Therapeutic mAbs

For the production of mAbs, the cell line with the best binding to the targeted epitope of the antigen is chosen from several engineered hybridoma cell lines. The obtained species of antibodies is referred to as mAbs because they derive from one original B lymphocyte and thus they are all identical (clones). 

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As of 2008, 25 therapeutic monoclonal antibodies (mAbs) mAbs had been approved for clinical use in the United States, and with over 400 antibodies being in preclinical and clinical development further increase of antibody therapies is assured (10, 11). As a general rule, the Fc fragment is a key component of therapeutic mAb design because it extends their pharmacokinetics. Inclusion of the Fc from IgG is also a key component of other bioactive proteins where prolongation of pharmacokinetics is desired, e.g., the tumor necrosis factor receptor (TNFR) fusion protein etan-ercept (Enbrel ) (12). Thus for both therapeutic antibodies and Fc-fusion proteins, the FcRn interaction is a generalized way to exploit FcRn protection to achieve the benefits of extended persistence in vivo. 

Conventional rodent model systems have proven problematic as they do not reliable model the pharmacokinetics of humanized mAb and Fc-fusion proteins. In contrast to the failure of mouse mAbs to be protected by human FcRn, humanized mAbs have an abnormally high affinity for mouse and rat FcRn, resulting in an artificially prolonged serum persistence (13, 16). This fact has greatly diminished the preclinical utility of standard mice for therapeutic mAb development and testing. The alternative cynamolo-gous monkey model has proven to be reliable, but it is hampered by considerable expense and ethical concerns that limit its routine use. 

Use of the humanized FCRN model is proving to be an effective preclinical surrogate to evaluate the serum persistence of therapeutic mAbs. With modification, this approach may also assist in the testing of the efficacy. For example, there is a need to... 

Following the success of recombinant proteins such as insulin, therapeutic mAbs today represent the second wave of innovation created by the biotechnology industry during the past 20 years. The recent success of a number of new mAb therapies, for example rituximab (Rituxan ) and infliximab (Remicade ), suggests a resurgence of the biotech industry for the coming years. For serious chronic diseases such as cancer or rheumatoid arthritis, mAb therapy has indeed proven its clinical efficacy. 

In the following, the four most important and best-understood effector functions/ modes of action of therapeutic mAbs or antibody-derived products (e. g., antibody fragments) will be discussed, and will focus on cancer therapy. The different modes of action of mAbs in cancer therapy are depicted in Fig. 3.4. As this topic is not entirely within the scope of this chapter, the reader is referred to textbooks on immunology for more details on the modes of action of mAbs. 

Before discussing the pharmacokinetic characteristics of therapeutic mAbs, the present section will focus on the catabolism of physiological antibodies. This process is also highly relevant for therapeutic mAbs. 

Compared to small-molecule dmgs, therapeutic mAbs display different pharmacokinetic characteristics, including nonlinear pharmacokinetic behavior. As the majority of therapeutic mAbs present IgG (or more specially IgGl) molecules, the emphasis will be placed on this isotype, although the characteristics of newer types of molecule such as antibody fragments will also be included. 

Although, during the early applications of therapeutic mAbs, pharmacokinetic modeling was rarely applied, a variety of analytical techniques has been used over the years to characterize the pharmacokinetics of this class of compounds. The application and information derived from three different methods of noncompart-mental analysis, individual compartmental analysis, and population analysis will be discussed in the following sections. 

One of the major obstacles to successful MAT was the limitation of the applicability of murine (or other xenogeneic) mAbs. Their biologic activity in the human environment is limited, since the host s immune response to these antibodies, namely production of human antimouse antibodies (HAMAs), is not only potentially associated with undesirable and sometimes life-threatening clinical side effects, but also with neutralization or enhanced elimination of the therapeutic mAb. This could be partly prevented by concomitant immunosuppression, including the use of immunosuppressive mAbs as in the case of organ transplantation. 

The value of therapeutic mAbs marketed in 2004 was above US 13 billion. At the same time, the market value for the many presentation forms of erythropoietin exceeded US 8 billion, and the global biopharmaceutical market surpassed US 50 billion. 

Some examples of therapeutic mAbs are presented in Table 16.1. However, because of the clinical and commercial importance of this class of therapeutic proteins, an entire chapter is dedicated to monoclonal antibodies (Chapter 17). 

However, the most promising class of biopharmaceuticals consists of the therapeutic mAbs. In 2004, total sales of therapeutic mAbs reached approximately US 11.2 billion, with an impressive annual growth rate of 42% in the period 2000-2004 (Research and Markets, 2005d). The forecast is that in 2010 this market will reach US 34 billion. 

According to Reichert and Pavlou (2004), 17 therapeutic mAbs, grouped into 4 different types, had been approved by the FDA at that time 3 murine, 5 chimeric, 8 humanized, and 1 human. Among them, Remicade / Infliximab was the top-selling one (US 1.6 billion in 2002), representing 30.5% of mAb sales in that year. 

It is forecast that up to the end of the current decade, the research focus regarding therapeutic mAbs will be on two categories oncology and arthritis, and inflammatory and immune disorders. A significant increase of sales is expected up to 2008 for chimeric mAbs, in absolute terms, and for human and humanized mAbs, in relative terms (Figure 16.2). Up to now, murine mAbs are those with the lowest approval rate (4.5%), whereas the chimeric are the most successful (26%). The approval rates for humanized mAbs (18%) and human antibodies (14%) were intermediate. However, as most of the last two types are still under development, the approval situation may change significantly in the future (Reichert and Pavlou, 2004). 

The application of mechanistic mathematical models for determining the properties of the therapeutic mAbs can help in maximizing the efficacy of the mAb. 

If the target antigen is a receptor, then therapeutic mAb may have a shorter half-life due to receptor-mediated internalization. For brevity, the set of differential equations for this case are not mentioned here. Figure 18.2 explores the... 

Inhibition of the biological function of the target antigen is a general safety concern and mechanistic mathematical modeling can help in optimally designing dosage and affinity of the therapeutic mAb. A mechanistic... 

The PD behavior of therapeutic MAbs is complex. Fortunately, the activity of these agents can be evaluated by the use of fluorescence activated cell sorting (FACS). Like most therapeutic biologies, the mechanism of action is commonly described using the standard indirect effect models. However, because FACS data can determine the fraction of cell surface receptor bound by the MAb, and because the change in receptor density can be followed using this same method, more mechanistic models have been proposed (29). In these models, the relationship between concentration of antibody and bound receptors can be explicitly described and the bound antibody is then used to drive the indirect effect model. A schematic of this model is provided in Figure 41.10. 

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