Monoclonal antibodies: From structure to therapeutic application

Abstract

The exciting field of therapeutic monoclonal antibodies (MABs) had its origins as Milstein and Koehler presented their murine hybridoma technology in 1975 (Kohler and Milstein 1975). This technology provides a reproducible method for producing monoclonal antibodies with unique target selectivity in almost unlimited quantities. In 1984, both scientists received the Nobel Prize for their scientific breakthrough, and their work was viewed as a key milestone in the history of MABs as therapeutic modalities and their other applications. Although it took some time until the first therapeutic MAB got market authorization from the FDA in 1986 (Orthoclone OKT3, Chap.​ 17), monoclonal antibodies are now the standard of care in several disease areas. In particular, in the areas of oncology (Chap.​ 16), transplantation (Chap.​ 17), and inflammatory diseases (Chap.​ 18), patients now have novel life-changing treatment alternatives for diseases which had very limited or nonexistent medical treatment options before the emergence of MABs. To date more than 30 MABs and MAB derivatives including fusion proteins and MAB fragments are available for different therapies (Table 7.1). Eight MABs and three immunoconjugates in oncology; 11 MABs, one Fab conjugate, and four Fc fusion proteins in inflammation; and three MABs and one Fc fusion protein in transplantation comprise the majority of the approved therapies. Technological evolutions have subsequently allowed much wider application of MABs via the ability to generate mouse/human chimeric, humanized, and fully humanized MABs from the pure murine origin. In particular, the reduction of the xenogenic portion of the MAB structure decreased the immunogenic potential of the murine MABs thus allowing their wider application. MABs are generally very safe drugs because of their target selectivity, thus avoiding unnecessary exposure to and consequently activity in nontarget organs. This is particularly apparent in the field of oncology, where MABs like rituximab, trastuzumab, and bevacizumab can offer a more favorable level of efficacy/safety ratios compared to common chemotherapeutic treatment regimens for some hematologic and solid tumors