Antibody-Conjugated Toxins

 Soon after the discovery of the high specificity of antibody binding, Paul Ehrlich proposed to exploit such specificity to redirect and restrict the activity of toxins to pathological tissues such as tumors (1-3). Such “magic bullets” could be developed only long after his proposal because of the need of antibodies of well-defined specificity, such as monoclonal antibodies, and to improve the understanding of the biochemistry and mechanism of the action of toxins. Such conjugates have been prepared by linking one of the many available cell-killing plant or bacterial toxins via a disulfide or thioether bond to an antibody specific for a cell surface antigen of cancer and noncancer cells. Chimeric toxins have also been prepared by fusing a toxin gene to a gene encoding a hormone, growth factor, or cytokine with the intention of depleting receptor-rich cell populations (1-3). In general, it is important that the linkage between the two immunotoxin parts be easily cleaved on or inside cells. Moreover, to restrict immunotoxin binding only to the cells to be intoxicated, the portion of the toxin determining its intrinsic specificity (the B subunit) must be either deleted or inactivated mutationally, and the F_c portion of the antibody must be removed. In this respect, ribosome-inactivating plant toxins lacking the B subunit have been frequently used. To avoid unspecific binding to F_c-receptor bearing cells, the toxin can be linked to the F(ab)2 portion of a monoclonal antibody. An additional problem may be presented by the presence of circulating antitoxin antibodies elicited in previous vaccination protocols (eg, antidiphtheria) or during the treatment with the immunotoxin. In the latter case, one can use another immunotoxin made with the same antibody and an immunologically unrelated toxin.

 Several antibody-conjugated toxins are very effective in killing target cells in culture or in isolated dispersed tissues, ie, bone marrow, but are less effective in vivo, because of the lack of accessibility of the cancer cells in solid tumors. However, protocols are being developed to overcome these problems and exploit the potentials of immunotoxins to reach small cancer populations that are undetected by physical and surgical methods (3) .

References

1. S. Olsnes, K. Sandvig, O. W. Petersen, and B. van Deurs (1989) Immunol. Today 10, 291–295.

2. D. A. Vallera (1994) Blood 83, 309–317. 

3. G. R. Trush, L. R. Lark, and E. S. Vitetta (1996) Ann. Rev. Immunol. 14, 49–71.