Monoclonal antibodies applications, 74, Table

The first mouse monoclonal antibody specific for human CD3 was produced in 1979 and named orthoclone OKT3. Aside from its use in the laboratory, OKT3 became the first anti-CD3 antibody to be utilized in transplantation medicine, but its wider application was hampered by its immunogenic and mitogenic properties (reviewed in [6]). Consequently, humanized and engineered anti-CD3 antibodies were developed to circumvent these limitations (Table 1). Since T cells and the TCR are involved in many immunological diseases, it is not surprising that the application of CD3 antibodies is not restricted to the field of transplantation. For example, CD3 antibodies are tested in clinical studies of diseases such as autoimmune diabetes (type 1 diabetes), immune-mediated inflammatory arthritis and inflammatory bowel disease [7]. 

Thus far, Lhe discussion relaling to the medical uses of monoclonals has focused exclusively upon cancer. Monoclonal antibodies (and their derivatives), however, have a far broader potential therapeutic application. Actual/potential additional uses include detection and treatment of cardiovascular disease, infectious agents, and various additional medical conditions (Table 13.2). 

Table 10.3. Range of clinical applications of monoclonal antibodies Induction of passive immunity...

Table 10.8. Some actual/potential medical applications of monoclonal antibodies (other than those relating to cancer). In many instances, these applications will entail use of chimaeric or humanized antibodies or antibody fragments...

Monoclonal antibodies were purified using immobilized protein A in expanded-bed mode.30 It was possible to capture 2 g of pure mouse IgG 2a per cycle from an unclarified hybridoma cell culture, by using a 5 cm diameter expanded-bed column. Recently recombinant proteins have been recovered from milk of transgenic live stock in a one-step expanded-bed adsorption process.31 Other applications of expanded bed purification of proteins are reviewed recently.19 Table 232 35 lists some relevant applications... 

The characteristics and uses of monoclonal antibodies are listed in Table 2.12, and their applications are discussed in greater detail in the following chapters. 

The issue of inadequate sampling time is exemplified by monoclonal antibodies. As shown in Table 32.12/ the Vi and Vss are similar and are similar in size to a vascular space of 2-3 L/m. It is also important to note that for the most part/ in the studies submitted to support New Drug Application (NDA) approval/ Vgs was determined with methods assuming linear/ first-order kineticS/ and clearly this is not the case for the majority of the monoclonal antibodies currently marketed/ such as cetuximab (Erbitux). In fact/ the use of noncompartmental methods to describe the pharmacokinetics of mABs oversimplifies their complex properties. 

Although thermistor devices involving the use of immobilized enzymes or antibodies for a number of clinically relevant substances have been described (Table 22), their practical use is at present limited to a few research laboratories. Thermometric enzyme linked immunosorbent assays are being routinely employed in monitoring the production of monoclonal antibodies. A broad application is restricted by the low sample throughput and the high equipment costs. 

The 30-year history of MAbs has been a rollercoaster ride to success. From hype to depression, and back to hype, is probably the shortest summary of what has happened. MAbs have been rapidly introduced into a number of applications within and outside the medical field (Table 1.2) [52-54]. Analytical in vitro methods such as enzyme-hnked immunosorbent assay (ELISA), radioimmunoassay (RIA), various blotting techniques, flow-cytometry, immunofluorescence, confocal imaging, and im-munohistochemistry are each dependent upon the use of polyclonal or monoclonal antibodies. 

Table 2.3.3. " Tc-labeled monoclonal antibodies and antibody fragments for potential application...

TABLE 5.1-4. CE Applications for the Heterogeneity Characterization of Monoclonal Antibodies... 

A major area for new research concerns the structural and functional consequences of adsorption of proteins to surfaces (items 3-5 in Table IV). Measurement of conformational change is still in an early stage of development. Most methods for studying adsorbed protein conformation are restricted to comparison of spectral differences induced by adsorption, without knowledge of the actual type or amount of change these differences reflect. Better methodology, especially on quantitative aspects, is sorely needed in this area. The orientation of adsorbed proteins may prove to be readily explored with the monoclonal antibody method and therefore certainly deserves wider application. Finally, the behavior of enzymes and antibodies at interfaces is not... 

The ability to produce/isolate specific antibodies to a number of different proteins from the phage display library offer a potential to provide antibodies for genome scale application of protein chips (Lee and Mrksich, 2002). Phage display of combinatorial antibody library (subsection 13.7.5) is uniquely capable of providing specific monoclonal antibodies in the number and at the rate required for bioinfoimatics research. Table 16.16 lists some commercial sources of phage display antibody libraries. 

As Cu has many interesting radionuclides for therapeutic as well as for diagnostic applications (O Tables 45. i and O 45.2), the development of ideal chelators for this metal is of interest. BFCs used for the coupling of Cu-radioisotopes to biomolecules are based on the 14-membered tetraazamacrocycle cyclam 14 (1,4,8,11-tetraazacyclotetradecane) O Fig. 45.17). Two bifunctional versions of cyclam-14, 4-[(l,4,8,ll-tetraazacyclotetradec-l-yl)methyl]-benzoic acid (= CPTA) and [6-(p-bromoacetamido)benzyl]-l,4,8,ll-tetraazacyclotetradecane-l,4,8,ll-tetraacetic acid (= BAT) (O Fig. 45.17), were coupled to monoclonal antibodies and somatostatin analogs (Smith-Jones et al. 1991 Anderson et al. 1995 Wilder et al. 1996). In addition to... 

---