Bispecific antibodies (BsAbs) are antibodies with two binding sites, directed against two different antigens or two different epitopes on the same antigen. BsAbs are clinically superior to monoclonal antibodies (MoAbs) and have a wide range of applications in tumor immunotherapy as well as in the treatment of other diseases such as hemophilia A, diabetes, Alzheimer's disease and ophthalmological diseases. Currently, there are thirteen bispecific antibodiesapproved worldwide (including withdrawn drugs), more than 180 BsAbs are in preclinical development, and over 50 BsAbs have been investigated in clinical trials.
How Do Bispecific Antibodies Work?
Since BsAbs have two binding sites for different antigens or recognize two different epitopes of an antigen simultaneously, their functional pathways are quite flexible.There are four main mechanisms of action of bispecific antibodies.
- ▶ Recruiting and activating of immune cells to exert their killing effect
- ▶Blocking of dual signaling pathways
- ▶Blocking of immune checkpoints
- ▶Forcing association of proteincomplexes
Recruiting And Activating Of Immune Cells
An important mechanism of action of bispecific antibodies is to activate immune cells. Bispecific antibodies have two antigen-binding arms, one of which binds to the target antigen and the other to a labeled antigen on the effector cell (T cells and NK cells are commonly used), which activates the effector cell and allows it to target and kill tumor cells. CD3 is currently a popular immune cell surface target for bispecific antibody development, with a greater ability to activate and recruit T cells.
The design of this bispecific antibody focuses on selecting a reasonable range of antibody affinities to inhibit Fc-mediated effector functions as much as possible while having stronger specificity for tumor targets. The marketed blinatumomab (targeting CD3×CD19) removes the Fc structure and reduces the risk of T cell overactivation. Both antibodies use single-chain antibody fragments that do not have an intact IgG structure, reducing CD3 affinity. The CD19 target with high tumor specificity was also selected, with relatively good safety.
Mechanism of blinatumomab
Blocking Of Dual Signaling Pathways
The growth of tumor cells can be simulated or modulated byreceptor tyrosine kinase(RTKs), including members of the Her family orinsulin-like growth factor(IGF). RTKs are are therefore important targets for tumor therapy. Single-target monoclonal antibodies against RTKs have been widely used in tumor therapy. However, tumor cells can undergo immune escape by switching signaling pathways or by activating intracellular signals through hom*o- or heterodimerization between HER family members themselves or different members. Therefore, the use of bispecific antibody drugs to interfere/block two (or more) RTK signaling pathways or their ligand simultaneously can reduce tumor cell escape and improve therapeutic efficacy.
Blocking Of Immune Checkpoints
As the development of immunotherapy advances, monoclonal drugs targeting immune checkpoints such as PD-1, PD-L1, and CTLA-4 have become an important tool for oncology treatment, but the clinical efficacy of immune checkpoint monoclonal drugs is still limited and the response rate of patients is still low. Combination therapies of immune checkpoint monoclonal antibodies have demonstrated stronger therapeutic effects than monotherapy in several clinical trials. Therefore, bispecific antibody drugs targeting 2 immune cell surface antigens based on the synergistic effect generated by combination drugs have become a hot research topic.
Forcing Association Of ProteinComplexes
The two antigenic arms of a bispecific antibody can bind different antigens. It is possible to make bispecific antibodies that bind two specific protein molecules to form a functional complex that can function in place of the missing functional protein.
For example, Emicizumab (Hemlibra®), a recombinant, humanized, bispecific monoclonal antibody, restores the function of missing activated factor VIII (FVIII) by bridging FIXa and FX to facilitate effective haemostasis in patients with haemophilia A.
Mechanisms of actions of Emicizumab
Clinical Advantages Of Bispecific Antibodies
BsAb has an additional specific antigen-binding site compared to conventional antibodies and has demonstrated the following therapeutic advantages.
- 1) Mediating immune cells to cancer cells to exert a killing effect.
- 2) Dual targeting immune checkpoints, which perform unique or overlapping functions, effectively prevent drug resistance.
- 3) Enhanced specificity, targetability and reduced off-target toxicity. The two antigen-binding arms of the bispecific antibody can bind two antigens on the surface of cancer cells, effectively enhancing the binding specificity and targeting of the antibody to cancer cells and reducing off-target side effects.
- 4) Effectively reduce the cost of treatment. Compared with traditional antibodies, BiTE, for example, has a strong competitive edge in terms of tissue penetration rate, tumor cell killing efficiency, off-target rate and clinical indications, with significant clinical advantages. Especially in terms of dose, since the therapeutic effect of BiTE can reach 100-1000 times that of conventional antibodies, the dose can be as low as 1/2000 of the original dose, which significantly reduces the cost of drug treatment. Compared to combination therapies, the cost of bispecific antibodies is also much lower than the cost of two single-drug combinations.
Global Approved Bispecific Antibodies
Currently, there are 13 bispecific antibodiesapproved worldwide, among them, eleven bispecific antibodies approved by FDA, including blinatumomab, emicizumab, amivantamab,tebentafusp-tebn,faricimab-svoa,mosunetuzumab, Teclistamab, Glofitamab, Epcoritamab, Talquetamab and Elranatamab (Table 1).
| Bispecific Antibody Drug Approvals | |||||
| Drug Name | Trade Name | Company | Targets | Approved Date | Indications |
| Catumaxomab | Removab | Trion Pharma | CD20/EpCAM | 2009 (withdrawn In 2017 ) | Malignant ascites |
| Blinatumomab | Blincyto | Amgen | CD3/CD19 | Dec 2014 (FDA) Nov 2015 (EMA) | Relapsed or refractory precursor B-cell acute lymphoblastic leukemia(ALL) |
| Emicizumab | Hemlibra | Roche | FIXa/FX | Nov 2017 (FDA) Jan 2018 (EMA) | Bleeding due to hemophilia A |
| Amivantamab-vmjw | Rybrevant | Janssen | EGFR/cMet | May 2021 (FDA) Dec 2021 (EMA) | Non-small cell lung cancer |
| Tebentafusp-tebn | Kimmtrak | Immunocore | GP100/CD3 | Jan 2022 (FDA) Apr 2022 (EMA) | unresectable or metastatic uveal melanoma |
| Faricimab-svoa | Vabysmo | Genentech | Ang-2/VEGF-A | Jan 2022 (FDA) Sep 2022 (EMA) | Wet AMD and DME |
| Cadonilimab | 开坦尼® | Akeso, Inc. | PD-1/CTLA-4 | Jun 2022 (NMPA) | cervical cancer |
| Mosunetuzumab | Lunsumio | Roche | CD20/CD3 | Jun 2022 (EMA) Dec 2022 (FDA) | relapsed or refractory (R/R) follicular lymphoma (FL) |
| Teclistamab | Tecvayli | Janssen | BCMA/CD3 | Aug 2022 (EMA) Oct 2022 (FDA) | relapsed and refractory multiple myeloma |
| Ozoralizumab | Nanozora | Taisho Pharmaceutical | TNFα /TNFα | Sep 2022 (Japan) | inflammatory diseases |
| Glofitamab | COLUMVI | Roche Canada | CD3/CD20 | Jun 2023 (FDA) Jul 2023 (EMA) | DLBCL |
| Epcoritamab | Epkinly | Genmab US | CD3/CD20 | May 2023 (FDA) | DLBCL |
| Talquetamab-tgvs | TALVEY | Janssen | GPRC5D/CD3 | Aug 2023 (FDA) Aug 2023 (EMA) | RRMM |
| Elranatamab | ELREXFIO | Pfizer | BCMA/CD3 | Aug 2023 (FDA) | RRMM |
Table 1. Approved Bispecific Antibodies by FDA & EMA
Future Developments
The global market for bispecific antibodies in oncology is expected to expand rapidly, potentially reaching $3.7 billion in sales by 2027. In hematologic cancers, bispecific antibody therapies targeting CD20xCD3 are expected to bring important new treatment options beyond CAR-T cell therapies and established targeted therapies for patients with B-cell non-Hodgkin's lymphoma and diffuse large B-cell lymphoma. In solid tumors, zanidatamab targeting different HER2 epitopes may benefit a large number of patients with HER2-positive gastroesophageal adenocarcinoma.
Beyond the treatment of tumors, bispecific antibody therapies are an important therapeutic modality for the treatment of inflammatory diseases as well as other disease types. They also have multiple other modes of action such as helping macromolecules cross the blood-brain barrier and acting as cofactors to activate signaling cascade pathways. We expect that this innovative therapeutic modality will benefit many more patients in the future.
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References:
[1] Esfandiari et al., (2022). Bispecific antibodies in oncology. Nature Reviews Drug Discovery, https://doi.org/10.1038/d41573-022-00040-2
[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 May 5;12:626616. doi: 10.3389/fimmu.2021.626616. PMID: 34025638; PMCID: PMC8131538.
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