Bispecific Antibodies - Current Status and Prospects (2023)

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 five bispecific antibodiesapproved for marketing globally, more than 180 BsAbs are in preclinical development, and over 50 BsAbs have been investigated in clinical trials.

Bispecific Antibodies - Current Status and Prospects (1)

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.

(Video) What are bispecific antibodies?

Bispecific Antibodies - Current Status and Prospects (2)
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 homo- 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.

(Video) What are bispecific antibodies?

Bispecific Antibodies - Current Status and Prospects (3)
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 five bispecific antibodiesapproved for listingglobally, among them,four bispecific antibodies approved by FDA, including blinatumomab, emicizumab, amivantamab and faricimab-svoa, and three approved by EMA, including emicizumab, amivantamab andmosunetuzumab (Table 1).

Bispecific Antibodies - Current Status and Prospects (4)
Table 1. Global Approved Bispecific Antibodies

  • ▶ In 2014, Amgen's blinatumomab (Blincyto)was approved by the FDA to treat relapsed or refractory precursor B-cell acute lymphoblastic leukemia(ALL) with CD3/CD19 dual targets. Later in 2015, it was approved by EMA.
  • ▶ Then in 2017, Roche's emicizumab (Hemlibra) was approved to treat bleeding due to hemophilia A, acting on factor FIXa/FX through the formation of a protein complex.Later in 2018, it was approved by EMA.
  • ▶ Later on May 21, 2021, the FDA approved amivantamab-vmjw (Rybrevant) for adult patients with non-small cell lung cancer, targetingthe epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways.
  • ▶ On January 28, 2022, Vabysmo (faricimab-svoa), a vascular endothelial growth factor (VEGF) inhibitor and angiopoietin-2 (Ang-2) inhibitor, was approved for treatment wet, or neovascular, age-related macular degeneration (AMD) and diabetic macular edema (DME).
  • On June 8, 2022, Roche announced that the European Commission has granted conditional marketing authorization for the CD20xCD3 T-cell binding bispecific antibody Lunsumio (mosunetuzumab) for the treatment of patients with relapsed or refractory (R) disease who have received at least two prior systemic therapies. /R) in adult patients with follicular lymphoma (FL).
  • ▶ By the way, Catumaxomab was approved in Europe on 20 April 2009. But in 2013, catumaxomab was voluntarily withdrawn from the US market and in 2017 in the EU market for commercial reasons.

Late-Stage Pipelines

The majority of the late-stage clinical development pipeline for bispecific antibodies are bispecific T-cell bridging agents that act to redirect and activate CD3-expressing cytotoxic T cells to target and kill tumor cells expressing specific antigens.

(Video) Webinar - Bispecific Antibodies: The Next Generation of Antibody Therapeutics

In hematological cancers, the main targets are CD20 and B-cell maturation antigen (BCMA). In solid tumors, the main targets are CTLA4, PD-1/PD-L1, LAG3, EGFR, and HER2/HER3. See the table below for some of the bispecific antibodies that have reached the Phase 3 clinical stage.

Bispecific Antibodies - Current Status and Prospects (5)
Selected oncology bispecific antibodies in phase 3 clinical development (data source: reference [1])

Early Stage Pipelines

In early clinical development, several bispecific antibodies are targeting existing or innovative targets. In the treatment of hematologic cancers, bispecific antibodies in or planned for registration clinical trials include Regeneron and AbbVie's BCMAxCD3 bispecific antibody, Janssen's GPRC5DxCD3 bispecific antibody talquetamab, MacroGenics' CD123xCD3 bispecific antibody flotetuzumab for acute myeloid leukemia, and Affimed's CD30xCD16A bispecific antibody AFM13 for the treatment of peripheral T-cell lymphoma, among others.

In solid tumors, multiple potential registrational Phase 1/2 clinical trials are underway. Please see the table below for information on some of the therapies in development.

Bispecific Antibodies - Current Status and Prospects (6)
Selected bispecific antibody therapies in early clinical development (data source: reference [1])

(Video) Drawn to Science | T-cell bispecific antibodies

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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(Video) Mechanistic model-informed discovery & development of bispecific antibodies for immuno-oncology

FAQs

How many bispecific antibodies are FDA approved? ›

So far, the FDA has approved three bispecific antibodies while over a hundred more are in development. The latest approval was for Janssen's Rybrevant (Amivantamab-vmjw), the first treatment for adult patients with non-small cell lung cancer, approved on 21 May.

Are there any bispecific antibodies on the market? ›

Currently, there are seven bispecific antibodies approved by FDA and EMA, among them, five bispecific antibodies approved by FDA, including blinatumomab, emicizumab, amivantamab, tebentafusp-tebn and faricimab-svoa, and seven approved by EMA (Table 1).

Why are bispecific antibodies important? ›

More recently, bispecific antibodies represent a valuable alternative antibody platform in immunotherapy treatment. These bispecifics work by binding to two different antigen sites and can provide more robust and tailored immunogenic targeting than what is possible with natural antibodies.

What is the meaning of bispecific antibody? ›

(BY-speh-SIH-fik AN-tee-BAH-dee) A type of antibody that can bind to two different antigens at the same time. Bispecific antibodies are being studied in the imaging and treatment of cancer. They are made in the laboratory.

Are bispecific antibodies monoclonal? ›

Bispecific antibodies are artificial proteins that have promising applications in the field of cancer immunotherapy. They are comprised of two monoclonal antibodies held together by a flexible peptide linker. As the name suggests, this makes them able to bind to two different antigens.

When was the first bispecific antibody approved? ›

In addition, research on a different class of antibody therapeutics, bispecific antibodies, has recently led to outstanding clinical results, and the first approval of the bispecific antibody catumaxomab, a T cell retargeting agent that was approved in the European Union in April 2009.

How do you purify bispecific antibodies? ›

Bispecific antibodies (BsAb) can be purified using protein A chromatography in only a single step. BsAb constructs were efficiently purified to give more than 90% purity and 85% yield in the early screening downstream process.

How are bispecific antibodies made? ›

Due to the single-chain configuration, bispecific antibodies can be build by connecting two scFvs through a linker (connector). Thus, these molecules are bivalent with one valency for each antigen, with a typically size in the range of 50–60 kDa.

How are bispecific monoclonal antibodies made? ›

IgG-like bispecific antibodies are generated by fusing a binding site with a different binding specificity to the N- or C-terminus of the heavy or light chains, resulting in tetravalent, symmetrical molecules. Asymmetric IgG molecules are formed by heterodimerization of two different heavy chains.

What is a bispecific protein? ›

A protein made in the laboratory that can bind to two different molecules on two different cells at the same time.

Why antibodies are called heterodimers? ›

Heterodimeric bispecific antibodies

When people refer to bispecific antibodies they are typically referring to heterodimeric antibodies, i.e. a traditional IgG molecule but with one arm targeting one antigen and the other are targeting a second antigen as shown in the figure below.

What is the mechanism of action of BiTE therapy? ›

Mechanisms of BiTE action. Different from natural antibodies, BiTEs can redirect T cells to specific tumor antigens and activate T cells directly. Natural antibodies are unable to recruit T cells directly because T cells lack Fcγ receptors [18].

Who invented bispecific antibodies? ›

Development history

The original concept of BsAbs was proposed by Nisonoff and his collaborators in the 1960s, including the first idea of antibody architecture and other findings.

What is a bispecific fusion protein? ›

Bispecific fusion protein is a major bispecific antibody format, which has been explored as a pre-targeting strategy for imaging and radioimmunotherapy. It is generated by linking antibody fragments to other proteins to achieve additional function or specificity.

What is the meaning of BSAB? ›

The Department of Business and Management offers the Bachelor of Science in Agribusiness (BSAB) curriculum. It is a four-year degree program designed to prepare undergraduate students to be technically and managerially competent as agribusiness managers and entrepreneurs.

How are recombinant bispecific antibodies made? ›

Using recombinant DNA technology, Bispecific IgG antibodies can be assembled from two different heavy and light chains expressed in the same cell line. But because of random assembly of the different chains, large proportions of nonfunctional molecules and undesirable HC homodimers are generated.

Who developed the technology of hybridoma cells used in the production of monoclonal antibodies? ›

In 1975, Kohler and Milstein discovered a technique called hybridoma technology for the production of monoclonal antibodies. It is one of the most widely used techniques in modern research and studies [1].

What is BiTE therapy? ›

BiTE therapy is an immunotherapy that works by serially killing tumor cells by placing them in proximity to T cells. The model for BiTE therapy is the anti-CD19 X anti-CD3 drug, blinatumomab (Blincyto), which was first approved because it outperformed standard therapy in relapsed acute lymphoblastic leukemia (ALL).

Is blinatumomab FDA approved? ›

About BLINCYTO™ (blinatumomab)

BLINCYTO is the first BiTE® antibody construct and the first single-agent immunotherapy to be approved by the U.S. Food and Drug Administration ( FDA ).

What are Biospecifics? ›

biospecific (not comparable) (biochemistry) Whose properties or activities vary according to the specific biological molecule that it interacts with. (biology) Of or relating to a biospecies.

How does protein A chromatography work? ›

Protein A chromatography is the most frequently used affinity chromatography method in biomanufacturing. It is the standard technique for capturing recombinant monoclonal antibodies, which relies on the reversible and specific binding between the immobilized protein A ligand and antibodies.

What does FC stand for Immunology? ›

The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system.

What is Fab arm exchange? ›

Human IgG4 is an unusually dynamic antibody, with half-molecule exchange (“Fab-arm exchange”) resulting in asymmetrical, bispecific antibodies with two different antigen binding sites, which contributes to its anti-inflammatory activity. The mechanism of this process is unknown.

What does Vhh stand for antibody? ›

Introduction. Single variable domain on a heavy chain (VHH) antibodies, also referred to as Nanobodies®, were discovered nearly 25 years ago. Heavy chain only antibodies (HcAb) are naturally produced by camelids and sharks.

What is adaptive cell therapy? ›

Listen to pronunciation. (uh-DOP-tiv sel THAYR-uh-pee) A type of immunotherapy in which T cells (a type of immune cell) are given to a patient to help the body fight diseases, such as cancer.

What is CrossMAb? ›

CrossMab is a type of IgG-like bispecific antibody. It remains the general structure and size of a conventional IgG, so it has similar biophysical properties to IgGs. In CrossMAb, KIH (knobs-into-holes) technology is used to permit the heavy chain heterodimerize.

What is DuoBody? ›

The DuoBody® platform is a versatile platform technology for the discovery and development of bispecific antibodies that may improve antibody therapy of cancer, autoimmune, infectious and central nervous system disease.

Where is CD3 found? ›

Initial expression of CD3 occurs in the cytoplasm in a peri-nuclear location of pro-thymocytes. As T cell maturation proceeds, cytoplasmic CD3 expression is lost and the CD3 antigen is found on the cell surface.

What is the clinical application of monoclonal antibodies Mcq? ›

6. What is the clinical application of monoclonal antibodies? Explanation: Application of monoclonal antibody in the biosensors is a diagnostic application of maps. Using in transplant rejection and infectious disease is the therapeutic application of monoclonal antibodies.

What advantage does an antibody fragment offer over a full size antibody? ›

One advantage of fragments over full-size antibodies is that antibody fragments are smaller than conventional antibodies and generally lack glycosylation, allowing their production in prokaryotic expression systems, which provide time and cost savings.

What does FC stand for Immunology? ›

The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system.

What is CrossMAb? ›

CrossMab is a type of IgG-like bispecific antibody. It remains the general structure and size of a conventional IgG, so it has similar biophysical properties to IgGs. In CrossMAb, KIH (knobs-into-holes) technology is used to permit the heavy chain heterodimerize.

What are Biospecifics? ›

biospecific (not comparable) (biochemistry) Whose properties or activities vary according to the specific biological molecule that it interacts with. (biology) Of or relating to a biospecies.

Who developed the technology of hybridoma cells used in the production of monoclonal antibodies? ›

In 1975, Kohler and Milstein discovered a technique called hybridoma technology for the production of monoclonal antibodies. It is one of the most widely used techniques in modern research and studies [1].

Videos

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