Antibodies Overview
Antibody basics
Antibodies are defence molecules in our body, produced by specialized immune cells known as B lymphocytes or B-cells. Their normal function is to protect us from infections. When used as therapeutics, antibodies can target specifically selected disease proteins, enabling us to fight illnesses that our bodies would not normally produce antibodies against, e.g., cancer.
Schematic representation of an antibody molecule
Antibodies are proteins that have a characteristic Y-shaped structure. Each B-cell generated by the immune system produces antibodies with a specific and unique target binding section, resulting in a huge diversity of target binding specificity. This ensures that almost any antigen that enters the body will be recognised by an antibody. B lymphocytes can be immortalized, resulting in cell lines producing monoclonal antibodies with a defined binding specificity.
Therapeutic antibodies overview
Antibodies are the body’s own defence molecules against viruses and bacterial infections. Medicine has, for a long time, sought methods for the selection, development and production of antibodies in order to use them as therapeutic drugs.
A major obstacle was that antibodies developed in laboratory animals, like mice and rats, (known as xenogenic antibodies) cannot be used for the treatment of human diseases, because they are recognized by the human immune system as foreign, causing an unwanted immune response and making the therapeutic antibody ineffective.
Schematic representation of the development of therapeutic antibodies.
The first generation of therapeutic antibodies were chimeric antibodies containing only the antigen binding domains (shown here in red) from non-human origin. However, these antibodies may still cause unwanted immunogenic reactions, as the non-humanized portions are recognized as foreign.
The next step in antibody development was achieved by the generation of humanized antibodies, which contained non-human specific antibody binding regions inserted into the framework of a human antibody. This minimized the risk of an unwanted immunogenic reaction but still could not fully remove it.
Currently most therapeutic antibodies in development are fully human, thereby eliminating unwanted immunogenic side effects from the immune system. Previously, the two main approaches for the production of fully human antibodies were:
- Phage display/pro-karyotic systems
- Transgenic animals
The phage display system enables the expression of antibody fragments in prokaryotic cells (bacteria), which are eventually expressed on the surface of bacteriophages, where they are subsequently screened for antigen (target) binding. In order to generate fully human antibodies by phage display the fragments that bind the target need to be re-engineered to full-length antibodies and expressed in mammalian cells.
The transgenic animal systems allow the antibodies to be raised in their natural (eukaryotic) environment and selected for biological and binding activities.