Monoclonal Antibodies - Regulatory Challenges

The development of new monoclonal antibodies (mAbs) is a still evolving field in finding new therapeutics. Structurally, mAbs have evolved over the past years by change from fully murine molecules to chimaeric antibodies or even humanized or fully human molecules. Although being "monoclonal" in terms of specificity, mAbs can be heteroge- neous with respect to molecular features like microheterogeneity and glycosylation due to their complex manufacturing processes. Small changes in these processes can have considerable consequences on the product and also clinical safety and/or efficacy. Thus, quality, non-clinical and clinical data should not be seen as separate fields, but can impact on each other. For clinical trials of mAbs, non-clinical data from relevant species are required to evaluate the potential toxicity. Demonstration of relevance can be a challenging task, and should not be restricted to comparison of amino acid sequence of the target. Non-clinical development should also be seen as a tool for proactive risk identification. For first-in-human clinical trials, recent incidences have had considerable impact on regulatory handling, and have meanwhile led to a Euro- pean guideline on risk identification and mitigation. For pivotal clinical trials, the requirements for mAbs are in principle the same as for other, non-biotechnological products. However, based on their long half-life and particular mechanism of action, enhanced safety measures can become necessary for mAbs to adequately detect and characterize also unexpected adverse reactions. † Christian K. Schneider is member of the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency, and member of the EMEA/CHMP Scientific Advice Working Party tumours, representing "magic bullets", based on his observa- tions from selective histological staining of bacteria (1). However, the use of antibodies to target structures and use them as medicines was for a long time hampered by the lack of methods to generate viable B cell clones which produce specific antibodies directed against defined structures. This became possible by the description of the hybridoma tech- nology by Kohler and Milstein (2) in 1975, which employs a fusion of murine B cells, derived from spleen of immunized donors, to mouse myeloma cells. With this principle, the ability of the B cell to produce antibodies was combined with the infinite growth of a tumour cell within one cellular system, allowing for the production of specific antibodies. With this technique and further ones to be developed thereaf- ter until today, Paul Ehrlich's dream of magic bullets has become a reality.