抗体药物偶联物在HER2阳性晚期胃癌中的应用进展和展望

doi:10.19401/j.cnki.1007-3639.2023.08.008

摘要/Abstract

摘要：

胃癌是一种异质性和侵袭性极高的恶性肿瘤，在全球范围内其发病率居第5位，死亡率居第3位。多数患者确诊时已处于进展期，预后极差。全身治疗是目前晚期胃癌最主要的治疗方式，人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）是HER2阳性胃癌的重要治疗靶点。随着HER2靶向药物和治疗方式的不断优化，一些胃癌患者已从中获益。但是耐药发生率高、不良反应严重仍是限制HER2靶向药物应用的瓶颈。因此，开发新型抗肿瘤药物对改善HER2阳性胃癌患者的长期生存具有重要意义。抗体药物偶联物（antibody drug conjugate，ADC）是一类新型、高效的抗肿瘤药物，由特异性靶向单克隆抗体、化学接头和小分子细胞毒性有效载荷组成，强大的治疗效果和适度的组织毒性是其主要优势。近年来，ADC在HER2阳性晚期胃癌的靶向治疗领域进展颇丰。首先，经过多年发展，包括DS-8201、RC48等在内的多种ADC已用于胃癌的二线及后线治疗。其次，随着ADC生物工程技术的进步，包括高药物抗体比例、可切割型连接子、能引发旁观者效应的毒性载荷等，使新型ADC能够在针对特定靶点肿瘤的治疗中发挥更为显著的治疗效果，其中一些ADC还具备多靶向性，能针对多个特异性靶点发挥抗癌功效。同时，ADC的研发已到达第三阶段，新一代ADC通过位点特异性偶联技术，其均质单一性更高，细胞毒性载荷更高效，精准度更高，非靶向毒性作用更低。此外，ADC和免疫检查点抑制剂（immune checkpoint inhibitor，ICI）组成的“靶免联合”治疗可能是晚期胃癌一种有前景的治疗策略。本文就靶向治疗时代ADC在HER2阳性晚期胃癌患者中的应用和最新研究进展进行综述，并讨论ADC联合ICI在HER2阳性晚期胃癌中的治疗前景和治疗过程中面临的挑战。

关键词: 人表皮生长因子受体2, 晚期胃癌, 抗体药物偶联物, 分子靶向治疗, 进展

Abstract:

Gastric cancer is a malignant tumor with high heterogeneity and invasiveness. Its incidence rate ranks fifth in the world, and its mortality ranks third in the world. Most patients are in a state that cancer cannot be removed by surgery when symptoms appear. At present, systemic treatment is the main treatment for advanced gastric cancer, and human epidermal growth factor receptor 2 (HER2) is one of the important treatment targets for HER2 positive gastric cancer patients. With the continuous optimization of chemotherapy regimen and targeted drugs, the prognosis of some HER2 positive gastric cancer patients has improved significantly. However, the high incidence of drug resistance and high toxicity and side effects are still the bottlenecks limiting the application of HER2 targeted drugs. Therefore, the development of new anti-tumor drugs is of great significance to improve the long-term survival of HER2 positive gastric cancer patients. Antibody drug conjugate (ADC) is a new and efficient anti-tumor drug, which is composed of specific targeted monoclonal antibody, chemical connector and small molecular cytotoxic payload. Its main advantages are strong therapeutic effect and moderate tissue toxicity. In recent years, ADC has set off a huge upsurge in the targeted treatment of HER2 positive advanced gastric cancer. First, after years of development, a variety of ADC including DS-8201 and RC48 have been used in the second- and second-line treatment of gastric cancer. Secondly, with the progress of ADC bioengineering technology, including high proportion of drug antibodies, cleavable linkers, toxic loads that can trigger bystander effect, the new type of ADC can play a more significant therapeutic role in the treatment of specific target tumors, and some of them also have multiple targets and can have anti-tumor effect on multiple specific targets. At the same time, the research and development process of ADC has reached the third stage. The new generation of ADC, through site-specific coupling technology, has higher homogeneity and uniformity, more effective cytotoxic molecules, higher accuracy and lower non-targeted toxicity. In addition, the "targeted immunotherapy" composed of ADC and immune checkpoint inhibitor (ICI) may be a promising treatment strategy for advanced gastric cancer. This article briefly reviewed the application and the latest research progress of ADC in HER2 positive advanced gastric cancer patients in the era of targeted therapy, and discussed the treatment prospects and challenges of ADC combined with ICI in HER2 positive advanced gastric cancer.

Key words: Human epidermal growth factor receptor 2, Advanced gastric cancer, Antibody drug conjugate, Molecular targeted therapy, Progress

中图分类号:

R735.2

康殷楠, 陈顺, 解有成, 郑英, 何昱静, 李初谊, 于晓辉. 抗体药物偶联物在HER2阳性晚期胃癌中的应用进展和展望[J]. 中国癌症杂志, 2023, 33(8): 790-800.

KANG Yinnan, CHEN Shun, XIE Youcheng, ZHENG Ying, HE Yujing, LI Chuyi, YU Xiaohui. Application and research progress of antibody drug conjugates in HER2 positive advanced gastric cancer[J]. China Oncology, 2023, 33(8): 790-800.

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参考文献 67

[1]	LE GALL C M, VAN DER SCHOOT J M S, RAMOS-TOMILLERO I, et al. Dual site-specific chemoenzymatic antibody fragment conjugation using CRISPR-based hybridoma engineering[J]. Bioconjug Chem, 2021, 32(2): 301-310. doi: 10.1021/acs.bioconjchem.0c00673
[2]	MAMOUNAS E P, UNTCH M, MANO M S, et al. Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE[J]. Ann Oncol, 2021, 32(8): 1005-1014. doi: 10.1016/j.annonc.2021.04.011 pmid: 33932503
[3]	ZHANG J H, FAN J J, ZENG X, et al. Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer[J]. Cell Death Dis, 2021, 12(4): 288. doi: 10.1038/s41419-020-03349-1 pmid: 33731670
[4]	VON MINCKWITZ G, HUANG C S, MANO M S, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer[J]. N Engl J Med, 2019, 380(7): 617-628. doi: 10.1056/NEJMoa1814017
[5]	《中国乳腺癌新辅助治疗专家共识2022年版》专家组. 中国乳腺癌新辅助治疗专家共识(2022年版)[J]. 中国癌症杂志, 2022, 32(1): 80-89. doi: 10.19401/j.cnki.1007-3639.2022.01.011
	Expert Group of Expert Consensus on Neoadjuvant Treatment of Breast Cancer in China (2022 edition). Expert consensus on neoadjuvant treatment of breast cancer in China (2022 edition)[J]. China Oncol, 2022, 32(1): 80-89.
[6]	SHITARA K, HONMA Y, OMURO Y, et al. Efficacy of trastuzumab emtansine in Japanese patients with previously treated HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: a subgroup analysis of the GATSBY study[J]. Asia Pac J Clin Oncol, 2020, 16(1): 5-13.
[7]	OGITANI Y, AIDA T, HAGIHARA K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase Ⅰ inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1[J]. Clin Cancer Res, 2016, 22(20): 5097-5108. doi: 10.1158/1078-0432.CCR-15-2822
[8]	SHITARA K, BANG Y J, IWASA S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer[J]. N Engl J Med, 2020, 382(25): 2419-2430. doi: 10.1056/NEJMoa2004413
[9]	MOD I, PARK H, MURTHY R K, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ⅰb study[J]. J Clin Oncol, 2020, 38(17): 1887-1896. doi: 10.1200/JCO.19.02318
[10]	KALMUK J, RINDER D, HELTZEL C, et al. An overview of the preclinical discovery and development of trastuzumab deruxtecan: a novel gastric cancer therapeutic[J]. Expert Opin Drug Discov, 2022, 17(5): 427-436. doi: 10.1080/17460441.2022.2050692
[11]	AOKI M, IWASA S, BOKU N. Trastuzumab deruxtecan for the treatment of HER2-positive advanced gastric cancer: a clinical perspective[J]. Gastric Cancer, 2021, 24(3): 567-576. doi: 10.1007/s10120-021-01164-x pmid: 33646464
[12]	LI L, XU M Z, WANG L, et al. Conjugating MMAE to a novel anti-HER2 antibody for selective targeted delivery[J]. Eur Rev Med Pharmacol Sci, 2020, 24(24): 12929-12937.
[13]	HA S Y Y, ANAMI Y, YAMAZAKI C M, et al. An enzymatically cleavable tripeptide linker for maximizing the therapeutic index of antibody-drug conjugates[J]. Mol Cancer Ther, 2022, 21(9): 1449-1461. doi: 10.1158/1535-7163.MCT-22-0362 pmid: 35793453
[14]	季双敏, 王玉珠, 杨进波. 抗体偶联药物的分子特点及其药代动力学研究考虑[J]. 中国临床药理学杂志, 2021, 37(6): 777-782.
	JI S M, WANG Y Z, YANG J B. Molecular characteristics and pharmacokinetic considerations of antibody coupled drugs[J]. Chin J Clin Pharmacol, 2021, 37(6): 777-782
[15]	BURKE J M, MORSCHHAUSER F, ANDORSKY D, et al. Antibody-drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin[J]. Expert Rev Clin Pharmacol, 2020, 13(10): 1073-1083. doi: 10.1080/17512433.2020.1826303
[16]	CHEN Z H, YUAN J J, XU Y Y, et al. From AVATAR mice to patients: RC48-ADC exerted promising efficacy in advanced gastric cancer with HER2 expression[J]. Front Pharmacol, 2021, 12: 757994. doi: 10.3389/fphar.2021.757994
[17]	HU Y X, ZHU Y X, WEI X W, et al. Disitamab vedotin, a novel HER2-directed antibody-drug conjugate in gastric cancer and other solid tumors[J]. Drugs Today (Barc), 2022, 58(10): 491-507. doi: 10.1358/dot.2022.58.10.3408812
[18]	LI H W, YU C, JIANG J, et al. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer[J]. Cancer Biol Ther, 2016, 17(4): 346-354. doi: 10.1080/15384047.2016.1139248 pmid: 26853765
[19]	金洋冰, 蔡劬, 计骏, 等. 抗体偶联药物维迪西妥单抗对HER-2不同表达水平胃癌细胞抑制效应的体外研究[J]. 临床肿瘤学杂志, 2023, 28(1): 1-7.
	JIN Y B, CAI Q, JI J, et al. In vitro study on the inhibitory effect of antibody coupled drug disitamab vedotin on gastric cancer cells with different expression levels of HER-2[J]. Chin Clin Oncol, 2023, 28(1): 1-7.
[20]	PENG Z, LIU T S, WEI J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase Ⅱ study[J]. Cancer Commun (Lond), 2021, 41(11): 1173-1182.
[21]	XU Y Y, WANG Y K, GONG J F, et al. Phase Ⅰ study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors[J]. Gastric Cancer, 2021, 24(4): 913-925. doi: 10.1007/s10120-021-01168-7
[22]	ClinicalTrials. gov. A study of trastuzumab emtansine versus taxane in participants with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT01641939.
[23]	ClinicalTrials. gov. A combination study of Kadcyla (trastuzumab emtansine) and capecitabine in participants with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) or HER2-positive locally advanced/metastatic gastric cancer (LA/mGC) (TRAXHER2)[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT01702558.
[24]	ClinicalTrials. gov. Targeted therapy directed by genetic testing in treating patients with advanced refractory solid tumors, lymphomas, or multiple myeloma (the MATCH screening trial)[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT02465060.
[25]	ClinicalTrials. gov. DS-8201a in human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer [DESTINY-Gastric01][EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT03329690.
[26]	ClinicalTrials. gov. Ph1b/2 study of the safety and efficacy of T-DXd combinations in advanced HER2⁺ gastric cancer (DESTINY-Gastric03) (DG-03) [EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04379596.
[27]	ClinicalTrials. gov. Trastuzumab deruxtecan for subjects with HER2-positive gastric cancer or gastro-esophageal junction adenocarcinoma after progression on or after a trastuzumab-containing regimen (DESTINY-Gastric04) [EB/OL]. [2022-10-25].https://clinicaltrials.gov/ct2/show/NCT04704934.
[28]	ClinicalTrials. gov. Phase 2 study of T-DXd in the neoadjuvant treatment for patients with HER2 positive gastric and GEJ adenocarcinoma[EB/OL]. [2022-10-25].
[29]	ClinicalTrials. gov. Study of T-DXd monotherapy in patients with HER2-expressing locally advanced or metastatic gastric or GEJ adenocarcinoma who have received 2 or more prior regimens (DG-06)[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04989816.
[30]	ClinicalTrials. gov. A study of T-DXd for the treatment of solid tumors harboring HER2 activating mutations (DPT01) [EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04639219.
[31]	ClinicalTrials. gov. A study of RC48-ADC in local advanced or metastatic gastric cancer subjects with the overexpression of HER2[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT03556345.
[32]	ClinicalTrials. gov. A study of RC48-ADC in local advanced or metastatic gastric cancer with the HER2-overexpression[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04714190.
[33]	ClinicalTrials. gov. To evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of disitamab vedotin combined with RC98 in the treatment of subjects with HER2-expressing locally advanced or metastatic gastric cancer (including AEG)[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT05514158.
[34]	ClinicalTrials. gov. RC48 plus AK105 and cisplatin in advanced gastric cancer[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT05313906.
[35]	ClinicalTrials. gov. A phase Ⅱ clinical study of fruquintinib combined with RC48 in the treatment of previously treated HER2-positive locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer[EB/OL]. [2022-10-25].https://clinicaltrials.gov/ct2/show/NCT05241899.
[36]	ClinicalTrials. gov. Disitamab vedotin combined with PD-1 and neoadjuvant chemotherapy for locally advanced gastric cancer(RC48-C018)[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT05113459.
[37]	NADAL-SERRANO M, MORANCHO B, ESCRIVÁ-DE-ROMANÍ S, et al. The second generation antibody-drug conjugate SYD985 overcomes resistances to T-DM1[J]. Cancers (Basel), 2020, 12(3): 670. doi: 10.3390/cancers12030670
[38]	DURO-SÁNCHEZ S, NADAL-SERRANO M, LALINDE-GUTIÉRREZ M, et al. Therapy-induced senescence enhances the efficacy of HER2-targeted antibody-drug conjugates in breast cancer[J]. Cancer Res, 2022, 82(24): 4670-4679. doi: 10.1158/0008-5472.CAN-22-0787
[39]	BANERJI U, VAN HERPEN C M L, SAURA C, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study[J]. Lancet Oncol, 2019, 20(8): 1124-1135. doi: S1470-2045(19)30328-6 pmid: 31257177
[40]	MENDERES G, BONAZZOLI E, BELLONE S, et al. SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression[J]. Gynecol Oncol, 2017, 146(1): 179-186. doi: S0090-8258(17)30804-1 pmid: 28473206
[41]	BAROK M, LE JONCOUR V, MARTINS A, et al. ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer[J]. Cancer Lett, 2020, 473: 156-163. doi: S0304-3835(19)30659-7 pmid: 31904483
[42]	ZHANG J, JI D M, SHEN W N, et al. Phase Ⅰ trial of a novel anti-HER2 antibody-drug conjugate, ARX788, for the treatment of HER2-positive metastatic breast cancer[J]. Clin Cancer Res, 2022. Online ahead of print.
[43]	LI H, ZHANG X, XU Z Y, et al. Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors[J]. Antib Ther, 2021, 4(3): 175-184. doi: 10.1093/abt/tbab017 pmid: 34532642
[44]	ClinicalTrials. gov. ISPY-P1.01: evaluating the safety of weekly paclitaxel with trastuzumab duocarmazine (SYD985) in patients with metastatic cancer[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04602117.
[45]	ClinicalTrials. gov. A dose-escalation, expansion study of ARX788, in advanced solid tumors subjects with HER2 expression (ACE-Pan Tumor 01)[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT03255070.
[46]	ClinicalTrials. gov. Study of A166 in patients with relapsed/refractory cancers expressing HER2 antigen or having amplified HER2 gene[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT03602079.
[47]	ClinicalTrials. gov. A study of MRG002 in the treatment of HER2-positive/HER2-low locally advanced or metastatic gastric/gastroesophageal junction cancer.[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT05141747..
[48]	ClinicalTrials. gov. A study of MRG002 in patients with HER2-positive advanced solid tumors and locally advanced or metastatic gastric/gastroesophageal junction (GEJ) cancer[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04492488.
[49]	ClinicalTrials. gov. A clinical trial of BAT8001 on safety, tolerability and pharmacokinetics for patients[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT04189211.
[50]	ClinicalTrials. gov. A dose finding study of ZW49 in patients with HER2-positive cancers[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT03821233.
[51]	ClinicalTrials. gov.A phase 1/2 study of MEDI4276 in adults subjects with select HER2-expressing advanced solid tumors. (MEDI4276) [EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT02576548.
[52]	ClinicalTrials. gov. Study of antibody drug conjugate in patients with advanced breast cancer expressing HER2[EB/OL]. [2022-10-25]. https://clinicaltrials.gov/ct2/show/NCT02952729.
[53]	JANJIGIAN Y Y, SHITARA K, MOEHLER M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial[J]. Lancet, 2021, 398(10294): 27-40. doi: 10.1016/S0140-6736(21)00797-2 pmid: 34102137
[54]	SHITARA K, VAN CUTSEM E, BANG Y J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial[J]. JAMA Oncol, 2020, 6(10): 1571-1580. doi: 10.1001/jamaoncol.2020.3370
[55]	JANJIGIAN Y Y, KAWAZOE A, YAÑEZ P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer[J]. Nature, 2021, 600(7890): 727-730. doi: 10.1038/s41586-021-04161-3
[56]	MERIC-BERNSTAM F, BEERAM M, HAMILTON E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study[J]. Lancet Oncol, 2022, 23(12): 1558-1570. doi: 10.1016/S1470-2045(22)00621-0
[57]	DELA CRUZ CHUH J, GO M, CHEN Y, et al. Preclinical optimization of Ly6E-targeted ADCs for increased durability and efficacy of anti-tumor response[J]. MAbs, 2021, 13(1): 1862452. doi: 10.1080/19420862.2020.1862452
[58]	TRAORE T, KHATTAR M. Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2[J]. Cancer Res, 2018, 78(13_Suppl)
[59]	IWATA T N, ISHII C, ISHIDA S, et al. A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model[J]. Mol Cancer Ther, 2018, 17(7): 1494-1503. doi: 10.1158/1535-7163.MCT-17-0749 pmid: 29703841
[60]	YU M H, LIANG Y, LI L H, et al. Research progress of antibody-drug conjugates therapy for HER2-low expressing gastric cancer[J]. Transl Oncol, 2023, 29: 101624. doi: 10.1016/j.tranon.2023.101624
[61]	SIMMONS J K, BURKE P J, COCHRAN J H, et al. Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation[J]. Toxicol Appl Pharmacol, 2020, 392: 114932. doi: 10.1016/j.taap.2020.114932
[62]	DÍAZ-RODRÍGUEZ E, GANDULLO-SÁNCHEZ L, OCAÑA A, et al. Novel ADCs and strategies to overcome resistance to anti-HER2 ADCs[J]. Cancers (Basel), 2021, 14(1): 154. doi: 10.3390/cancers14010154
[63]	GINZEL J D, ACHARYA C R, LUBKOV V, et al. HER2 isoforms uniquely program intratumor heterogeneity and predetermine breast cancer trajectories during the occult tumorigenic phase[J]. Mol Cancer Res, 2021, 19(10): 1699-1711. doi: 10.1158/1541-7786.MCR-21-0215 pmid: 34131071
[64]	TARANTINO P, CARMAGNANI PESTANA R, CORTI C, et al. Antibody-drug conjugates: smart chemotherapy delivery across tumor histologies[J]. CA Cancer J Clin, 2022, 72(2): 165-182. doi: 10.3322/caac.v72.2
[65]	候涛涛, 张剑锋, 雷世睿, 等. HGF、c-Met及p-Erk蛋白在胃癌组织中的表达及意义[J]. 现代肿瘤医学, 2021, 29(5): 819-823.
	HOU T T, ZHANG J F, LEI S R, et al. Expression and significance of HGF, c-Met and p-Erk in gastric cancer tissues[J]. J Mod Oncol, 2021, 29(5): 819-823.
[66]	王俏丽, 杜娟. CLDN18.2在消化系统恶性肿瘤中作用的研究进展[J]. 中国肿瘤生物治疗杂志, 2022, 29(7): 681-685.
	WANG Q L, DU J. Research progress on the role of CLDN18.2 in malignant tumors of the digestive system[J]. Chin J Tumor Biother, 2022, 29(7): 681-685.
[67]	BOSE A, BANERJEE S, VISWESWARIAH S S. Mutational landscape of receptor guanylyl cyclase C: functional analysis and disease-related mutations[J]. IUBMB Life, 2020, 72(6): 1145-1159. doi: 10.1002/iub.2283 pmid: 32293781