Upstream Processing: Regulatory Considerations Regarding Quality Aspects of Monoclonal Antibodies - An alternative to the hybridoma method is producing engineered antibody molecules and fragments

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Upstream Processing: Regulatory Considerations Regarding Quality Aspects of Monoclonal Antibodies
An alternative to the hybridoma method is producing engineered antibody molecules and fragments by in vitro methods.


BioPharm International
Volume 20, Issue 7

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, 41.0.31.344.5022,

REFERENCES

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