双特异性抗体在非小细胞肺癌治疗中的进展

摘要/Abstract

摘要：

双特异性抗体（BsAb）是一种可以同时或先后特异性结合两个抗原或抗原表位的新型高效抗肿瘤药物。目前，靶向表皮生长因子受体（EGFR）和cMET的埃万妥珠单抗已获批应用于治疗EGFR ex20ins的局部晚期或转移性非小细胞肺癌（NSCLC），靶向程序性死亡蛋白配体-1（PD-L1）和细胞毒性T淋巴细胞相关抗原-4（CTLA-4）、程序性死亡蛋白-1（PD-1）和CTLA-4、PD-L1和转化生长因子-β、PD-1和血管内皮生长因子的抑制剂应用于NSCLC的治疗正在进行中，均表现出良好的安全性和有效性。深入探讨BsAb在NSCLC治疗中的研究进展，将为临床治疗NSCLC提供新的诊疗思路。

关键词:癌，非小细胞肺,抗体，双特异性,治疗

Abstract:

Bispecific antibody （BsAb） is a new type of highly effective anti-tumor drug that can specifically bind two antigens or epitopes simultaneously or successively. At present， evantuzumab targeting epidermal growth factor receptor （EGFR） and cMET has been approved for the treatment of EGFR ex20ins in locally advanced or metastatic non-small cell lung cancer （NSCLC）. Inhibitors targeting programmed death-ligand 1 （PD-L1） and cytotoxic T lymphocyte antigen-4 （CTLA-4）， programmed death-1 （PD-1） and CTLA-4， PD-L1 and transforming growth factor-β， PD-1 and vascular endothelial growth factor are applied to NSCLC. The treatment of NSCLC is underway， showing good safety and efficacy. Further exploring the research progress of BsAbs in the treatment of NSCLC will provide a new diagnosis and treatment idea for the clinical treatment of NSCLC.

Key words:Carcinoma，non-small-cell lung,Antibodies，bispecific,Therapy

秦雪倩, 杨宏宇, 王真, 王孟超, 张欣. 双特异性抗体在非小细胞肺癌治疗中的进展[J]. 国际肿瘤学杂志, 2023, 50(9): 558-563.

Qin Xueqian, Yang Hongyu, Wang Zhen, Wang Mengchao, Zhang Xin. Progress of bispecific antibody in the treatment of non-small cell lung cancer[J]. Journal of International Oncology, 2023, 50(9): 558-563.

参考文献36

[1]	Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020[J].Chin Med J (Engl),2021,134(7): 783-791. DOI:10.1097/CM9.0000000000001474.
[2]	Passaro A, Brahmer J, Antonia S, et al. Managing resistance to immune checkpoint inhibitors in lung cancer: treatment and novel strategies[J].J Clin Oncol,2022,40(6): 598-610. DOI:10.1200/JCO.21.01845. pmid:34985992
[3]	Liu WJ, Du Y, Wen R, et al. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer[J].Pharmacol Ther,2020,206: 107438. DOI:10.1016/j.pharmthera.2019.107438.
[4]	Nisonoff A, WisslerI FC, Lipman LN. Properties of the major component of a peptic digest of rabbit antibody[J].Science,1960,132(3441): 1770-1771. DOI:10.1126/science.132.3441.1770. pmid:13729245
[5]	Suurs FV, Lub-de Hooge MN, de Vries EGE, et al. A review of bispecific antibodies and antibody constructs in oncology and clinical challenges[J].Pharmacol Ther,2019,201: 103-119. DOI:10.1016/j.pharmthera.2019.04.006.
[6]	Li H, Er Saw P, Song E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics[J].Cell Mol Immunol,2020,17(5): 451-461. DOI:10.1038/s41423-020-0417-8. pmid:32313210
[7]	Shim H. Bispecific antibodies and antibody-drug conjugates for cancer therapy: technological considerations[J].Biomolecules,2020,10(3): 360. DOI:10.3390/biom10030360.
[8]	Ma J, Mo Y, Tang M, et al. Bispecific antibodies: from research to clinical application[J].Front Immunol,2021,12: 626616. DOI:10.3389/fimmu.2021.626616.
[9]	Vijayaraghavan S, Lipfert L, Chevalier K, et al. Amivantamab (JNJ- 61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis[J].Mol Cancer Ther,2020,19(10): 2044-2056. DOI:10.1158/1535-7163.MCT-20-0071. pmid:32747419
[10]	Yun J, Lee SH, Kim SY, et al. Antitumor activity of amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR exon 20 insertion-driven NSCLC[J].Cancer Discov,2020,10(8): 1194-1209. DOI:10.1158/2159-8290.CD-20-0116.
[11]	Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase Ⅰ study[J].J Clin Oncol,2021,39(30): 3391-3402. DOI:10.1200/JCO.21.00662.
[12]	Syed YY. Amivantamab: first approval[J].Drugs,2021,81(11): 1349-1353. DOI:10.1007/s40265-021-01561-7. pmid:34292533
[13]	Krebs M, Spira AI, Cho BC, et al. Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: updated results from the CHRYSALIS study[J].J Clin Oncol,2022,40(16_suppl): 9008. DOI:10.1200/JCO.2022.40.16_suppl.9008.
[14]	Hou J, Li H, Ma S, et al. EGFR exon 20 insertion mutations in advanced non-small-cell lung cancer: current status and perspectives[J].Biomark Res,2022,10(1): 21. DOI:10.1186/s40364-022-00372-6. pmid:35418149
[15]	Wang Q, Yang S, Wang K, et al. MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer[J].J Hematol Oncol,2019,12(1): 63. DOI:10.1186/s13045-019-0759-9.
[16]	Shu CA, Goto K, Ohe Y, et al. Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy: updated results from CHRYSALIS-2[J].J Clin Oncol,2022,40(16_suppl): 9006. DOI:10.1200/JCO.2022.40.16_suppl.9006.
[17]	Park KJ, Jeon E, Choi J, et al. Abstract 3044: the novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling[J].Cancer Res,2020,80(16_suppl): 3044. DOI:10.1158/1538-7445.AM2020-3044.
[18]	Shin J, Kim M, Lee M, et al. Abstract 3046: anti-tumor efficacy of CKD-702 in EGFR TKI-resistant patient-derived xenograft model[J].Cancer Res,2020,80(16_suppl): 3046. DOI:10.1158/1538-7445.AM2020-3046.
[19]	Kim D, Lee S, Jang I, et al. A phase Ⅰ study of CKD-702, an EGFR-cMET bispecific antibody, in advanced or metastatic non-small cell lung cancer (NSCLC)[J].Ann Oncol,2022,33(7_suppl): S1010. DOI:10.1016/j.annonc.2022.07.1124.
[20]	Kaplon H, Crescioli S, Chenoweth A, et al. Antibodies to watch in 2023[J].MAbs,2023,15(1):2153410. DOI:10.1080/19420 862.2022.2153410.
[21]	Zhou C, Xiong A, Fang J, et al. A phase Ⅱ study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed first line treatment[J].Ann Oncol,2022,33(7_suppl): S1022. DOI:10.1016/j.annonc.2022.07.1148.
[22]	Zhou C, Xiong A, Fang J, et al. A phase Ⅱ study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed prior EFGR-TKIs[J].Ann Oncol,2022,33(7_suppl): S1028. DOI:10.1016/j.annonc.2022.07.1160.
[23]	Zhao Y, Chen G, Li X, et al. Two-year follow-up from KN046 in combination with platinum doublet chemotherapy as first-line (1L) treatment for NSCLC: an open-label, multi-center phase Ⅱ trial[J].Ann Oncol,2022,33(7_suppl): S1025-S1026. DOI:10.1016/j.annonc.2022.07.1155.
[24]	Dovedi SJ, Elder MJ, Yang C, et al. Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1⁺activated T cells[J].Cancer Discov,2021,11(5): 1100-1117. DOI:10.1158/2159-8290.CD-20-1445. pmid:33419761
[25]	Ahn M, Kim S, Costa EC, et al. LBA56 MEDI5752 or pembrolizumab (P) plus carboplatin/pemetrexed (CP) in treatment-naïve (1L) non-small cell lung cancer (NSCLC): a phase Ⅰb/Ⅱ trial[J].Ann Oncol,2022,33(7_suppl): S1423. DOI:10.1016/j.annonc.2022.08.058.
[26]	Huang Z, Pang X, Zhong T, et al. 289 Cadonilimab, an anti-PD1/CTLA4 bi-specific antibody with Fc effector null backbone[J].J Immunother Cancer,2021,9(Suppl 2): A313-A314. DOI:10.1136/jitc-2021-SITC2021.289.
[27]	Keam SJ. Cadonilimab: first approval[J].Drugs,2022,82(12): 1333-1339. DOI:10.1007/s40265-022-01761-9. pmid:35986837
[28]	Wu L, Chen B, Yao W, et al. 1300P A phase Ⅰb/Ⅱ trial of AK104 (PD-1/CTLA-4 bispecific antibody) in combination with anlotinib in advanced NSCLC[J].Ann Oncol,2021,32(5_suppl): S1006. DOI:10.1016/j.annonc.2021.08.1902.
[29]	Cheng B, Ding K, Chen P, et al. Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer[J].Cancer Commun (Lond),2022,42(1): 17-36. DOI:10.1002/cac2.12244.
[30]	Feng J, Chen J, Li K, et al. 1278P SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, as first-line therapy for PD-L1⁺advanced/metastatic NSCLC: data from a clinical expansion cohort of a phase Ⅰ study[J].Ann Oncol,2021,32(5_suppl): S995. DOI:10.1016/j.annonc.2021.08.1880.
[31]	Shi M, Chen J, Li K, et al. SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, for advanced NSCLC with EGFR mutations: data from a multicenter phase 1 study[J].J Clin Oncol,2021,39(15_suppl): 9055. DOI:10.1200/JCO.2021.39.15_suppl.9055.
[32]	Wu YL, Zhou Q, Pan Y, et al. LBA5 A phaseⅡ study of neoadjuvant SHR-1701 with or without chemotherapy (chemo) followed by surgery or radiotherapy (RT) in stage Ⅲ unresectable NSCLC (uNSCLC)[J].Immunooncol Technol,2022,16(1_suppl): 100361. DOI:10.1016/j.iotech.2022.100361.
[33]	Lind H, Gameiro SR, Jochems C, et al. Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRⅡ agent: status of preclinical and clinical advances[J].J Immunother Cancer,2020,8(1): e000433. DOI:10.1136/jitc-2019-000433.
[34]	Paz-Ares L, Kim TM, Vicente D, et al. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial[J].J Thorac Oncol,2020,15(7): 1210-1222. DOI:10.1016/j.jtho.2020.03.003. pmid:32173464
[35]	Zhong T, Huang Z, Pang X, et al. 521 AK112, a tetravalent bispecific antibody targeting PD-1 and VEGF, enhances binding avidity and functional activities and elicits potent anti-tumor efficacy in pre-clinical studies[J].J Immunother Cancer,2022,10(Suppl 2): A546-A547. DOI:10.1136/jitc-2022-SITC2022.0521.
[36]	Zhao Y, Fang W, Yang Y, et al. A phase Ⅱ study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer[J].J Clin Oncol,2022,40(16_suppl): 9019. DOI:10.1200/JCO.2022.40.16_suppl.9019.