Bispecific monoclonal antibody

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A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. [1] Naturally occurring antibodies typically only target one antigen. BsAbs can be manufactured in several structural formats. BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes. [2] BsAbs have been explored for cancer immunotherapy, drug delivery, and Alzheimer's disease. [1] [3]

Contents

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. [4] [5] In 1975, the problem of producing pure antibodies was solved by the creation of hybridoma technology, and the new era of monoclonal antibodies (MoAbs) came. [6] In 1983, Milstein and Cuello created hybrid-hybridoma (quadroma) technology. [7] In 1988, the single-chain variable fragment (scFv) was invented by the Huston team to minimize the refolding problems, which contains the incorrect domain pairing or aggregation of two-chain species. [8] In 1996, the BsAbs became more developed when the knobs-into-holes technology emerged. [1] [9]

Structural types and manufacturing methods

Three types of bispecific antibodies: trifunctional antibody, chemically linked Fab and bi-specific T-cell engager (bottom row). Blue and yellow parts distinguish parts from separate monoclonal antibodies. Engineered monoclonal antibodies.svg
Three types of bispecific antibodies: trifunctional antibody, chemically linked Fab and bi-specific T-cell engager (bottom row). Blue and yellow parts distinguish parts from separate monoclonal antibodies.

There are many formats of BsAbs, but the two main categories are IgG-like and non-IgG-like. [3] The main types of manufacturing methods are quadromas, chemical conjugation, and genetic recombination, and each method results in a unique format. [3] [10]

IgG-like

This format retains the traditional monoclonal antibody (mAb) structure of two Fab arms and one Fc region, except the two Fab sites bind different antigens. The most common types are called trifunctional antibodies, as they have three unique binding sites on the antibody: the two Fab regions, and the Fc region. Each heavy and light chain pair is from a unique mAb. The Fc region made from the two heavy chains forms the third binding site. These BsAbs are often manufactured with the quadroma, or the hybrid hybridoma, method. [11] [12] [13]

The "knobs into holes" approach for manufacturing IgG-like bsMabs is shown on the left, while a diagram depicting the DVD-Ig format is on the right. The red dot indicates a possible site for introducing mutations in the heavy chain. Blue and yellow correspond to separate monoclonal antibodies. DVD-Ig Knob in Hole.png
The "knobs into holes" approach for manufacturing IgG-like bsMabs is shown on the left, while a diagram depicting the DVD-Ig format is on the right. The red dot indicates a possible site for introducing mutations in the heavy chain. Blue and yellow correspond to separate monoclonal antibodies.

However, the quadroma method relies on random chance to form usable BsAb, and can be inefficient. Another method for manufacturing IgG-like BsAb is called "knobs into holes," and relies on introducing a mutation for a large amino acid in the heavy chain from one mAb, and a mutation for a small amino acid in the other mAb's heavy chain. This allows the target heavy chains (and their corresponding light chains) to fit together better, and makes the production of BsAbs more reliable. [3] [10]

Non-IgG-like

There are other BsAbs that lack an Fc region entirely, and thus leads to relatively simple design strategies. [1] These include chemically linked Fabs, consisting of only the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (ScFvs). There are also fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs), which uses the G4S linker to connect two ScFvs-one CD3 antibody ScFv and one tumor-associated antigen (TAA) or tumor-specific ScFv-to redirect T cells to cancer cells for target killing. [14] [15] [16] Other platforms include tetravalent antiparallel structure (TandAbs) and VH only (Bi-Nanobody). The TandAb platform is formed by a tetravalent antibody molecule containing two binding sites for each of two antigens. [17] In this platform, the reverse pairing of two peptide chains forms a homodimer molecule. As an example, AFM11 is based on the TandAbs platform and targets both CD3 and CD19 to achieve therapeutic effects. AFM11 showed dose-dependent inhibition of Raji tumors in vivo. [18] The Bi-Nanobody platform forms multi-specific binding through the connection between the VH regions of two or more antibody molecules. The products that are designed based on this platform are small molecules and these small molecules have high stability and better tissue permeability in vivo. [19] Even though non-IgG-like BsAbs have low molecular weight and thus high tumor tissue permeability, their half-life is relatively short and they require multiple doses. [1]

Despite the considerable differences between the various types and formats of bispecific antibodies, their manufacturing processes correspond in several steps:

Mechanism of action

The mechanism of action of a BsAb, exemplified by catumaxomab, representing the first approved bispecific trifunctional antibody. Catumaxomab mechanism.svg
The mechanism of action of a BsAb, exemplified by catumaxomab, representing the first approved bispecific trifunctional antibody.

Recruiting and activating of immune cells

The binding of a BsAb to its target antigens can lead to a variety of effects. The most widely used application of this approach is in cancer immunotherapy, where BsAbs are engineered to simultaneously bind a cytotoxic cell and a target (a tumour cell) to be destroyed. It is possible to observe the bridging effect that BsAbs have on T cell/cancer cell interactions using label-free live cell imaging. Catumaxomab, one of the first trifunctional antibodies approved for therapeutic use, binds both CD3 on cytotoxic T cells and EpCAM on human adenocarcinomas. [11] [12] The Fc region additionally binds to a cell that expresses Fc receptors, like a macrophage, natural killer cell or dendritic cell. Since the Fc region is still intact, this allows for the BsAb to trigger common immune responses when recognized by an Fc receptor, such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity. [13] [15]

Example of cancer cells being killed cytotoxic T-cells. Imaged with a label-free live cell imaging microscope. T-cell killing cancer cell.gif
Example of cancer cells being killed cytotoxic T-cells. Imaged with a label-free live cell imaging microscope.

Interfering with receptor signaling and inactivating signaling ligands

The growth of tumor cells can be simulated or modulated by receptor tyrosine kinase (RTKs), including members of the Her family or insulin-like growth factor (IGF). The RTKs are therefore preferred targets in cancer therapy. Although monospecific RTK-targeting IgGs have already been available in the market, such as cetuximab (Erbitux) and panitumumab (Vectibix), both of which are directed against HER1. However, cancer cells can switch to a different pathway to escape the growth inhibition generated by blocking one signaling pathway. To improve the therapeutic efficacy, simultaneously interfering/blocking of two (or more) RTK signaling pathways, achieved through the mediation of BsAb to inactivate either the RTKs or their ligand, reduces the possibility of the escape mechanisms adopted by the tumor cells. [21] [22]

In addition, in working with Ebolavirus vaccines, a study has shown that a DVD-Ig antibody can be used to prevent viral escape from the endosome. Ebolaviruses infect cells by receptor-mediated endocytosis. Researchers developed DVD-Igs where the outer variable regions bind to the surface glycoproteins of the viral coat and enter the cell with the virus. These outer regions are cleaved in the viral endosome, revealing the inner variable regions that then bind to both the virus and internal receptors in the endosome. Blocking the interaction between the virus and endosomal proteins prevents viral escape from the endosome and further infection. [23]

Forcing association of protein complexes

As an example, emicizumab (formerly RG6013) is an IgG derivative containing H-chain heterodimerization motifs, which was combined with the common light chain approach to prevent L-chain mispairing issues. [24] [25] With a bivalent composition, emicizumab brings two protein antigens together into one complex. Factor IXa and Factor X in the coagulation cascade are the cognate antigens which are bound by RG6013. These two factors are brought together by coagulation factor VIIIa in a healthy individual, while patients with bleeding disorder hemophilia A do not have VIIIa. Current treatment of this disorder is to supplement the patients with FVIII to reduce bleeding complications. But FVIII can be recognized as a foreign protein in these patients due to the absence of this protein and thus an immune response will be generated against this protein. Besides, FVIII has a short half-life (less than 15 hours) and thus is cleared rapidly. However, the humanized BsAb has lower immunogenicity and long serum half-life compared with FVIII and thus provide a better treatment for hemophilia. [2]

Advantages over ordinary monoclonal antibodies

Cancer immunotherapy with ordinary monoclonal antibodies does not activate T-lymphocytes because the Fab regions are already used for binding the tumor cells, and this type of cell does not have Fc receptors. [26] Bispecific antibodies also have a higher cytotoxic potential, and bind to antigens that are expressed relatively weakly. [27] The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square meter body surface area per day), which is several orders of magnitude lower than with ordinary antibodies. [26] For non-IgG-like BsAbs, their smaller size allows them to reach antigens usually unavailable to conventional antibodies. [3] In the case of Ebola vaccines, this method allows the antibody to target intracellular targets not usually accessible by traditional monoclonal antibody treatments. [23]

Additionally, targeting more than one molecule can be useful to circumvent the regulation of parallel pathways and avoid resistance to the treatment. Binding or blocking multiple targets in a pathway can be beneficial to stopping disease, as most conditions have complicated multifaceted effects throughout the body. [28] Together with combination therapies, BsAbs are being used more and more to treat certain types of cancers, as, over time, some tumors develop resistances to checkpoint inhibitors and/or co-stimulatory molecules. [29]

Current Scenario of bsAb drugs

Currently, nine bsAb drugs have been approved by the US FDA / EMA and over 180 are currently in clinical trials. The first bispecific antibody to gain regulatory approval, blinatumomab, targets CD19 on B cells and CD3 on T cells, leading to the activation of T cells and the destruction of B cells. [30] A total of eight more bispecific antibody drugs have since been approved by the US FDA: blinatumomab, emacizumab, amivantamab, tebentafusp, faricimab, teclistamab, mosunetuzumab, epcoritamab, glofitamab. [31] Among the bsAb programs currently under development, the combination of CD3 and tumor surface targets are the most popular targets pairs. Other popular targets are CD3, HER2, PD-1, PD-L1, EGFR, CTLA-4, etc., which as well as immune targets of PD-1, PD-L1, BCMA, CD47, CTLA-4, LAG-3, 4 -1BB. [32] Additionally, with the approval of the several new bsAb since 2022, and new mechanisms for improving efficacy like development of hetero-dimer bispecific molecules, several additional possibilities of target pairs have emerged. [32]

Problems and current disadvantages

IgG-like antibodies can be immunogenic, which means the Fc region could cause detrimental downstream immune responses caused by cells that are activated by Fc receptors. [3] The therapeutic use of BsAbs as a whole is still largely in development, with many clinical trials currently ongoing that are determining the efficacy and safety of BsAbs for treatment. [14]

Applications

Bispecific antibodies have a wide variety of applications in diagnosis and therapy. BsAbs can be combined with HRPO, can be used in pre-targeting strategies, and can be used to provide better imaging for early detection in diagnosis. To treat cancer, BsAbs can target immune cells precisely, help and reactive the immune cells, fine-tune the fate and function of immune cells, improve the tolerance of immune cells, and promote the return to immune homeostasis. BsAbs can also be applied to treat other diseases, including hemophilia A, diabetes, Alzeimer's disease, and ophthalmological diseases. [1]

BsAbs on the market

Three bispecific antibodies are presently in clinical use. Blinatumomab, which targets CD19 and CD3, is used in the treatment of Philadelphia chromosome negative B cell acute lymphoblastic leukemia (ALL). Emicizumab, which targets clotting factors IXa and X, is used in the treatment of hemophilia A. [33] Catumaxomab was withdrawn from the European market in 2017 for commercial reasons. [34] Amivantamab, which targets epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. [35]

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

<span class="mw-page-title-main">Single-chain variable fragment</span> Fragment

A single-chain variable fragment (scFv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of ten to about 25 amino acids. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of the linker. The image to the right shows how this modification usually leaves the specificity unaltered.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in Homo sapiens

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">Protein A</span>

Protein A is a 42 kDa surface protein originally found in the cell wall of the bacteria Staphylococcus aureus. It is encoded by the spa gene and its regulation is controlled by DNA topology, cellular osmolarity, and a two-component system called ArlS-ArlR. It has found use in biochemical research because of its ability to bind immunoglobulins. It is composed of five homologous Ig-binding domains that fold into a three-helix bundle. Each domain is able to bind proteins from many mammalian species, most notably IgGs. It binds the heavy chain within the Fc region of most immunoglobulins and also within the Fab region in the case of the human VH3 family. Through these interactions in serum, where IgG molecules are bound in the wrong orientation, the bacteria disrupts opsonization and phagocytosis.

<span class="mw-page-title-main">CD3 (immunology)</span> Protein complex and T cell co-receptor

CD3 is a protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell and T helper cells. It is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the T-cell receptor (TCR) and the CD3-zeta (ζ-chain) to generate an activation signal in T lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

<span class="mw-page-title-main">Fragment crystallizable region</span> Tail region of an antibody

The fragment crystallizable 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 region allows antibodies to activate the immune system, for example, through binding to Fc receptors. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains in each polypeptide chain. The Fc regions of IgGs bear a highly conserved N-glycosylation site. Glycosylation of the Fc fragment is essential for Fc receptor-mediated activity. The N-glycans attached to this site are predominantly core-fucosylated diantennary structures of the complex type. In addition, small amounts of these N-glycans also bear bisecting GlcNAc and α-2,6 linked sialic acid residues.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

<span class="mw-page-title-main">Bi-specific T-cell engager</span>

Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies that are investigated for use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.

<span class="mw-page-title-main">Trifunctional antibody</span> Monoclonal antibody

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.

<span class="mw-page-title-main">Chemically linked Fab</span>

Two chemically linked fragments antigen-binding form an artificial antibody that binds to two different antigens, making it a type of bispecific antibody. They are fragments antigen-binding of two different monoclonal antibodies and are linked by chemical means like a thioether. Typically, one of the Fabs binds to a tumour antigen and the other to a protein on the surface of an immune cell, for example an Fc receptor on a macrophage. In this way, tumour cells are attached to immune cells, which destroy them.

Solitomab is an artificial bispecific monoclonal antibody that is being investigated as an anti-cancer drug. It is a fusion protein consisting of two single-chain variable fragments (scFvs) of different antibodies on a single peptide chain of about 55 kilodaltons. One of the scFvs binds to T cells via the CD3 receptor, and the other to EpCAM as a tumor antigen against gastrointestinal, lung, and other cancers.

<span class="mw-page-title-main">ImmTAC</span>

ImmTACs are a class of bispecific biological drug being investigated for the treatment of cancer and viral infections which combines engineered cancer-recognizing TCRs with immune activating complexes. ImmTACs target cancerous or virally infected cells through binding human leukocyte antigen (HLA) presented peptide antigens and redirect the host's cytotoxic T cells to recognise and kill them.

Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.

Recombinant antibodies are antibody fragments produced by using recombinant antibody coding genes. They mostly consist of a heavy and light chain of the variable region of immunoglobulin. Recombinant antibodies have many advantages in both medical and research applications, which make them a popular subject of exploration and new production against specific targets. The most commonly used form is the single chain variable fragment (scFv), which has shown the most promising traits exploitable in human medicine and research. In contrast to monoclonal antibodies produced by hybridoma technology, which may lose the capacity to produce the desired antibody over time or the antibody may undergo unwanted changes, which affect its functionality, recombinant antibodies produced in phage display maintain high standard of specificity and low immunogenicity.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

PD-icon.svg This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.

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