双特异抗体药物研发现状及发展对策

doi:10.19586/j.2095-2341.2022.0150

生物技术进展 ›› 2023, Vol. 13 ›› Issue (3): 353-358.DOI: 10.19586/j.2095-2341.2022.0150

双特异抗体药物研发现状及发展对策

李永超¹^,²(), 杨昭¹^,²()

^1.塔里木大学生命科学与技术学院，新疆生产建设兵团塔里木盆地生物资源保护利用重点实验室，新疆阿拉尔 843300
^2.北京化工大学生命科学与技术学院，分子诊断技术创新研究中心，北京 100029

收稿日期:2022-08-23 接受日期:2022-11-08 出版日期:2023-05-25 发布日期:2023-06-12
通讯作者: 杨昭
作者简介:李永超E-mail:lyc4399@qq.com；
基金资助:
中央高校基本科研业务费(201910);2021年新疆科协青年人才托举工程项目;京津冀基础研究合作专项（19JCZDJC65800〔Z〕）;新疆生产建设兵团重点领域科技攻关计划项目(2022AB022)

Status and Countermeasures of Bispecific Antibody Drugs

Yongchao LI¹^,²(), Zhao YANG¹^,²()

^1.Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin of Xinjiang Production and Construction Corps，College of Life Science and Technology，Tarim University，Xinjiang Alar 843300，China
^2.Innovation Center of Molecular Diagnostics，College of Life Science and Technology，Beijing University of Chemical Technology，Beijing 100029，China

Received:2022-08-23 Accepted:2022-11-08 Online:2023-05-25 Published:2023-06-12
Contact: Zhao YANG

摘要/Abstract

摘要：

双特异性抗体（bispecific antibody，BsAb）是具有两个特异性抗原结合位点的人工抗体，能够在靶细胞的两个功能分子之间或靶细胞与其他细胞类型之间发挥桥接作用，在抗血管生成、清除肿瘤细胞、调节肿瘤微环境和增强抗肿瘤免疫反应等方面具有广阔的应用前景，是生物医药领域重要的研究方向之一。全球已有近200种BsAb药物进入临床试验，其中7款药物已获批上市。我国有60余种BsAb药物，但大多数BsAb药物处于临床Ⅰ期或者Ⅱ期阶段，仅有Cadonilimab已获批上市以及KN046和AK112处于临床Ⅲ期。综述了BsAb药物的前沿进展及其在研发和转化过程中所面临的难点与挑战，并提出了合理可行的解决方案，以期为我国在BsAb药物的研发与布局提供参考。

关键词: 双特异性抗体, 抗血管生成, 肿瘤微环境, 肿瘤免疫, Cadonilimab

Abstract:

Bispecific antibody （BsAb） is an artificial antibody with two specific antigen-binding sites， playing a bridging role between two functional molecules of target cells or between a target cell and another cell type. It has broad application prospects in anti-angiogenesis， clearance of tumor cells， regulation of tumor microenvironment and enhancement of anti-tumor immune response， etc. The research and development of BsAb is one of the important research directions in the field of biomedicine. Approximately two hundred BsAb drugs are entering clinical trials worldwide， and seven of them have been approved for marketing. More than 60 BsAb drugs are being investigated in China. However， most of them are in phase Ⅰ/Ⅱ clinical trials. Only Cadonilimab has been approved for marketing， and KN046 and AK112 are in phase Ⅲ clinical trials. This paper summarized the research progress， difficulties and challenges of the development and transformation of BsAb drugs， and proposed the reasonable and feasible solutions， which was expected to provide a reference for the development and strategic layout of BsAb drugs in China.

Key words: bispecific antibodies, anti-angiogenesis, tumor microenvironment, tumor immunity, Cadonilimab

中图分类号:

R914.2

李永超, 杨昭. 双特异抗体药物研发现状及发展对策[J]. 生物技术进展, 2023, 13(3): 353-358.

Yongchao LI, Zhao YANG. Status and Countermeasures of Bispecific Antibody Drugs[J]. Current Biotechnology, 2023, 13(3): 353-358.

图/表 1

参考文献 39

1	LABRIJN A F, JANMAAT M L, REICHERT J M, et al.. Bispecific antibodies: a mechanistic review of the pipeline[J]. Nat. Rev. Drug Discov., 2019, 18(8): 585-608.
2	WANG S, CHEN K, LEI Q, et al.. The state of the art of bispecific antibodies for treating human malignancies[J/OL]. EMBO Mol. Med., 2021, 13(9): e14291[2022-12-20]. .
3	HEISS M M, MURAWA P, KORALEWSKI P, et al.. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial[J]. Int. J. Cancer, 2010, 127(9): 2209-2221.
4	K P, EB H, NB L, 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.
5	BUDDE L E, ASSOULINE S, SEHN L H, et al.. Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: phase I dose-escalation study[J]. J. Clin. Oncol., 2022, 40(5): 481-491.
6	KEAM S J. Cadonilimab: first approval[J]. Drugs, 2022, 82(12): 1333-1339.
7	DE-GASPARO R, PEDOTTI M, SIMONELLI L, et al.. Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice[J]. Nature, 2021, 593(7859): 424-428.
8	SCHAEFER W, REGULA J T, BÄHNER M, et al.. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies[J]. Proc. Natl. Acad. Sci. USA, 2011, 108(27): 11187-11192.
9	ROBBIANI D F, GAEBLER C, MUECKSCH F, et al.. Convergent antibody responses to SARS-CoV-2 in convalescent individuals[J]. Nature, 2020, 584(7821): 437-442.
10	HASSAN A O, CASE J B, WINKLER E S, et al.. A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies[J]. Cell, 2020, 182(3): 744-753.
11	KU Z, XIE X, LIN J, et al.. Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth[J/OL]. Nat. Commun., 2022, 13(1): 5552[2022-09-22]. .
12	AKOENIG P, DAS H, LIU H, et al.. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape[J/OL]. Science, 2021, 371(6530): eabe6230[2021-02-12]. .
13	ANTONIO M, MICHELLE N V, BRYAN A J. Mouse adapted SARS-CoV-2 protects animals from lethal SARS-CoV challenge[J/OL]. PLoS Biol., 2021, 5: 36[2022-12-20]. .
14	WU Y, WANG F, SHEN C, et al.. A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2[J]. Science, 2020, 368(6496): 1274-1278.
15	LI Z, LI S, ZHANG G, et al.. An engineered bispecific human monoclonal antibody against SARS-CoV-2[J]. Nat. Immunol., 2022, 23(3): 423-430.
16	OLDENBURG J, MAHLANGU J N, KIM B, et al.. Emicizumab prophylaxis in hemophilia A with inhibitors[J]. New Engl. J. Med., 2017, 377(9): 809-818.
17	MAHLANGU J, OLDENBURG J, PAZ-PRIEL I, et al.. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors[J]. New Engl. J. Med., 2018, 379(9): 811-822.
18	HEIER J S, KHANANI A M, QUEZADA R C, et al.. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials[J]. Lancet, 2022, 399(10326): 729-740.
19	李耿, 刘晓志, 王志明, 等. 双特异性抗体药物应用进展[J]. 生物技术进展, 2015, 5(6): 420-424.
20	魏雪晨, 颜炜群. 双特异性抗体的作用机制及制备与纯化方法研究进展[J]. 生物技术, 2021, 31(1): 89-95+88.
21	王璐瑶, 魏振华, 熊伟佳, 等. 双特异性抗体构建在肿瘤临床治疗中的应用[J]. 生物工程学报, 2021, 37(2): 513-529.
22	张峰, 王开芹, 王兰. 双特异性抗体研发进展[J]. 药物分析杂志, 2019, 39(1): 78-85.
23	陶维红, 李宗海, 李荣秀. 我国单克隆抗体药物产业化进展浅谈[J]. 生物产业技术, 2019 (2): 75-80.
24	DENGL S, MAYER K, BORMANN F, et al.. Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices[J/OL]. Nat. Commun., 2020, 11(1): 4974[2022-12-20]. .
25	STEINMETZ A, VALLÉE F, BEIL C, et al.. CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications[J]. MAbs, 2016, 8(5): 867-878.
26	HOFMANN T, SCHMIDT J, CIESIELSKI E, et al.. Intein mediated high throughput screening for bispecific antibodies[J/OL]. mAbs, 2020, 12(1): 1731938[2022-12-20].
27	WEI H, CAI H, JIN Y, et al.. Structural basis of a novel heterodimeric Fc for bispecific antibody production[J]. Oncotarget, 2017, 8(31): 51037-51049.
28	WANG C, HONG J, YANG Z, et al.. Design of a novel fab-like antibody fragment with enhanced stability and affinity for clinical use[J/OL]. Small Methods, 2022, 6(2): e2100966[2022-12-20]. .
29	FANSLOW W C, LIU Z, HU Z, et al.. Development of PSB205, a bifunctional MabPair product that targets PD-1 and CTLA-4[J]. Cancer Res., 2019, 79(13): 4069-4069.
30	WRANIK B J, CHRISTENSEN E L, SCHAEFER G, et al.. LUZ-Y, a novel platform for the mammalian cell production of full-length IgG-bispecific antibodies[J]. J. Biol. Chem., 2012, 287(52): 43331-43339.
31	KIM H S, DUNSHEE D R, YEE A, et al.. Tethered-variable CL bispecific IgG: an antibody platform for rapid bispecific antibody screening[J]. Protein Engin. Design Select., 2017, 30(9): 627-637.
32	SUROWKA M, SCHAEFER W, KLEIN C. Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins[J/OL]. mAbs, 2021, 13(1): 1967714[2022-12-20]. .
33	DE NARDIS C, HENDRIKS L J A, POIRIER E, et al.. A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1[J]. J. Biol. Chem., 2017, 292(35): 14706-14717.
34	PODUST V N, BALAN S, SIM B C, et al.. Extension of in vivo half-life of biologically active molecules by XTEN protein polymers[J]. J. Control. Release, 2016, 240: 52-66.
35	KAMATA-SAKURAI M, NARITA Y, HORI Y, et al.. Antibody to CD137 activated by extracellular adenosine triphosphate is tumor selective and broadly effective in vivo without systemic immune activation[J]. Cancer Discov., 2021, 11(1): 158-175.
36	HILL Z B, MARTINKO A J, NGUYEN D P, et al.. Human antibody-based chemically induced dimerizers for cell therapeutic applications[J]. Nat. Chem. Biol., 2018, 14(2): 112-117.
37	HABER L, OLSON K, KELLY M P, et al.. Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning[J]. Sci. Rep., 2021, 11(1): 14397[2021-06-13]. .
38	薛雯, 贾宇, 江一帆, 等. 免疫检查点抑制剂在肿瘤治疗中的研究进展[J]. 生物技术进展, 2019, 9(4): 341-349.
39	杨懿祺, 张志高, 游小龙, 等. 抗体药物的发展与应用[J]. 生物技术进展, 2022, 12(3): 358-365.

商品名	通用名	针对靶点	企业名称	适应症	上市年份
Removab	Catumaxomab	EpCAM+CD3	Trion Pharma	EpCAM-阳性的恶性腹水患者	2009 （2017退市）
Blincyto	Blinatumomab	CD19+CD3	安进	急性B淋巴细胞白血病	2014
Hemlibra	Emicizumab	IXa+X	罗氏	A型血友病	2017
Rybrevant	Amivantamab	EGFR+C-MET	强生	转移性非小细胞肺癌成人患者	2021
Vabysmo	Faricimab	VEGF+Ang2	基因泰克	湿性年龄相关性黄斑变性和糖尿病性黄斑水肿	2022
Lunsumio	Mosunetuzumab	CD20+CD3	罗氏	治疗既往接受过至少2次系统治疗后复发或难治性滤泡性淋巴瘤成人患者	2022
开坦尼	Candonilimab	PD-1/CTLA-4	康方生物	用于治疗既往接受含铂化疗失败的复发或转移性宫颈癌患者	2022

商品名	通用名	针对靶点	企业名称	适应症	上市年份
Removab	Catumaxomab	EpCAM+CD3	Trion Pharma	EpCAM-阳性的恶性腹水患者	2009 （2017退市）
Blincyto	Blinatumomab	CD19+CD3	安进	急性B淋巴细胞白血病	2014
Hemlibra	Emicizumab	IXa+X	罗氏	A型血友病	2017
Rybrevant	Amivantamab	EGFR+C-MET	强生	转移性非小细胞肺癌成人患者	2021
Vabysmo	Faricimab	VEGF+Ang2	基因泰克	湿性年龄相关性黄斑变性和糖尿病性黄斑水肿	2022
Lunsumio	Mosunetuzumab	CD20+CD3	罗氏	治疗既往接受过至少2次系统治疗后复发或难治性滤泡性淋巴瘤成人患者	2022
开坦尼	Candonilimab	PD-1/CTLA-4	康方生物	用于治疗既往接受含铂化疗失败的复发或转移性宫颈癌患者	2022

[1]	杨懿祺, 张志高, 游小龙, 张婧, 林冠峰, 吴英松. 抗体药物的发展与应用[J]. 生物技术进展, 2022, 12(3): 358-365.
[2]	李耿,刘晓志,王志明,高健. 双特异性抗体药物应用进展[J]. 生物技术进展, 2015, 5(6): 420-424.

双特异抗体药物研发现状及发展对策

Status and Countermeasures of Bispecific Antibody Drugs

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