SUMMARY AND OUTLOOK
Hybridoma technology has achieved broad regulatory acceptance as evidenced by licensure of about 20 MAbs. However, the method
is laborious and does not work for certain immunogens (e.g., toxins, highly conserved proteins, pharmacological active molecules)
which are not suitable for obtaining high affinity antibodies.5,11 An alternative to the hybridoma method is to produce engineered antibody molecules and fragments by in vitro methods. These methods are based on complex combinatorial libraries containing a large collection of variant antibody-like
molecules. They involve the selection of candidate molecules by screening procedures. Several discovery platforms (e.g. phage,
bacterial, yeast, and ribosome display) have been developed. Most advanced is phage display. This approach allows the insertion
of human antibody genes into phage DNA and the production of combinatorial libraries containing random heavy- and light-chain
pairings which are presented as variant antibody fragments on the surface of filamentous phages. In vitro screening assays can identify antibodies that bind to the target. After initial antibody isolation, the affinity of candidate
molecules can be further increased by reiterative in vitro maturation processes.11,44 Recently, a fully human phage-display engineered MAb, adalimumab (Humira) has been approved for treatment of rheumatoid
arthritis.42 In the next several years, many more monoclonals prepared in vitro will enter the market.
Acknowledgment: I would like to thank Dr. Richard Peck for his critical review of the manuscript.
Manfred Kurz, PhD, is a regulatory affairs associate at CSL Behring, Bern, Switzerland, 188.8.131.524.5022, email@example.com
1. Baker M. Upping the ante of antibodies. Nature Biotechnology 2005;23:1065-1072.
2. Reichert JM, Pavlou A. Monoclonal antibodies market. Nature Reviews Drug Discovery 2004; 3:383–384.
3. Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC. Monoclonal antibody successes in the clinic. Nature Biotechnology 2005;1073–1078.
4. Hopkins AL, Groom CR. The druggable genome. Nature Reviews Drug Discovery 2002;730.
5. Stockwin LH, Holmes S. Antibodies as therapeutic agents: vive la renaissance. Expert Opinion on Biological Therapy 2003;3:1133-1152.
6. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495-497.
7. http://grants.nih.gov/grants/policy/antibodies.pdf [Accessed 2005;Sept 2].
8. Little M, Kipriyanov SM, Le Gall F, Moldenhauer G. Of mice and men: hybridoma and recombinant antibodies. Immunology Today
9. Pendley C, Schantz A, Wagner C. Immunogenicity of therapeutic monoclonal antibodies. Current Opinion in Molecular Therapeutics
10. Monoclonal antibodies: the market. European Antibody Arena, October: ING Barrings; 2001.
11. Moroney S, Plückthun A. Modern antibody technology: the impact on drug development. In: Modern biopharmaceuticals (Knäblein
J, ed.) Vol. 3, 1st ed., 1147-1186, Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2005.
12. Peterson NC. Advances in monoclonal antibody technology: genetic engineering of mice, cells, and immunoglobulins. ILAR
13. Derivation and characterization of cell substrates used for production of biotechnological/ biological products; http://
http://www.ich.org/LOB/media/MEDIA429.pdf [Accessed 2005 Sept 6].
14. Ph. Eur. Monograph 2031.
http://www.fda.gov/cber/gdlns/ptc_mab.pdf [Accessed 2005;Aug 12].