Immunotoxins

Abstract

Immunotoxins are protein molecules composed of a cell surface-directed ligand covalently linked to a peptide cytotoxin. This definition excludes a number of important therapeutic compounds with distinct pharmacologic properties which react with intracellular targets. Such molecules would be unlikely to find and react with their intracellular targets due to the permeability barrier of the plasma membrane. Thus, the ligands must bind cell surface receptors or antigens. Ligands which have been used include monoclonal antibodies and antibody fragments, adhesion molecules, growth factors, and cytokines. The toxophore must be peptide in nature. This excludes radiolabels such as⁹⁰Y, ²¹³Bi, or¹³¹I and small molecular weight drugs such as calicheamicin and doxorubicin [1, 2]. These immunoconjugates are the subjects of other chapters in this book. We have further restricted the toxin moieties to cytotoxins. Thus, peptides which modify coagulation [3], complement [4], or immune responses [5] are not considered here. Conjugates with these compounds are important potential therapeutics and are considered separately in chapters discussing anti-angiogenesis and cell-directed therapies. There are three major classes of peptide cytotoxins [6, 7]. Class I toxins are proteins which are intracellular enzymes. They catalytically modify critical intracellular functions. Class II toxins bind to cell surfaces and trigger intracellular signal pathways. Class III toxins are pore-forming peptides which cause leaks in the plasma membrane. Immunotoxins have been prepared with toxins of each class, as listed in Table 1 and discussed below. We will first review the structure and molecular mechanisms of cell intoxication for the peptide cytotoxins used in preparation of immunoconjugates.