Editorial [Hot Topic: Therapeutic Antibodies and Derivatives: From the Bench to the Clinic(Guest Editor: Alain Beck)]

Today, monoclonal antibodies (MAbs) are the fastest growing class of human pharmaceuticals. Nearly 30 antibodies and antibodyderivatives (Fab fragments, radioimmunoconjugates, immunoconjugates and Fc-fusion proteins) based on mice and human G-type immunoglobulins (IgGs) have been approved worldwide in around 20 years (see Fig. 1 and A Beck et al in this issue). Several hundreds more are investigated in clinical trials in various therapeutic indications including oncology, autoimmune and infectious diseases, organ transplantation, cardiology, rheumatoid diseases, allergy, tissue growth and repair (J. Reichert in this issue). The worldwide revenues of antibody treatments generated around 20 billion USD in 2007. Seven therapeutic antibodies reached ‘blockbuster’ status with more than 1 billion USD turnover. The sale growth forecast from 2006 to 2012 is 14 % a year, compared to 0.6 % for small molecules. Monoclonal antibodies belong to a safe and target-specific category of pharmaceuticals that have a relative high success rate from early clinical to the licensure (25-29 % for antibodies vs. 11 % for small-molecule drugs; J. Reichert in this issue). These highly promising therapeutic and commercial features translated during the past few years into several business acquisitions of biotechs companies by large pharmaceutical companies, such as Cambridge Antibody Technology and MedImmune by Astra Zennecca or Abgenix by Amgen. The physicochemical structure of recombinant humanized or human antibodies is similar to that of circulating IgGs existing in >10 g/L concentration in human serum. By themselves, these molecules are potentially less toxic than xenobiotic small drugs. Nevertheless, blocking, activating or cross-linking an antigen target can trigger adverse events like for others conventional drugs. Particularly, new targets or new antibody formats have to be carefully investigated in pre-clinical safety studies especially following the dramatic experience of TGN-1412 anti-CD28 superagonist MAb first-in-man trial (C. Schneider in this issue). Several new regulatory issues are currently under discussion by European and US Agencies, such as the application of a more stringent calculation of the ‘first dose in man’ based on the MABEL (minimal anticipated biological effect level) approach and it will likely be recommended for high-risk medicinal products (e.g., novel protein format, novel target protein). As illustrated below, a major breakthrough for therapeutic applications of monoclonal antibodies, was achieved in 1997 with the commercialization of the first chimeric and humanized Mabs (Rituxan and Zenapax, respectively). Since that time, thirteen humanized antibodies as well as two fully human antibodies generated by phage-display (Humira; H. Thies, S. Dubel et al. in this issue) or by using transgenic mice bearing an human IgG repertoire (Vectibix) and immunized with the targeted antigen have been introduced on the market. For all these different kind of antibodies, approximately ten years were needed between the first paper dealing with the new technology and the market approval of the first candidate. Currently, most of the recombinant chimeric (Ch), humanized (Hz) or human (Hu) IgGs and Fc-fusion proteins (Enbrel, Amevive, Orencia and Arcalyst) are produced in mammalian cells (CHO, NS0, SP2/0) in up to 20,000 liters bioreactors by straightforward and wellestablished bioprocesses (M. Chartrain and L. Chu in this issue). Alternatively, two of the commercial Fab-fragments, which are not glycosylated are produced in E. coli (Lucentis and Cimzia).