Until the 19th century, when anesthesia, improved techniques and histological control made surgery more efficient, cancer was more or less regarded as incurable. Surgery was first complemented by radiation therapy. In this regard, the invention of the linear accelerator in the first half of the 20th century advanced radiotherapy from a palliative method to a cancer treatment with a curative intent. Both therapies, however, are in most cases not sufficient to control metastatic disease. Consequently, the introduction of nitrogen mustard in the early 1940s initiated chemotherapy, targeting proliferating cells in general (Papac 2001). Still, cancer remains one of the most life threatening diseases. Notably, despite intensive research on cancer and cancer therapy over the past 30 years the prognosis of metastatic cancer has not sufficiently improved as yet; however, many pathways and characteristics of different tumor entities have been unraveled. Based on this information, specific tumor therapies are being pursued either by directly targeting the proteins involved in the neoplastic process, or by targeting toxic drugs to the tumor.
Both strategies can be achieved using monoclonal antibodies (mAbs). In this regard, Paul Ehrlich already envisioned at the end of the 19th century antibodies as "magic bullets," but not until 1975 when Köhler and Milstein described the generation of murine monoclonal antibodies did the necessary munition become available (Köhler and Milstein 1975). Among other problems, the patients' immune response readily inactivating antibodies of non-human origin hampered the development of mAbs as therapeutic agents until these had been solved by technical advances in the process of antibody generation. To this end, the first therapeutic antibody for cancer therapy was approved by the US Food and Drug Administration (FDA) in 1997 and mAb based therapies became a major strategy in medicine (Grillo-Lopez et al. 2002). Unconjugated mAbs can exert their anti-tumor effect by inducing immune responses, blocking highly expressed and activated growth factor receptors on tumor cells or inhibiting angiogenesis. In addition, tumor specific antibodies also provide the means to target therapeutic measures to tumor cells. Indeed, conjugates of cytotoxic drugs, cytokines, toxins or radionuclides (see Chapter 6, this volume) and tumor-specific mAbs have been evaluated in preclinical and clinical settings with the aim of increasing the specificity of the therapeutic intervention and thereby minimizing the side effects while maximizing the desired effects. Here, we discuss recent preclinical and clinical data on immunconjugates of cytotoxic drugs and focus on components conjugated to antibodies which exert their therapeutic efficacy by utilizing biological processes.
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