Immunotoxin protein toxins used

The development of monoclonal antibodies (mAbs) has revolutionized cancer treatment, and several mAbs are today approved for clinical use. Treatment resistance is often a problem in mAbs-treatment where multiple treatment series are necessary [100]. Dmg response can be increased by binding mAbs to cytotoxic compounds, such as protein toxins, forming immunotoxins (ITs) [101]. The historical problems with first and second generation ITs are largely solved by the use of recombinant DNA technology where chimeric proteins consisting of the Fv-ffagment of an antibody and... 

Fig. 3.3 shows the principle behind the design of immunotoxins. A number of protein toxins of bacterial and plant origin are useful for the production of immunotoxins. These include the diphtheria toxin and pseudomonas exotoxin from bacteria, and ricin, arbin, pokeweed antiviral proteins, saporin, and gelonin from plants (Pastan et al, 1986 Pastan and FitzGerald, 1991). All of these toxins kill cells by entering the cells, and enzymatically inactivating the translational machinery of the cells. Some, such as diphtheria toxin, arbin, and ricin, are composed of two protein chains, A and B. The B chains bind to the cell-surface... 

Rybak, S. M. and Youle, R. J. (1991) Clinical use of immunotoxins monoclonal antibodies conjugated to protein toxins. Immunol. Allergy Clin. N. Am. 11(2), 359-380. 

A-chain immunotoxins, however, may not be quite as cytotoxic as conjugates formed from intact toxin molecules (Manske et al., 1989). In an alternative approach to A chain use, the intact toxin of two-subunit proteins is directly conjugated to a monoclonal without isolation of the A chain. Conjugation of an antibody with intact A-B chain toxins can be done without a cleavable linker, as long as the A chain can still separate from the B chain once it is internalized. Therefore, it is important to avoid intramolecular crosslinking during the conjugation process which can prevent release of the A-B complex. In addition, since the B chain... 

Examination of genotoxicity of pharmaceuticals is required to assess the interaction of the drug with DNA. These studies are generally not applicable to immunotoxins. Unlike chemotherapeutics that cause cell death through DNA interaction, immunotoxins mediate cell death by preventing protein synthesis. However, immunotoxins use a linker to connect the toxin to the antibody that may need to be examined if it is an organic linker and has the ability to bind DNA (per ICH S6). The majority of immunotoxins use either a nonreducible thioether linker for intact toxins or a disulfide bond for A chains and ribosome-inactivating proteins and do not interact with DNA. 

Immunotoxins (ITs) are chimeric proteins consisting of an antibody linked to a toxin. The antibody confers specificity (ability to recognize and react with the target), whereas the toxin confers cytotoxicity (ability to kill the target) (1-3). ITs have been used in both mice and humans to eliminate tumor cells, autoimmune cells, and virus-infected cells (4-6). 

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