Bispecific Antibodies: From Research to Clinical Application

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 May 24

PMID 34025638

Citations 123

Authors

Jiabing Ma

Yicheng Mo

Menglin Tang

Junjie Shen

Yanan Qi

Wenxu Zhao

Yi Huang

Yanmin Xu

Cheng Qian

Affiliations

Soon will be listed here.

Abstract

Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical therapeutic effects of BsAbs are superior to those of monoclonal antibodies (MoAbs), with broad applications for tumor immunotherapy as well as for the treatment of other diseases. Recently, with progress in antibody or protein engineering and recombinant DNA technology, various platforms for generating different types of BsAbs based on novel strategies, for various uses, have been established. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. The detailed mechanisms of clinical/therapeutic action have been demonstrated with these different types of BsAbs. Three kinds of BsAbs have received market approval, and more than 110 types of BsAbs are at various stages of clinical trials. In this paper, we elaborate on the classic platforms, mechanisms, and applications of BsAbs. We hope that this review can stimulate new ideas for the development of BsAbs and improve current clinical strategies.

Citing Articles

Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1/PD-L1 Monoclonal Antibodies.

Roussot N, Kaderbhai C, Ghiringhelli F Cancers (Basel). 2025; 17(5).

PMID: 40075753 PMC: 11898530. DOI: 10.3390/cancers17050906.

Bispecific antibodies as powerful immunotherapeutic agents for urological cancers: Recent innovations based on preclinical and clinical evidence.

Hushmandi K, Einollahi B, Lee E, Sakaizawa R, Glaviano A, Reiter R Int J Biol Sci. 2025; 21(4):1410-1435.

PMID: 39990653 PMC: 11844292. DOI: 10.7150/ijbs.96155.

Quantifying antibody binding: techniques and therapeutic implications.

Lodge J, Kajtar L, Duxbury R, Hall D, Burley G, Cordy J MAbs. 2025; 17(1):2459795.

PMID: 39957177 PMC: 11834528. DOI: 10.1080/19420862.2025.2459795.

Two Are Better than One: The Bi-Specific Antibody Mosunetuzumab Reveals an Improved Immune Response of Vγ9Vδ2 T Cells Targeting CD20 in Malignant B Cells in Comparison to the Mono-Specific Antibody Obinutuzumab.

Marischen L, Fritsch J, Ilic J, Wahl L, Bertsch T, Knop S Int J Mol Sci. 2025; 26(3).

PMID: 39941030 PMC: 11818642. DOI: 10.3390/ijms26031262.

Comprehensive Review of Early and Late Toxicities in CAR T-Cell Therapy and Bispecific Antibody Treatments for Hematologic Malignancies.

Bangolo A, Amoozgar B, Mansour C, Zhang L, Gill S, Ip A Cancers (Basel). 2025; 17(2).

PMID: 39858064 PMC: 11764151. DOI: 10.3390/cancers17020282.

References

Verkleij C, Frerichs K, Broekmans M, Absalah S, Maas-Bosman P, Kruyswijk S . T-cell redirecting bispecific antibodies targeting BCMA for the treatment of multiple myeloma. Oncotarget. 2020; 11(45):4076-4081. PMC: 7665238. DOI: 10.18632/oncotarget.27792. View

Couch J, Yu Y, Zhang Y, Tarrant J, Fuji R, Meilandt W . Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier. Sci Transl Med. 2013; 5(183):183ra57, 1-12. DOI: 10.1126/scitranslmed.3005338. View

Bostrom J, Yu S, Kan D, Appleton B, Lee C, Billeci K . Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science. 2009; 323(5921):1610-4. DOI: 10.1126/science.1165480. View

Gellatly S, Hancock R . Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathog Dis. 2013; 67(3):159-73. DOI: 10.1111/2049-632X.12033. View

Zhou Y, Zong H, Han L, Xie Y, Jiang H, Gilly J . A novel bispecific antibody targeting CD3 and prolactin receptor (PRLR) against PRLR-expression breast cancer. J Exp Clin Cancer Res. 2020; 39(1):87. PMC: 7216678. DOI: 10.1186/s13046-020-01564-4. View

Klapper L, Glathe S, Vaisman N, Hynes N, ANDREWS G, Sela M . The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A. 1999; 96(9):4995-5000. PMC: 21805. DOI: 10.1073/pnas.96.9.4995. View

Schuurman J, Van Ree R, Perdok G, van Doorn H, Tan K, Aalberse R . Normal human immunoglobulin G4 is bispecific: it has two different antigen-combining sites. Immunology. 1999; 97(4):693-8. PMC: 2326875. DOI: 10.1046/j.1365-2567.1999.00845.x. View

Davis J, Aperlo C, Li Y, Kurosawa E, Lan Y, Lo K . SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng Des Sel. 2010; 23(4):195-202. DOI: 10.1093/protein/gzp094. View

Luo Y, Ye S, Li X, Lu W . Emerging Structure-Function Paradigm of Endocrine FGFs in Metabolic Diseases. Trends Pharmacol Sci. 2019; 40(2):142-153. DOI: 10.1016/j.tips.2018.12.002. View

10.

Guy D, Uy G . Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia. Curr Hematol Malig Rep. 2018; 13(6):417-425. PMC: 6295344. DOI: 10.1007/s11899-018-0472-8. View

11.

Adams C, Allison D, Flagella K, Presta L, Clarke J, Dybdal N . Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2005; 55(6):717-27. PMC: 11030689. DOI: 10.1007/s00262-005-0058-x. View

12.

Wang Q, Chen Y, Park J, Liu X, Hu Y, Wang T . Design and Production of Bispecific Antibodies. Antibodies (Basel). 2019; 8(3). PMC: 6783844. DOI: 10.3390/antib8030043. View

13.

Chen Z, Qian Y, Song Y, Xu X, Tao L, Mussa N . Design of next-generation therapeutic IgG4 with improved manufacturability and bioanalytical characteristics. MAbs. 2020; 12(1):1829338. PMC: 7577236. DOI: 10.1080/19420862.2020.1829338. View

14.

Wu C, Ying H, Grinnell C, Bryant S, Miller R, Clabbers A . Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol. 2007; 25(11):1290-7. DOI: 10.1038/nbt1345. View

15.

. MCLA-128 Fights Fusion-Positive Cancers. Cancer Discov. 2019; 9(12):1636. DOI: 10.1158/2159-8290.CD-NB2019-128. View

16.

Kohler G, Milstein C . Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256(5517):495-7. DOI: 10.1038/256495a0. View

17.

Seshacharyulu P, Ponnusamy M, Haridas D, Jain M, Ganti A, Batra S . Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012; 16(1):15-31. PMC: 3291787. DOI: 10.1517/14728222.2011.648617. View

18.

de Vries Schultink A, Bol K, Doornbos R, Murat A, Wasserman E, Dorlo T . Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors. Clin Pharmacokinet. 2020; 59(7):875-884. DOI: 10.1007/s40262-020-00858-2. View

19.

Nisonoff A, WISSLER F, LIPMAN L . Properties of the major component of a peptic digest of rabbit antibody. Science. 1960; 132(3441):1770-1. DOI: 10.1126/science.132.3441.1770. View

20.

De Nardis C, Hendriks L, Poirier E, Arvinte T, Gros P, Bakker A . A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G. J Biol Chem. 2017; 292(35):14706-14717. PMC: 5582861. DOI: 10.1074/jbc.M117.793497. View