Background

Structure: all antibodies share the same basic structure. They are large ‘Y' shaped protein molecules, comprising two chains; a ‘heavy' chain and a ‘light' chain. The tips of the forked area or "variable region", which come into contact with the antigen, are highly variable in structure, enabling the antibody to be specific for a particular antigen. The ‘backbone' of the molecule or ‘constant region' is reasonably consistent between different antibodies and has an important role in activating the next steps in the body's response to neutralise/eliminate the foreign molecule or pathogen (the effector functions).

Classification: antibodies are globular proteins known as immunoglobulins. There are several classes and sub-classes of immunoglobulin or Ig – each with a different distinct set of molecular characteristics and/or functions. The major Ig class is IgG, which has four sub-classes, IgG₁, IgG₂, IgG₃ and IgG₄. Each of these classes interacts with the rest of the body's immune system in a different way (effector functions). Antibodies currently being developed by MedImmune Cambridge fall into the IgG₁ and IgG₄ sub-classes: IgG₁ molecules contain molecular structures that activate the complement system - a complex group of serum proteins which mediate inflammatory reactions; IgG₄ molecules work by blocking a physiological process and do not activate complement. Other immunoglobulin classes are IgM, IgA, IgD and IgE.

History: in 1975 a breakthrough in monoclonal antibody production (hybridoma technology) made it possible to obtain sufficient quantities of antibodies for research purposes and therapeutic development. However, this method involved producing antibodies from mice. When administered to humans, the immune system recognised these mouse (murine) antibodies as foreign and triggered severe immune responses (the Human Anti-Mouse Antibody or HAMA reaction), rendering them ineffective. Efforts were then focused on making murine antibodies more human, initially, by producing chimaeric antibodies; a mixture of mouse and human antibody components, and later by producing humanised antibodies by grafting binding sites from a mouse antibody onto a human antibody structure.  However, the need for ‘fully' human antibody therapeutics remained.

Now two quite different methods of making human antibodies have been established and the possibility of making human antibody therapeutics has become a reality with the successful approval and introduction of HUMIRA^® for the treatment of rheumatoid arthritis, early rheumatoid arthritis and psoriatic arthritis.

The first method, which CAT pioneered, is the technique of Phage Display, the engineering of bacteriophages (viruses that infect bacteria but are harmless to humans) to display human antibodies on their surface. We have used this proprietary technology to create a Phage Display library containing over 100 billion human antibodies, which we use in the design and development of antibody therapeutics. CAT also developed Ribosome Display, a cell free biological system using complexes of ribosomes (complex molecules involved in protein production) and mRNA (molecules carrying DNA coding) for the generation of larger and more varied libraries of antibodies. 

The second method involves the use of transgenic mice: mice that have their antibody genes replaced by human genes and which produce human antibodies in response to immunisation with an antigen. Following the recent announcement of a non-exclusive licence agreement with Regeneron, MedImmune will be combining Regeneron’s VelocImmune^® technology with its proprietary Display technologies, extending further the company’s industry-leading biologics platform.