Biomedical Engineering Reference
In-Depth Information
22
IMMUNORNASE FUSIONS
W OJCIECH A RDELT
Tamir Biotechnology, Inc. Monmouth Junction, NJ, USA
22.1 Introduction
22.2 Development of immunoRNase fusion proteins as
biopharmaceuticals
22.3 Aspects of immunoRNase design and production
22.4 Alternatives
22.5 Conclusions and future perspectives
References
recombinant DNA technology (recombinant immunotox-
ins). Antibody fragments and other “alternative antibody
formats” have recently been reviewed [12].
Effector moieties are usually toxic proteins from plants
(like ricin, saporin, gelonin, and viscumin) or from bacteria
(Pseudomonas exotoxin and diphtheria toxin). They have also
been extensively modified in the course of immunotoxins
development, for example, their natural binding domainswere
frequently removed to facilitate specific immune targeting.
Immunotoxins bind to cells as a result of specific interaction
between the targeting moieties and cell surface antigens.
Next, they are internalized and translocated to cell cytosol
where their effector moieties interfere with the translation
step of protein biosynthesis. This leads to cell death.
Immunotoxins have been used in the clinic mainly to treat
cancer (see Reference 7 for recent review). Main problems
with this therapy are usually large molecular size of those
drugs (that limits their penetrability to solid tumors) and the
immunogenicity of the bacterial or plant proteins constitut-
ing their effector moieties. The latter usually precludes
multiuse of these drugs because neutralizing antibodies
are formed in patients. Immunotoxins may also damage
endothelial cells and this frequently leads to a severe condi-
tion known as vascular leakage syndrome [7,13]. Liver and
kidney toxicity are other complications. The adverse side
effects of immunotoxins inspired a search for alternative
effector moieties, which would be less or not immunogenic
and better tolerated by patients.
22.1
INTRODUCTION
More than 100 years ago, Paul Ehrlich predicted that it
would be possible to develop “magic bullets” that would
selectively kill cancers or pathogenic microorganisms [1-3].
He reasoned that compounds specifically targeting cancer
cells or bacteria could be designed and toxins could be
delivered along with those targeting agents.
22.1.1 Immunotoxins
Many years later, in 1980, monoclonal antibodies were used
first time to deliver a plant toxin to neoplastic cells [4,5]. The
antibodies (targeting, binding, or immune moieties) were
covalently linked to ricin (effector or cell-killing moiety).
Such constructs were later termed immunotoxins [6]. Immu-
notoxins are covered in another chapter of this topic; they have
also been discussed in numerous review articles [3,7-11].
Initially, entire molecules of monoclonal antibodies were
chemically conjugated to toxins. Later, various antibody
fragments retaining the ability to bind specific antigens on
the surfaces of targeted cancer cells were developed and
fused to the effector moieties at
22.1.2 Cytotoxic Activity of Ribonucleases
Ribonucleases (RNases) are potentially cytotoxic by virtue
of their ability to catalyze cleavages of phosphodiester bonds
in RNA. Intracellular degradation of various RNA species
the genetic level by
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