CLASSIC IMMUNOTOXINS WITH PLANT OR MICROBIAL TOXINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 262

18

CLASSIC IMMUNOTOXINS WITH PLANT OR
MICROBIAL TOXINS

J UNG H EE W OO AND A RTHUR F RANKEL

Cancer Research Institute of Scott and White Memorial Hospital, Texas A&M Health Science Center College of Medicine,
Temple, TX, USA

18.1 Introduction
18.2 Toxins used in immunotoxin preparation
18.3 Immunotoxin design and synthesis
18.4 Clinical update of immunotoxin trials
18.5 Challenges and perspective of classic immunotoxins
18.6 Conclusions
References

either holotoxins or hemitoxins. Holotoxins (ricin, diphthe-
ria toxin [DT], Pseudomonas exotoxin [PE]) consist of a
catalytic moiety and a binding moiety in either a single chain
protein or two proteins. Hemitoxins (saporin, gelonin, poke-
weed antiviral protein [PAP]) have only a catalytic chain.
Type I toxins must be internalized and then translocated into
the cytosol.
The major application is cancer treatment due to the
targeted cell killing effect of immunotoxins. Some immuno-
toxins have been tested in patients with autoimmune diseases.
Cancer treatments include surgery, radiation therapy, and
chemotherapy. Chemotherapy is the last treatment option
for widespread metastatic cancer patients. However, the
success of chemotherapy in many cancers is hindered by
acquired chemotherapy resistance. Most chemotherapy drugs
are small molecules that target DNA, mitotic mechanisms, or
transcription factors. These small molecules can be exported
by various pump mechanisms that can be enhanced by
selection processes leading to cancer chemotherapy resist-
ance. Alternative approaches to cancer treatment are needed.
Immunotoxins can selectively target malignant cells and
induce cell death by a different mechanism than conventional
chemotherapy drugs. Therefore, targeted therapy with
immunotoxins is a potential treatment option for rela-
psed/refractory cancers that have resistance to chemotherapy
drugs. Although immunotoxins have a unique mechanism of
action toward malignant cells, their clinical use and repeated
dosing are limited by nonspecific cell toxicity and immuno-
genicity. Nonspecific cell toxicity causes transient elevation
of liver enzymes and endothelial damage. The latter
often results in vascular leak syndrome. Classic immunotox-
ins are immunogenic. Immunogenicity of immunotoxins

18.1 INTRODUCTION

Immunotoxins are protein molecules consisting of one or
two cell surface-directed ligands covalently linked to a
peptide toxin either from plants or microorganisms. The
ligand moiety of immunotoxins recognizes cell surface
proteins on target cells and the toxin moiety kills targeted
cells according to the mechanism of action of its toxin.
Ligands include monoclonal antibodies and antibody frag-
ments, adhesion molecules, growth factors, and cytokines.
There are two types of peptide toxins that have been used in
immunotoxin construction (Table 18.1). Type I toxins are
proteins whose enzymatic action takes place in the cytosol.
They enzymatically inhibit or modify critical intracellular
functions, mostly protein synthesis. Most of plant and
microbial toxins belongs to type I. Type II toxins are
membrane-acting peptides, which cause changes or leaks
in the plasma membrane, resulting in cell death. No inter-
nalization of toxins is required for cell intoxication but
nonspecific cell toxicity is a major drawback. Most of the
immunotoxins have been made with type I toxins. Toxins are