Based on his observations from selective histological staining of bacteria, Paul Ehrlich in 1900 published his idea that certain compounds could be used as "magic bullets" to selectively target external pathogens or even tumours (Ehrlich 1900). With the description of the hybridoma technology by Kohler and Milstein in 1975, the production of targeted monoclonal antibodies (mAbs) became possible and Paul Ehrlich's dream of magic bullets a reality. Currently, more than a dozen mAbs are licensed (Reichert et al. 2005), and more promising products are about to enter clinical development. While the first antibodies were of completely murine origin due to the underlying technology, scientists started an "evolution" of mAbs in order to reduce immunogenicity (Borchmann et al. 2001). Murine proteins are highly immunogenic, and continuous use in humans in most cases is not possible due to the occurrence of neutralizing antibodies, leading to loss of efficacy and/or safety problems like infusion reactions. Therefore, chimaeric antibodies such as infliximab (Remicade) were developed, reducing immunogenicity by replacement of the murine Fc part by the human counterpart. Still being considerably immunogenic, monoclonal antibodies were further "humanized" also by replacing large parts of the Fab part of the molecule by human sequences (for example, in trastuzumab, Herceptin). With the latest techniques, the production of fully human mAbs has also become possible, further reducing immunogenicity to a small but still existent extent. The only fully human mAb licensed so far in Europe is adalimumab (Humira), an anti-TNF-a mAb (Salfeld and Kupper 2007).

Despite these achievements in a more structural "evolutionary chain" of mAbs, mechanisms of action are also evolving. While the "classical" mAbs have rather clear-cut hypotheses as regards the way they function, for example targeting tumour epitopes on the surface of tumour cells, newer mAbs appear to be becoming more specific, targeting distinct subepitopes of certain structures. A recent example is the anti-CD28 mAb TGN1412, which is directed against a certain substructure of the CD28 molecule, the C''D loop (Luhder et al. 2003), exhibiting a distinct pharmacodynamic effect, representing a so-called "super-agonist". This product has gained unfavourable publicity due to serious adverse events during testing in a first-in-man trial (Schneider et al. 2006; Suntharalingam et al. 2006). Cases like this demonstrate that therapeutic intervention with biologics can be harmful to a considerable extent, and that safety is a central aspect to be considered for these products. In this context it is important to note that possible adverse events might be deducible from the (putative) mechanism of action of a particular compound, for example potential toxicity to skin kera-tinocytes of mAbs directed against epidermal growth factor receptor-1 (EGFR-1), like cetuximab (Erbitux). However, experience clearly shows that such considerations might not be sufficient, and that other aspects need to be taken into account. mAbs might exhibit a certain fine specificity that discriminates them from others, although directed against the same antigen. As discussed above, TGN1412 might again serve as an example. Another important aspect influencing safety of mAbs is the design of the antibody with respect to the isotype. An IgG1 mAb can be expected to behave differently from, for example, an IgG4 mAb, although directed against the same epitope. This can be explained by the different effector mechanisms mediated by the Fc parts of the IgG isotypes. While IgG1 can fix and activate complement, thereby triggering complement-mediated cytotoxicity when directed against a cell-membrane bound antigen, IgG4 might be expected to only bind to and block the epitope, potentially without directly affecting the viability of the target cell, since IgG4 cannot activate complement. Monoclonal antibodies are under development with mutated Fc parts, modulating the interaction with Fc receptors. For such molecules, the possible effects cannot solely be imputed by considerations about blockage of the epitope. Chemical modification such as PEGylation can change pharmacokinetic behaviour, tissue penetration capacity, and immunogenicity, thereby considerably changing the pharmacodynamic behaviour of a mAb.

Therapeutic intervention with mAbs can be achieved by several principles, for example, neutralization of soluble and/or membrane bound cytokines, blockage of membrane-bound molecules that mediate intercellular communication, and blockage of growth factor receptors with or without triggering of cell death. This chapter highlights recent examples of licensed mAbs representative for each of these mechanisms, discusses specific safety aspects concomitant with these interventions, and briefly describes the regulatory measures aiming at a reduction of these identified risks.

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