Bispecific monoclonal antibody
Encyclopedia
A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein
that is composed of fragments of two different monoclonal antibodies
and consequently binds to two different types of antigen
. The most widely used application of this approach is in cancer immunotherapy
, where BsMAbs are engineered that simultaneously bind to a cytotoxic cell (using a receptor like CD3
) and a target like a tumour cell to be destroyed.
, has been developed. It consists of two heavy and two light chains
, one each from two different antibodies. The two Fab regions (the arms) are directed against two antigens. The Fc region (the foot) is made up from the two heavy chains and forms the third binding site; hence the name.
Other types of bispecific antibodies have been designed to overcome certain problems, such as short half-life
, immunogenicity
and side-effects caused by cytokine
liberation. They include chemically linked Fab
s, consisting only of the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (scFvs), fusion protein
s mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs).
s that form the tops of the variable domains, one can be directed against a tumour antigen and the other against a T-lymphocyte antigen like CD3. In the case of trifunctional antibodies, the Fc region additionally binds to a cell that expresses Fc receptor
s, like a macrophage
, a natural killer cell
or a dendritic cell
. In sum, the tumour cell is connected to one or two cells of the immune system, which subsequently destroy it.
relatively weakly. The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square metre body surface area
per day), several orders of magnitude lower than with ordinary antibodies.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that is composed of fragments of two different monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
and consequently binds to two different types of antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
. The most widely used application of this approach is in cancer immunotherapy
Cancer immunotherapy
Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease...
, where BsMAbs are engineered that simultaneously bind to a cytotoxic cell (using a receptor like CD3
CD3 receptor
In immunology, the CD3 T-Cell Co-Receptor is a protein complex and 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 a molecule known as the T cell receptor and the ζ-chain to generate an activation...
) and a target like a tumour cell to be destroyed.
Structure
In order to overcome manufacturing difficulties, a first-generation BsMAb, called trifunctional antibodyTrifunctional 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...
, has been developed. It consists of two heavy and two light chains
Immunoglobulin light chain
]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...
, one each from two different antibodies. The two Fab regions (the arms) are directed against two antigens. The Fc region (the foot) is made up from the two heavy chains and forms the third binding site; hence the name.
Other types of bispecific antibodies have been designed to overcome certain problems, such as short half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
, immunogenicity
Immunogenicity
Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.- Immunogenicity :The ability to induce humoral and/or cell-mediated immune responses....
and side-effects caused by cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
liberation. They include chemically linked Fab
Chemically linked Fab
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...
s, consisting only of the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (scFvs), fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
s mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs).
Mechanism of action
Of the two paratopeParatope
The paratope is the part of an antibody which recognises an antigen, the antigen-binding site of an antibody. It is a small region of the antibody's Fv region and contains parts of the antibody's heavy and light chains....
s that form the tops of the variable domains, one can be directed against a tumour antigen and the other against a T-lymphocyte antigen like CD3. In the case of trifunctional antibodies, the Fc region additionally binds to a cell that expresses Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....
s, like a macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
, a natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
or a dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
. In sum, the tumour cell is connected to one or two cells of the immune system, which subsequently destroy it.
Advantages over ordinary monoclonal antibodies
Cancer immunotherapy with ordinary monoclonal antibodies does not activate T-lymphocytes because this type of cell does not possess Fc receptors, so the Fc region cannot bind to them, and the Fab regions are already used for binding the tumour cells. Bispecific antibodies have a higher cytotoxic potential. They bind to antigens that are expressedGene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
relatively weakly. The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square metre body surface area
Body surface area
In physiology and medicine, the body surface area is the measured or calculated surface of a human body. For many clinical purposes BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass...
per day), several orders of magnitude lower than with ordinary antibodies.
External links
- Bispecific monoclonal antibody entry in the public domain NCI Dictionary of Cancer Terms