The application of antibodies has expanded from being an immunologically important protein to an important research tool and a rapidly growing class of therapeutic agents. Since the successful generation of monocolonal antibodies from antibody libraries in 1980’s, many biotech companies and research institutes started constructing antibody libraries. Depending on the methods of construction, antibody libraries can be divided into four categories: naïve antibody libraries, fully synthetic libraries, semi-synthetic antibody libraries and combinatorial antibody libraries.
Naïve antibody libraries
Naïve antibody libraries are based on B-cells from unimmunized or healthy donors. A representative naïve antibody library is constructed by Cambridge Antibody Technology Group Plc (CAT) in 1990’s. In 1996, CAT published its 10E10-sized naïve antibody library in Nature Biotechnology. Such antibody library has been successfully used to generate monoclononal antibodies, among which the most successful one is the immunosuppressant adalimumab (Humira), whose global sale in 2013 was as high as 10.6 billion US dollars.
Fully synthetic libraries
Fully synthetic libraries are those made by in vitro randomization of the three complementarity-determining regions (CDRs) of the variable region in both the light chain and heavy chain with PCR. A good example of such library is Human Combinatorial Antibody Library (HuCAL) by Morphosys AG., which was sold to Bio-RAD in December 2012. It now offers customized monoclonal antibodies generated from HuCAL, the only currently available provider of such services.
Semi-synthetic antibody libraries
In semi-synthetic libraries, genes encoding the CDR are mainly isolated from nature sources, and thus providing large diversity. In 2000, BioInvent reported its 2x10E9- sized semi-synthetic antibody library in Nature Biotechnology. Three antibody drugs generated from such library are currently in clinical development
Combinatorial antibody libraries
Combinatorial antibody library is the hybrid of two or three other types of antibody libraries. It keeps the advantage of high diversity from nature sources while allowing engineering and optimization with synthetic methods. It allows both the rapid generation of antibodies and the isolation of rare antibodies. It offers bright future for antibodies to be used not only in simple antigen binding, but in probing cellular function as well as generating therapeutic agents for inflammation and cancer therapy.