From 1960, when the concept of bispecific antibodies was first introduced, to the end of 2021, only four bispecific antibodies, catumaxomab, blinatumomab, emicizumab and amivantamab-vmjw, have been marketed in nearly six decades, with cataosumab being withdrawn from the market due to poor performance.
But, a turnaround came in 2022. Until Spetemper 2022, there were 5 bispecific antibodies approved. Here, let's find out what bispecific antibody is, how it works and how many bispecific antibodies are approved.
What Are Bispecific Antibodies?
Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. Compared with monoclonal antibodies, bispecific antibodies not only have stronger specificity, better targeting ability and lower off-target toxicity, but also can effectively prevent drug resistance, reduce treatment costs and improve patient access to drugs, achieving a superior therapeutic effect.
Figure 1. Bispecific Antibodies, source: reference 
Because BsAbs have two binding sites directed at different antigens or recognize two different epitopes of one antigen simultaneously, the functioning pathways are quite flexible.
Figure 2. Mode of action of therapeutic bispecific antibodies (bsAbs). Source: Reference 
(a) Recruitment and Activation of Immune Cells: Bispecific antibodies bind and activate immune cells at one binding site and recognize specific antigens on tumor cells at the other binding site, which mechanically recruit immune cells (e.g. T cells and NK cells) to the tumor area for killing. Examples include CD3×CD19 BsAbs, CD3×CD20 BsAbs, etc.
(b) Blocking of Dual Signaling Pathways: The onset and progression of diseases such as tumors usually involve multiple signals, and blocking a single signal may not completely inhibit tumor progression, and sometimes cause activation of other pathways. Bispecific antibodies work by targeting two receptors on the cell surface, inhibiting or activating two signals at the same time. Examples include PD-1 x CTLA-4 BsAbs, HER2 dual epitope BsAbs, etc.
(c) Forcing Association Of Protein Complexes: Bispecific antibodies can act on factors that are free in the body and promote the formation of protein complexes. A heterodimeric common light chain IgG connects FXIa and FX and thereby overcomes FVIII deficiency.
Development of Bispecific Antibodies
Bispecific antibodies have a long history, starting in the 1960s when antigen-binding fragments (Fabs) from two different polyclonal sera were re-associated into bispecific F(ab')2 molecules. Boosted by the hybridoma technology established in 1975, it became possible to generate bispecific antibodies of defined specificities by chemical conjugation of two monoclonal antibodies or by fusion of two antibody-producing hybridomas, generating hybrid hybridomas.
The development of bispecific antibodies has entered a breakthrough period since the 21st century. To date, eight bispecific antibodies have been approved worldwide, of which five bispecific antibodies have been approved for marketing in 2022. Despite the small number of approved products, blockbuster drugs have emerged, with emicizumab generating sales of $3.3 billion in 2021.
Figure 3. Approved Bispecific Antibodies
In 2009, the world's first bispecific antibody drug, Removab (target: CD3, Epcam), developed by Trion for the treatment of malignant ascites, was approved for marketing by the European Medicines Agency (EMA). However, due to depressed sales, Removab was temporarily withdrawn from the market in 2017.
Since then bispecific antibody research has stalled. It was not until 2014 that Blincyto (Blinatumomab), a bispecific antibody developed by Amgen, was approved for marketing by the FDA for the treatment of adult patients with Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL). In late 2015, Blincyto received accelerated approval from the European Commission for the aforementioned indication. The launch of Blincyto has given hope for the development of a bispecific antibody.
In November 2017, Hemlibra (emicizumab), the third bispecific antibody, was approved by the FDA for the routine prophylactic treatment of adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors. to prevent or reduce bleeding episodes.
At this point, bispecific antibody technology has become increasingly sophisticated. In May 2021, the FDA granted accelerated approval to Rybrevant (amivantamab-vmjw), an EGFR/c-Met bispecific antibody developed by Janssen Pharmaceuticals, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. This is the fourth bispecific antibody to be approved for marketing, four years after the last bispecific antibody was approved for marketing.
Bispecific antibody drugs enter the explosion in 2022. In January, the FDA approved the marketing of Kimmtrak (Tebentafusp), a bispecific antibody targeting gp100/CD3 developed by Immunocore, for the treatment of unresectable or metastatic uveal melanoma.
Also in January, the FDA approved Vabysmo (Faricimab-svoa), a bispecific antibody targeting Ang-2/VEGF-A from Roche, for treatment of wet, or neovascular, age-related macular degeneration (AMD) and diabetic macular edema (DME). Vabysmo targets and inhibits two disease pathways linked to a number of vision-threatening retinal conditions by neutralizing angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A).
In June, Lunsumio (Mosunetuzumab), Roche's CD20xCD3 bispecific antibody, was granted conditional marketing authorization by the European Commission for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) who have received at least two prior systemic treatments. Lunsumio has been designed to attach to CD20, a protein found on B lymphocytes, and to CD3, a protein on T cells. By binding to the CD20 and CD3 proteins, the medicine acts like a bridge to bring together the cancer cells and T cells. This encourages the T cells to destroy the cancer cells and helps control the disease.
On June 29, Cadonilimab, a PD-1/CTLA-4 bispecific antibody from Akeso, was approved for marketing by the NMPA for the last-line treatment of cervical cancer. This is the first PD-1/CTLA-4 bispecific antibody to be launched worldwide.
On August 24, the European Commission (EC) has granted conditional marketing authorisation (CMA) of TECVAYLI® (teclistamab) as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma (RRMM).
New Technologies for Bispecific Antibodies
Do you also have this question? Why did the development of bispecific antibody suddenly explode in 2022 after being slow for the past decade or so?
The concept of bispecific antibodies may seem simple, just put two antibodies together to get a more powerful innovative drug. However, there are many constraints in the actual development process, and every step forward in the technology is incredibly difficult. Specifically, previous constraints in the field of bispecific antibodies were mainly in two areas: low efficiency in drug formation and industrialization, and short drug half-life.
Bispecific antibodies are divided into two major classes: IgG like bispecific antibodies which carry an Fc region and therefore retain Fc-mediated effector functions and the non-IgG like formats which rely entirely on their antigen binding capacity to exert therapeutic effects.
The major challenge in the generation of bispecific IgG antibodies is enforcement of the correct heavy and light chain association. This also leads to a high level of impurity proteins and low industrialization efficiency of bispecific antibodies. The development of KiH, Crossmab and DuoBody technologies help solve this problem.
For Fc-less non-IgG like bispecific antibody, the major problem is rapid clearance from the circulation.
These bispecific antibodies have a small molecular weight and are susceptible to degradation by target cell lysosomes, resulting in a half-life of typically only two hours. Blincyto has a half-life of only two hours and patients need to take the drug frequently. This has been one of the factors limiting the sales of Blincyto. Various technologies have emerged to extend the half-life.
In conclusion, it is thanks to the continuous efforts of scientists over the past decades that bispecific antibodies are as successful as they are today.
However, there is still much that can be improved in the future with bispecific antibodies, such as the exploration of targeting solid tumors. Most of the current achievements of bispecific antibodies are based on hematologic tumors, as the development of drugs for hematologic tumors is much less difficult.
However, only breakthroughs in solid tumor indications can bring exponential growth to the imagination of bispecific antibodies, like the success of DS-8201. But there is no doubt that the same story may play out in the field of bispecific antibodies.
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 Kontermann, Roland & Brinkmann, Ulrich. (2015). Bispecific Antibodies. Drug Discovery Today. 20. 10.1016/j.drudis.2015.02.008.
 Runcie, K., Budman, D.R., John, V. et al. Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics. Mol Med 24, 50 (2018). https://doi.org/10.1186/s10020-018-0051-4