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Page 62 Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46

survival, and improved signs and symptoms of ascites [28,62] . Subsequent intravenous administration of
catumaxomab resulted in severe AEs including cytokine release syndrome (CRS) and dose-dependent
hepatotoxicity, which led to fulminant liver failure in one patient [62,63] . Ultimately, catumaxomab was
voluntarily withdrawn from the market in 2017.

Solitomab (MT110 or AMG 110) is an alternative anti-EpCAM first-generation BiTE that was investigated
in a phase I dose-escalation trial consisting of 65 patients with relapsed or refractory advanced-stage solid
tumor malignancies known to express EpCAM, 3 (5%) of which had metastatic castrate-resistant prostate
cancer. The results of the trial demonstrated grade 3 or higher AEs in over 20% of patients including severe
diarrhea, abdominal pain, as well as liver enzyme and lipase elevations [63-65] . Thereafter, the study was
discontinued prior to achieving dose escalation to any potentially therapeutic levels.

Currently, there are no active BiTE or CAR-T trials targeting EpCAM in prostate cancer. To some extent,
the severe AEs observed are suspected to be related to OTOT cross-tissue reactivity, given the expression of
EpCAM in many non-neoplastic epithelial cells. While no significant therapeutic benefits were gained from
targeting EpCAM in early studies, it served as an important lesson in the development of future
immunotherapy. It reinforces the importance of identifying a TAA with expression restricted to target
tissue.

Prostate-specific membrane antigen
Prostate-specific membrane antigen (PSMA), or folate hydrolase 1, is a type II transmembrane protein that
is composed of 750 amino acids, of which 707 are located extracellularly [66,67] . The protein is endogenously
expressed in the secretory acinar epithelium of prostate glandular cells, as well as within the proximal
tubules of the kidney, salivary glandular cells, and the jejunal brush border of the small intestine to regulate
folate metabolism [68-70] . PSMA also functions within nervous system glial cells, such as astrocytes and
Schwann cells, to modulate glutamate signaling . However, PSMA has also served as a therapeutic target
[71]
TAA for prostate cancer due to its large extracellular domain, weak expression under normal physiologic
conditions, and its profound degree of increased expression in prostate adenocarcinoma of 100 to
[72]
1,000 fold . Additionally, PSMA levels directly correlate with Gleason score, tumor staging, metastasis, and
advancing disease, with higher levels linked to advanced, castration-resistant prostate cancer with a poor
prognosis [35,67] . It is hypothesized that the extracellular folate hydrolase activity during PSMA upregulation
results in increased extracellular levels of folate that ultimately stimulate proliferation and angiogenesis
pathways, leading to the growth and progression of malignancy [73,74] . Therefore, PSMA serves as an ideal
TAA target with the potential for therapeutic success due to its structure, expression profile, and
downstream effects.

PSMA has already demonstrated efficacy as a radionucleotide target for imaging and as a therapeutic target
for radioligand theranostic therapy. These developments have allowed for radiologic detection of PSMA-
positive disease, including disease recurrence, which was otherwise not detected with conventional imaging
177
modalities [73-75] . Theranostic treatment utilizing Lu-PSMA-617, a beta-emitting radionucleotide, has
demonstrated antitumor response with associated radiographic response in patients with metastatic
castrate-resistant prostate cancer. In the landmark phase III randomized control VISION trial, 831 patients
demonstrated remarkable improvements in progression-free survival (8.7 vs. 3.4 months) and overall
survival (15.3 vs. 11.3 months) compared to standard-of-care treatment, which ultimately led to FDA
approval of the therapy [74-77] .