Therapeutics
New ways to optimise therapeutic and
diagnostic antibodies paving the way to better antibodies
Monoclonal antibodies are the fastest-growing category of research within the biotech and pharmaceutical industries. Several monoclonal antibodies are listed in the top 10 selling blockbusters, and the market forecast predicts that the number of monoclonal antibodies within the top 10 will further increase1.
T
he first therapeutic monoclonal antibody (mAb), muromonomab, was approved in 1986 by the US Food and Drug Administration (FDA). Muromonomab, an immunosuppressant, targets CD3 and is prescribed for the reduction of acute rejection in patients with organ transplants. Muromonomab and the other early therapeutic antibodies that first entered into the clinic are murine antibodies. The first mAbs were made from mouse-derived hybridomas and caused a relatively high incidence of immunogenici- ty. Immune responses to therapeutic antibodies can neutralise their effect, and hypersensitivity can cause serious adverse events. Therefore, researchers put a lot of effort into the development of antibodies with a decreased risk of immunogenicity to further broaden the clinical use of antibodies in the clinical setting. The result of these efforts was the develop- ment of chimeric mAbs, mouse-human antibodies made up of two-thirds human sequence homology and humanised mAbs, which have 95% human sequence homology. Two-thirds of the monoclonal antibodies currently on the US market are either chimeric or humanised monoclonal antibodies. More recently, technologies such as phage-dis- play or transgenic mice have paved the way for the development of fully humanised mAbs. Today
Drug Discovery World Winter 2010/11
there are several human mAbs approved in the US, and they account for the majority of mAbs in clin- ical development. Fully humanised mAbs are thought to be less immunogenic than humanised or chimeric mAbs due to the complete elimination of murine-derived protein structures2.
Antibody screening
The human immune system has the ability to create millions of different antibodies that selectively target specific antigens. The specificity of antibodies is deter- mined by the amino acid sequence of the tips of the typical Y-shape structured molecule. The molecular structure of antibodies includes a specified variable region at the end of the light and heavy chains. Specifically, the antigen-binding activity of mAbs is determined by the conformation of its amino acids in its complementary determining regions (CDRs). Three CDRs are located in the variable region of both the light and the heavy chains of the antibody. The goal of biomedical research focused on antibodies is to mimic the screening process of the human immune system as closely as possible in order to identify anti- bodies with the highest target/antigen specificity3. Antibody libraries have become one of the most important tools for screening and identifying mAbs that complement a variety of targets/antigens while
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By Dr Markus Enzelberger
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