Glutamate Carboxypeptidase II as a Therapeutic Target - Proteinases as Drug Targets - page 84

advanced, with several ongoing clinical trials analyzing both bone and soft-
tissue metastases in prostate cancer patients as well as the neovasculature of
solid tumors of non-prostatic origin. 132-134
In addition to macromolecular diagnostics, low-molecular-weight com-
pounds show a promise as a platform for the development of novel imaging
reagents. The Pomper lab reported the synthesis and experimental in vivo use of
several high-anity urea-based probes labeled with 11 C, 18 F, 125 I, and 99m Tc for
PET and/or SPECT imaging. Using mouse models of prostate cancer, the
authors showed specific binding to target tissues, high tumor/muscle and tumor/
blood ratios, metabolic stability, and rapid washout kinetics. 102-104,106,107,135,136
The [ 18 F]DCFBC probe has entered human clinical trials in 2010. Similar
encouraging results in prostate-cancer experimental models were reported by
several other labs—Frangioni (near-infrared fluorescent small-molecule con-
trast agents), Low (optical probes), and Berkman (fluorescent probes). 96,137,138
In addition to prostate-cancer imaging, low-molecular-weight radiologics
showed some utility for imaging GCPII in rodent brains as well as in patients
with schizophrenia, with their use expanding into the area of neurological
disorders. 105,139
GCPII thus seems to be a viable and attractive target for imaging prostate
cancer and solid tumors. GCPII imaging techniques may complement (or even
supersede in the future) other imaging modalities, resulting in more accurate
disease characterization and better evaluation of the therapeutic response, and
leading to improvements in the overall management of prostate cancer.
3.8.2.2 Experimental Therapy
In the past few years, there has been a steep increase in the number of pre-
clinical and early-phase clinical studies utilizing GCPII for treatment of pros-
tate cancer and other cancers. Most of these studies employ antibody-based
therapeutics using antibodies conjugated to cytotoxins or radionucleotides, or
these can be modified to stimulate the host immune system to attack cancer
cells. Only antibodies that bind to viable GCPII-expressing cells can be used in
such trials. The antibody most frequently used in clinical testing is J591, which
has nanomolar anity for GCPII 45 and was modified by replacing the more
antigenic regions of this mouse antibody by human sequences (denoted
huJ591).
3.8.2.2.1 Radiotherapy. Early-phase clinical trials with radiolabeled huJ591
antibody have demonstrated its generally good tolerance and non-immuno-
genicity. In contrast to trials with the 7E11 antibody, all known bone and soft-
tissue metastases as well as the main tumor were eciently targeted by
huJ591. 132,133,140,141 90 Y-J591 and 177 Lu-J591 radioconjugates were compared
in terms of toxicity and dosimetry, showing that the 177 Lu conjugate has a less
toxic and more predictable response. 140 It has been shown that 111 In-J591
selectively targets the neovasculature of solid tumors with acceptable toxicity,
thus confirming the antibody's potential as a vascular-targeting agent. 142,143