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Page 64 Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46

patients in the SC group developed neutralizing anti-drug antibodies and this arm of the study was
discontinued due to non-viable drug formulation. The cIV treatment group demonstrated a PSA reduction
in 14 out of 16 patients and a dose-dependent CTC reduction. All patients experienced at least one AE, with
the most common symptoms being fever (85%), chills (38%), and fatigue (34%). Nevertheless, the trial was
terminated prior to the identification of a MTD. The extremely short half-life of the drug required
[87]
continuous infusion, which proved to be logistically challenging for clinical use .
Acapatamab (AMG 160), a second-generation BiTE, required a short IV infusion administered every 14
days and boasted an increased half-life compared to Pasotuxizumab. Preclinical studies suggested that
therapy upregulated PD-L1 and elicited a strong T-cell activation signal. Phase I study (NCT03792841) of
acapatamab enrolled 32 patients and treatment was associated with a PSA reduction in 63% of patients;
however, 84.4% experienced AEs, with cytokine release syndrome being the most common. The trial was
terminated without reaching a MTD [88,89] . A phase I/II (NCT04631601) trial is currently ongoing to evaluate
the therapeutic potential of acapatamab in combination with either abiraterone, enzalutamide, or AMG 404,
a PD-1 receptor monoclonal antibody .
[90]
AMG 340 is yet another PSMA targeting BiTE, which has been engineered with a lower CD3 affinity
compared to prior BITE iterations in efforts to reduce OTOT toxicities. An ongoing phase I dose escalation
trial (NCT04740034) is currently recruiting patients to evaluate the safety profile and MTD.

Several innovative BiTE designs are currently being engineered to attempt to mitigate AEs, prolong half-life,
and improve the efficacy of previous-generation therapy. APVO4141 (MOR209 or ES414) was one such
construct that demonstrated improved half-life and stability; however, treated patients experienced high
levels of immune activation leading to systemic toxicity and the development of anti-drug antibodies,
[91]
resulting in early termination of the drug . Similarly, JNJ-081 (JNJ-63898081) was designed with the
potential of increased drug stability and improved safety profile, yet phase I study (NCT03926013)
demonstrated minimal PSA reductions, high incidence of treatment-related AEs (most commonly pyrexia
and CRS), and anti-drug antibody formation that resulted in cessation of the trial . HPN424 is another
[92]
BiTE developed with a third binding domain to albumin, in the hopes of increasing half-life. Phase I/IIa
testing (NCT03577028) of 80 patients with metastatic castrate-resistant prostate cancer demonstrated a PSA
reduction in 21% of patients and a CTC decline in 57%. AEs were notable for grade 3 AST increase (18%),
ALT increase (11%), and anemia (11%), with CRS occurring in 64% of patients but only 4% > grade 3. MTD
was not achieved and HPN424 was deemed not suitable for further studies based on its treatment efficacy
[93]
and risk/benefit profile . Another novel BiTE, CC-1, has shown preliminary results indicative of prolonged
half-life with tolerable AEs, including no CRS of > grade 2 events . Phase I trial of CC-1 is currently
[94]
recruiting patients (NCT04104607). Furthermore, BiTE therapy targeting both PSMA and KLK2
(Kallikrein-Related Peptidase 2) TAAs are currently recruiting patients in highly anticipated clinical studies
(NCT06095089). Additional ongoing trials are summarized in Table 2.

Prostate stem cell antigen
Prostate stem cell antigen (PSCA) is a surface glycoprotein that was first identified as a TAA overexpressed
in prostate cancer. PSCA has been hypothesized to be involved in intracellular signaling; however, its true
physiologic function and regulatory mechanisms remain largely unknown . PSCA has been noted to have
[95]
minimal expression in non-neoplastic tissue, with its highest degree of expression in prostate glandular
tissue; however, it is also present with limited expression in the bladder, pancreas, stomach, kidney, skin,
and esophagus [95-97] . PSCA is expressed in 94% of primary prostate cancers and 100% of metastatic prostate
cancers with bone involvement express PSCA , and increased PSCA expression correlates with increased
[98]