Drug Targeting Organ-Specific Strategies

ples onto anti-EGP-2 scFv. Biologically-active fusion proteins were produced by directing them
through the endoplasmic reticulum-based protein folding machinery of eukaryotic cells.This
procedure may help to identify those fusion proteins that which desirable characteristics such
stability and biological activity in the presence of serum and at low protein concentrations.
Biophysical properties such as high thermal stability are thus of paramount importance in
the decision as to whether or not these molecules are useful in vivo.The above described approaches
may provide a strategy to meet these requirements and may eventually result in attractive
modalities for the targeting of solid tumours in patients.
8.5.1.4 Immunotoxins (ITs)
8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 213
The conjugates referred to as ITs are hybrid molecules consisting of MAbs linked to powerful
toxins (or toxin subunits) purified from plants, fungi, or bacteria [64] (Figure 8.1e and
Table 8.1). These toxins inhibit protein synthesis after internalization, leading to death of the
targeted cell. Small quantities of ITs when compared with unconjugated MAbs, are needed
for effective target cell killing. In fact, a single toxin molecule in the cytosol can kill a target
cell, and, unlike chemotherapeutic agents, ITs will kill both resting and dividing cells.
Limitations to IT therapy include their immunogenicity and toxicity. Dose-limiting side-effects
of IT therapy include hepatotoxicity and vascular leak syndrome.
Table 8.1. Toxins ued for the preparation of ITs.
Source Toxin Enzymatic activity
Plant Type I RIPs* (single chain)
Pokeweed anti-viral protein (PAP)
Saporin (SAP)
Gelonin
Momordin
Trichosanthin
Barley toxin
Type II RIPs (two chains)
Abrin
Ricin
Viscumin
N-glycosidase for 28s rRNA
Bacteria Diphtheria toxin (DT)
Pseudomonas exotoxin (PE)
ADP Ribosylation of EF2
Fungi α-Sarcin
Restrictocin
Ribonuclease for 28 S RNA
* RIP: Ribosome-Inactivating Proteins
8.5.1.5 Monoclonal Antibody–Drug Conjugates
MAb–drug conjugates offer the advantages of improving the therapeutic index by increasing
drug uptake by tumour cells, reducing drug toxicity to normal cells, and prolonging bioavailability
of the drug and thus more extensive exposure to tumour cells.