Conclusions

Monoclonal antibodies have emerged as important therapeutic agents for the treatment of malignant disease. Indeed, they have proved to be well tolerated and effective for the treatment of different cancers and have consequently been approved by the FDA. Besides their role as cancer therapeutics per se, their targeting potential earmarks them as compounds able to increase selectivity of different kinds of therapeutic measures. For some of these measures, such as toxins, fusion to such a targeting moiety is inevitable in order to use them therapeutically. However, for their broader use as a targeting device a few problems still have to be addressed, namely (1) immunogenicity, (2) selectivity and (3) penetration into solid tumors. The generation of fully human antibodies will solve the problem of the inherited immunogenicity of earlier constructs. To increase the selectivity of antibodies and thus reduce unspecific toxicity of fusion proteins, new tumor antigens and the respective mAb have to be identified. This can be achieved by phage display technology, which not only enables the identification of differentially expressed antigens but can also be used to isolate respective Abs (Trepel et al. 2002). Notably, the behavior of the antigen upon antibodybinding should be taken into account with respect to the delivered drug; those approaches aiming at the direct killing of the tumor cells require antigens which become internalized upon binding, whereas those modulating biological processes should stay on the surface of the tumor cells. Since lympho-hematopoetic malignancies are easier to access, the body of evidence for these diseases is much larger and most of the targeted therapies approved so far are for these indications. In order to affect solid tumors, the therapeutic agent must overcome several obstacles including the vascular endothe-lium, stromal and epithelial barriers and high interstitial pressure (Stohrer et al. 2000). In this regard, smaller recombinant mAb constructs like single chain antibodies should overcome some of these problems (Yokota et al. 1992), but have the disadvantage that they are more rapidly cleared from the plasma (Adams et al. 1998). An alternative approach for solid tumors is to target the tumor microenvironment in general and the endothelium of tumor blood vessels in particular (Hofmeister et al. 2005). The advantages of targeting the tumor vasculature are accessibility, the relative genetic stability (thereby avoiding antigen loss variants), and that many tumor cells, irrespective of their antigen expressing profile, are hit via this route.

Recent years have demonstrated the wide variety of agents which can be targeted to tumors. In preclinical models, these tumor targeted therapies have revealed impressive results. The clinical value for targeted cancer therapy has to date only been confirmed for conjugates of cytotoxic drugs and radionucleotides. However, the success of tumor-specific mAbs per se is fueling optimism towards this attractive approach.

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