Fusion Toxins

Abstract

Two different approaches have been undertaken to develop chimeric targeted biomole- cules for therapeutics. The first was the construction of immunotoxins consisting of murine monoclonal antibodies chemically linked through a disulfide bond linker to a toxin or radionuclide. The plant toxin ricin and the bacterial exotoxins of Pseudomonas aeruginosa (Pseudomonas exotoxin A) and Corynebacterium diphtheriae (diphtheria toxin) have been used in the construction of the first immunotoxins. These enzymes inhibit protein synthesis by scission of the large ribosomal subunit in the case of ricin or by modification — adenosine diphosphate (ADP)—ribosylation — of elongation factor 2 in the case of the bacterial toxins. A detailed knowledge of the structure—function organization of these toxins separate domains which function in cell binding, membrane translocating, and catalytic activity has allowed for genetic manipulation of the toxin molecules to replace the native receptor binding domains with the targeting antibody,preserving the necessary membrane—translocating sequences and active catalytic domain. While immunotoxins have demonstrated promising clinical activity in early studies, nonspecific binding and toxicities have been attributed to the instability of the chemical conjugation of the toxin moiety to the antibody, and therapeutic index has been compromised by the generation of neutralizing antibodies to the murine antibody component of the immunotoxin. Newer generations of immunotoxins have utilized murine complementarity—determining regions on human antibody frameworks to prevent immunogenicity of the immunotoxin; they have improved the chemical linkages to prevent dissociation of the toxin from the antibody and modified the toxin moieties to reduce nonspecific toxicities, such as deglycosylation in the case of the ricin A chain immunotoxins. Clinical studies are underway with these newer immunotoxins.