Biomedical Engineering Reference
In-Depth Information
3.8.2.2.2 Immunotoxins. Immunotoxin-based strategies involve the delivery
and subsequent internalization of cytotoxic agents to GCPII-expressing cells
by means of anti-GCPII antibodies, fragments thereof, specific immunopep-
tides, or aptamers.
The first of these studies tested three anti-GCPII antibodies linked to ricin A-
chain in vitro and selected the J591 antibody as the most effective.
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Since then,
J591 has been conjugated to melittin-like peptide, saporin, and maytansinoid
1.
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All of these conjugates showed anticancer activity in mouse xenografts
of prostate cancer and exhibited IC
50
s on GCPII-positive prostate cancer cell
lines in the low-nanomolar or subnanomolar range. The maytansinoid con-
jugate with huJ591 (MLN2704) entered phase I clinical trials and was found to
have a low toxicity and anti-tumor activity.
148
Antitumor effects on mouse
xenograft models of prostate cancer were further demonstrated by (1) rat
antibody E6 conjugated to ricin A-chain, (2) scFvA5 single-chain fragment of
the 3/A12 antibody conjugated to a truncated form of Pseudomonas exotoxin
A, and (3) fully human anti-GCPII antibody linked to monomethylauristatin
E.
51,87,149-151
These antibodies exhibited IC
50
s in the picomolar range.
In addition to antibodies, GCPII-specific aptamers have been tested as direct
conjugates to toxins or as directed delivery agents on drug-encapsulated
nanoparticles.
112,113,149,150,152,153
The latter carry PEG molecules on their sur-
face that improve their pharmacokinetics and eliminate uptake by non-targeted
cells. The nanoparticle conjugates may be especially useful for early-stage
cancer.
3.8.2.2.3 Immune System-Mediated Therapy. There is a broad repertoire of
GCPII-based therapies that induce the immune system to target the cancer
cells under investigation. This includes re-targeting of T lymphocytes, GCPII
vaccines, plasmid DNA and adenoviral immunizations, and use of antibody-
recruiting small molecules. A description of these fascinating endeavors is
beyond the scope of this review, and these lines of investigation have been
described elsewhere.
151
A novel strategy to recruit endogenous antibodies against GCPII-positive
cancer cells was recently described.
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The strategy combines immune therapy
with the advantageous properties of small molecules—small GCPII-specific
urea-based ligands are conjugated to an effector group (2,4-dinitrophenyl,
DNP) that has the capacity to recruit endogenous anti-DNP antibodies. These
are abundant in human blood and can eciently cause target-cell death via
eliciting their immune response. The conjugate anity to GCPII lies in the high
picomolar to low nanomolar range and demonstrated its in vitro capacity to
mediate LNCaP cell death.
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3.9 Conclusions and Future Perspectives
GCPII is being investigated as a drug target in two therapeutic areas.
Based on the well-defined proteolytic function of GCPII in the nervous
system, GCPII inhibition is being tested as a potential anti-neurodegeneration
