ADC	MMAE	Cleavable Val-Cit	HUPT4 and PATU8998S pancreatic xenograft	Phase Ⅰ: NCT05156866
c-MET	SHR-A1403 (HTI-1066)	SHR152852	Non-cleavable thioether linker ATPPA	AsPC-1 pancreatic xenograft	Phase Ⅰ: NCT03398720; Phase Ⅰ: NCT03856541
TR1801	SG3199	Cleavable Val-Ala	Patient-derived pancreatic model (PDX1334 and PDX1342)	Phase Ⅰ: NCT03859752
RC108	MMAE	Cleavable Val-Cit	Not available	Phase Ⅰ: NCT04617314; Phase Ⅱ: NCT05628857
CEACAM5	Labetuzumab-SN-38	SN-38	Cleavable CL2 linker	Capan-1 pancreatic xenograft	Preclinical
Tusamitamab ravtansine (SAR408701)	DM4	Cleavable SPDB	Not available	Phase Ⅰ: NCT02187848
Trop2	Sacituzumab govitecan (IMMU-132)	SN-38	Cleavable CL2A linker	Capan-1 and BxPC-3 pancreatic xenograft	Phase Ⅰ/Ⅱ: NCT01631552
¹⁷⁷Lu-DOTA-hIMB1636	¹⁷⁷Lu	DOTA-NHS-ester	T3M4 pancreatic xenograft	Preclinical
hIMB1636-MMAE	MMAE	Cleavable Val-Cit	T3M4 and BxPc-3 pancreatic xenograft	Preclinical
HuNb_TROP2-HSA-MMAE	MMAE	Cleavable Val-Cit	BxPC-3 pancreatic xenograft	Preclinical
EGFR	RC68-MMAE	MMAE	Cleavable Val-Cit	BxPC-3 pancreatic xenograft	Preclinical
CTX-MMAE	MMAE	Cleavable Val-Cit	MIA PaCa-2 and PANC-1 pancreatic xenograft	Preclinical
LR004-DM1	DM1	Noncleavable SMCC	Capan-2 pancreatic xenograft	Preclinical
ICAM-1	ICAM-1-DM1	DM1	Noncleavable SMCC	PANC-1 pancreatic xenograft	Preclinical
MUC1	SAR566658	DM4	Cleavable SPDB	Capan-2 pancreatic xenograft	Preclinical
HzMUC1-MMAE	MMAE	Cleavable Val-Cit	CFPAC-1 and Capan-2 pancreatic xenograft	Preclinical
GPC-1	GPC-1-MMAE	MMAE	Cleavable Val-Cit	Patient-derived pancreatic model (PK565, PK645, PK175 and KPK1)	Preclinical

Target antigen

ADC name

Payload

Linker

Pre-clinical model

Status

Mesothelin

Anetumab ravtansine (BAY 94-934)

DM4

Cleavable SPDB

MIA PaCa-2/meso pancreatic xenograft and patient-derived pancreatic model (PAXF736)

Phase Ⅰ: NCT01439152; Phase Ⅱ: NCT03023722; Phase Ⅰb: NCT03816358

Globo H

OBI-999

MMAE

Cleavable Val-Cit

HPAC pancreatic xenograft

Phase Ⅰ/Ⅱ: NCT04084366

Claudin18.2

CMG901

MMAE

Cleavable linker

Not available

Phase Ⅰa: NCT04805307

SYSA-1801

MMAE

Cleavable linker

Not available

Phase Ⅰ: NCT05009966

RC118

MMAE

Cleavable linker

Not available

Phase Ⅰ/Ⅱ: NCT05205850

CLDN18.2-307-ADC

MMAE

Cleavable Val-Cit

HUPT4 and PATU8998S pancreatic xenograft

Phase Ⅰ: NCT05156866

c-MET

SHR-A1403 (HTI-1066)

SHR152852

Non-cleavable thioether linker ATPPA

AsPC-1 pancreatic xenograft

Phase Ⅰ: NCT03398720; Phase Ⅰ: NCT03856541

TR1801

SG3199

Cleavable Val-Ala

Patient-derived pancreatic model (PDX1334 and PDX1342)

Phase Ⅰ: NCT03859752

RC108

MMAE

Cleavable Val-Cit

Not available

Phase Ⅰ: NCT04617314; Phase Ⅱ: NCT05628857

CEACAM5

Labetuzumab-SN-38

SN-38

Cleavable CL2 linker

Capan-1 pancreatic xenograft

Preclinical

Tusamitamab ravtansine (SAR408701)

DM4

Cleavable SPDB

Not available

Phase Ⅰ: NCT02187848

Trop2

Sacituzumab govitecan (IMMU-132)

SN-38

Cleavable CL2A linker

Capan-1 and BxPC-3 pancreatic xenograft

Phase Ⅰ/Ⅱ: NCT01631552

¹⁷⁷Lu-DOTA-hIMB1636

¹⁷⁷Lu

DOTA-NHS-ester

T3M4 pancreatic xenograft

Preclinical

hIMB1636-MMAE

MMAE

Cleavable Val-Cit

T3M4 and BxPc-3 pancreatic xenograft

Preclinical

HuNb_TROP2-HSA-MMAE

MMAE

Cleavable Val-Cit

BxPC-3 pancreatic xenograft

Preclinical

EGFR

RC68-MMAE

MMAE

Cleavable Val-Cit

BxPC-3 pancreatic xenograft

Preclinical

CTX-MMAE

MMAE

Cleavable Val-Cit

MIA PaCa-2 and PANC-1 pancreatic xenograft

Preclinical

LR004-DM1

DM1

Noncleavable SMCC

Capan-2 pancreatic xenograft

Preclinical

ICAM-1

ICAM-1-DM1

DM1

Noncleavable SMCC

PANC-1 pancreatic xenograft

Preclinical

MUC1

SAR566658

DM4

Cleavable SPDB

Capan-2 pancreatic xenograft

Preclinical

HzMUC1-MMAE

MMAE

Cleavable Val-Cit

CFPAC-1 and Capan-2 pancreatic xenograft

Preclinical

GPC-1

GPC-1-MMAE

MMAE

Cleavable Val-Cit

Patient-derived pancreatic model (PK565, PK645, PK175 and KPK1)

Preclinical