Generation, Engineering and Production of Human Antibodies Using Hucal®

Abstract

It is almost three decades since Köhler and Milstein published their work on the use of cell fusion for the production of monoclonal antibodies from immunized mice (Köhler & Milstein, 1975). The technique was rapidly and widely adopted and has provided an enormous repertoire of useful research reagents (Little et al., 2000). On the other hand, these antibodies have had limited success in human therapy (Glennie & Johnson, 2000). One reason is that murine antibodies often cause immune response in humans and lead to the generation of human anti-mouse antibodies (HAMA reaction), limiting the efficacy in long term and repeated administration (Jaffers et al., 1986; Schellekens, 2002). Only in certain indications, e.g. for the treatment of immuno-suppressed cancer patients, murine antibodies can be used. Two examples are the radioisotope conjugated murine anti-CD20 antibodies Bexxar® (tositumomab) and Zevalin™ (ibritumomab), which are both applied for treatment of lymphoma. The development of genetic engineering has allowed the conversion of existing mouse monoclonal antibodies into chimeric mouse-human antibodies, and humanised molecules where only the complementarity-determining regions (CDR) are of murine origin (Queen et al., 1989). To date, 13 therapeutic antibodies have obtained regulatory approval. Nowadays it is also possible to generate fully human antibodies, using either transgenic mice (Kellermann & Green, 2002), or in vitro technologies like phage display (Kretzschmar & von Rüden, 2002), ribosomal display (Hanes et al, 2001), bacterial display (Chen & Georgiou, 2002) or yeast display (Boder & Wittrup, 2000).