Bispecific antibodies (BsAbs) are engineered antibodies that can bind two different antigens or two different epitopes at the same time, which gives them advantages over conventional monoclonal antibodies in recognizing disease targets and coordinating biological effects.[1] The concept emerged from early antibody-reassembly work in the 1960s and later advanced through hybridoma technology, antibody engineering, and recombinant DNA methods, which made more stable and clinically useful formats possible. BsAbs are now a major therapeutic platform in oncology, hematology, immunology, ophthalmology, and coagulation disorders.
Figure 1. the general structure of the bispecific antibody (a), and the general mechanism of action (b).
The defining feature of a bispecific antibody is dual specificity: one molecule can engage two different targets simultaneously, which can be used to redirect immune cells, block two signaling pathways, or bring a payload to a specific cell type (Figure 1). [2] Structurally, BsAbs are commonly divided into two major classes: IgG-like and non-IgG-like formats. IgG-like BsAbs retain an Fc region and often have better stability and longer half-life, while non-IgG-like formats without an Fc region such as BiTEs are smaller, penetrate tissue well, but usually have shorter half-lives. The advent of recombinant DNA methodologies has resulted in a range of recombinant BsAbs with over 50 different formats now being produced. See examples of few formats in the Figure 2 below. [3]
Figure 2: First bispecific antibodies were developed by chemical cross-linking of monoclonal antibodies (mAbs) or of Fab fragments, or by quadroma technology. Recombinant antibody engineering has allowed for the creation of recombinant bispecific antibody fragments comprising the variable heavy (VH) and light (VL) domains of the parental mabs. Few examples include scFv (single-chain variable fragment), BsDb (bispecific diabody), scBsDb (single-chain bispecific diabody), scBsTaFv (single-chain bispecific tandem variable domain), DNL-(Fab)3 (dock-and-lock trivalent Fab), sdAb (single-domain antibody), BssdAb (bispecific single-domain antibody).
Common engineering formats include knobs-into-holes, CrossMab, DuoBody, DEKK, DVD-Ig, FIT-Ig, BiTE, DART, and TandAbs, each designed to solve chain-mispairing or optimize function and pharmacokinetics. This structural diversity is important because the format strongly affects manufacturability, effector function, half-life, and clinical use.
BsAbs are most widely used in cancer therapy, especially as T-cell engagers that bring CD3-positive T cells into contact with tumor cells to induce cytotoxicity. [4] They are also used to block paired oncogenic pathways, such as EGFR and MET or VEGF and ANG-2, and to target immune checkpoints or tumor microenvironment pathways. Beyond oncology, BsAbs are clinically relevant in hemophilia A, where emicizumab mimics factor VIII activity, and in ophthalmology, where faricimab targets VEGF-A and Ang-2.
In broader preclinical and translational research, BsAbs are being explored for autoimmune disease, infectious disease, neurodegeneration, and inflammatory disorders. The major therapeutic value of BsAbs lies in their ability to combine two biological functions in one molecule, which can improve specificity and reduce the need for combination therapy.
There are 15 FDA-approved bispecific antibodies which we summarized in Table 1.[5] There are currently more than 600 bispecific antibodies (bsAbs) actively undergoing clinical trials worldwide. This clinical landscape has expanded rapidly from fewer than 100 trials in 2015, with the vast majority of these candidates being developed for oncology, hematology, and immunology, and that number has continued to grow since then.
Table 1. FDA-approved bispecific antibodies on the market [5]
Recent work is showing that bispecific antibody-drug conjugates, or BsADCs, may improve on standard ADCs by combining the dual-targeting ability of BsAbs with the payload delivery of ADCs. The BsADCs as a modular next-generation platform that can improve recognition, internalization, and therapeutic index, while potentially reducing some limitations of classical ADCs such as off-target toxicity and insufficient internalization. The BsADCs as a “1+1>2” strategy that can enhance selectivity and broadens the design space for next-generation conjugates. [6]
Current BsADC research focuses on several design questions: which target pairs are best, how to preserve bispecific binding after conjugation, how to optimize linker-payload choice, and how to balance internalization with stability in circulation. [7] In practical terms, BsADCs are being developed to use one arm for tumor selectivity and the other for internalization or resistance avoidance, which may help overcome weaknesses of traditional single-target ADCs. At this stage, BsADC development is still mostly preclinical and early translational, but it is one of the most active frontier areas in antibody engineering.
As a leading supplier of ADC linkers, payloads and antibodies supplier, BroadPharm offers a variety of high quality BsAbs including clinical approved BsAbs biosimilars and newly developed BsAbs for Pharmaceutical & biotech R&D. BroadPharm also provides comprehensive bioconjugation services and custom synthesis solutions tailored to customer project’s specific requirements. We deliver the flexibility, precision, and technical expertise you need from early discovery through advanced development stages.
[1] Lopatnikova JA, Sennikov SV. Bispecific immunotherapy based on antibodies, T-cell receptors, and aptamers: mechanisms of action, adverse effects, and future perspectives. Front Immunol. 2025, 16:1679092. doi: 10.3389/fimmu.2025.1679092.
[2] Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, Huang Y, Xu Y, Qian C. Bispecific Antibodies: From Research to Clinical Application. Front Immunol. 2021, 12:626616. doi: 10.3389/fimmu.2021.626616.
[3] Brinkmann U, Kontermann RE. The making of bispecific antibodies. 2017, 9(2):182-212. doi: 10.1080/19420862.2016.1268307.
[4] Choi SM, Lee JH, Ko S, Hong SS, Jin HE. Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies. Biomol Ther (Seoul). 2024, 32(6):708-722. doi: 10.4062/biomolther.2024.146.
[5] Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, Huang Y, Xu Y, Qian C. Bispecific Antibodies: From Research to Clinical Application. Front Immunol. 2021, 12:626616. doi: 10.3389/fimmu.2021.626616.
[6] Gu Y, Wang Z, Wang Y. Bispecific antibody drug conjugates: Making 1+1>2. Acta Pharm Sin B. 2024 May;14(5):1965-1986. doi: 10.1016/j.apsb.2024.01.009.
[7] Bai Y, Lei H, Gou S, Lan J, Cai D, Zheng X, Shen J, Chen Y, Zhao Y, Deng S, Wu X, Li M, Xiao Z, Zhang Y, Du F. Bispecific antibody-drug conjugates: a modular blueprint for next-generation cancer therapeutics. Arch Pharm Res. 2026, 49(1):61-100. doi: 10.1007/s12272-026-01595-z.